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1.  Trans-ethnic genome-wide association studies: advantages and challenges of mapping in diverse populations 
Genome Medicine  2014;6(10):91.
Genome-wide association studies (GWASs) are the method most often used by geneticists to interrogate the human genome, and they provide a cost-effective way to identify the genetic variants underpinning complex traits and diseases. Most initial GWASs have focused on genetically homogeneous cohorts from European populations given the limited availability of ethnic minority samples and so as to limit population stratification effects. Transethnic studies have been invaluable in explaining the heritability of common quantitative traits, such as height, and in examining the genetic architecture of complex diseases, such as type 2 diabetes. They provide an opportunity for large-scale signal replication in independent populations and for cross-population meta-analyses to boost statistical power. In addition, transethnic GWASs enable prioritization of candidate genes, fine-mapping of functional variants, and potentially identification of SNPs associated with disease risk in admixed populations, by taking advantage of natural differences in genomic linkage disequilibrium across ethnically diverse populations. Recent efforts to assess the biological function of variants identified by GWAS have highlighted the need for large-scale replication, meta-analyses and fine-mapping across worldwide populations of ethnically diverse genetic ancestries. Here, we review recent advances and new approaches that are important to consider when performing, designing or interpreting transethnic GWASs, and we highlight existing challenges, such as the limited ability to handle heterogeneity in linkage disequilibrium across populations and limitations in dissecting complex architectures, such as those found in recently admixed populations.
doi:10.1186/s13073-014-0091-5
PMCID: PMC4254423  PMID: 25473427
2.  Genetics of Ischaemic Stroke among Persons of Non-European Descent: A Meta-Analysis of Eight Genes Involving ∼ 32,500 Individuals 
PLoS Medicine  2007;4(4):e131.
Background
Ischaemic stroke in persons of European descent has a genetic basis, but whether the stroke-susceptibility alleles, the strength of any association, and the extent of their attributable risks are the same in persons of non-European descent remains unanswered. Whether ethnicity itself has a relevant or substantial contribution on those effect estimates is controversial. Comparative analyses between the ethnic groups may allow general conclusions to be drawn about polygenic disorders.
Methods and Findings
We performed a literature-based systematic review of genetic association studies in stroke in persons of non-European descent. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined for each gene–disease association using fixed and random effect models. We further performed a comparative genetic analysis across the different ethnic groups (including persons of European descent derived from our previous meta-analysis) to determine if genetic risks varied by ethnicity. Following a review of 500 manuscripts, eight candidate gene variants were analysed among 32,431 individuals (12,883 cases and 19,548 controls), comprising mainly Chinese, Japanese, and Korean individuals. Of the eight candidate genes studied, three were associated with ischaemic stroke: the angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism with a mean OR of 1.90 (95% CI 1.23–2.93) in the Chinese and 1.74 (95% CI 0.88–3.42) in the Japanese; the summary OR for the C677T variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) was 1.18 (95% CI 0.90–1.56) in Chinese and 1.34 (95% CI 0.87–2.06) in Koreans; and the pooled OR for the apolipoprotein E (APOE) gene was 2.18 (95% CI 1.52–3.13) in Chinese and 1.51 (95% CI 0.93–2.45) in Japanese. Comparing the commonly investigated stroke genes among the Asian groups against studies in persons of European descent, we found an absence of any substantial qualitative or quantitative interaction for ORs by ethnicity. However, the number of individuals recruited per study in the studies of persons of non-European descent was significantly smaller compared to studies of persons of European descent, despite a similar number of studies conducted per gene.
Conclusions
These data suggest that genetic associations studied to date for ischaemic stroke among persons of non-European descent are similar to those for persons of European descent. Claims of differences in genetic effects among different ethnic populations for complex disorders such as stroke may be overstated. However, due to the limited number of gene variants evaluated, the relatively smaller number of individuals included in the meta-analyses of persons of non-European descent in stroke, and the possibility of publication bias, the existence of allele variants with differential effects by ethnicity cannot be excluded.
This meta-analysis found that genetic associations so far studied for ischemic stroke among non-Europeans are similar to those found for persons of European descent.
Editors' Summary
Background.
A stroke occurs when the blood supply to part of the brain is interrupted, either because a blood vessel supplying the brain becomes blocked or because one ruptures. Strokes are a substantial cause of death and disability worldwide, with most of the burden affecting people living in developed countries. Most strokes fall into a category termed ischemic stroke. This type is caused by blockages in the blood vessels supplying the brain, which can happen when there is a buildup of fatty deposits or clots within the blood vessels. Many of the risk factors for this particular type of stroke are affected by an individual's behavior, including for example smoking, high blood pressure, diabetes, inactivity, and so on. In addition, variations in an individual's genetic makeup might affect his or her chance of having a stroke. Previous research studies have shown that variants in many different genes are likely to be involved in determining the overall risk of having a stroke, each variant contributing in a small way to the risk.
Why Was This Study Done?
The group performing this study had previously carried out a systematic review of existing research, looking specifically at the genetics of ischemic stroke among people of European origin (often called “Caucasians”). However, it was not obvious whether the genetic risk factors for stroke they found would be the same for people from a different ethnic background. Therefore the research group wanted to find out what the genetic risk factors were for stroke among people of non-European origin and to compare these findings with those of their previous systematic review. This research might help to find out whether the genetic risk factors for stroke were different in people from different parts of the world.
What Did the Researchers Do and Find?
As a starting point, these researchers wanted to find all the different studies that had already been carried out examining the effect of genetic risk factors on stroke among people of non-European origin. To do this, searches were carried out of electronic databases using a particular set of terms. All resulting studies that involved genetic research in people of non-European origin and in which strokes were confirmed by brain scanning were then evaluated in more detail. The findings of different studies were combined if at least three studies were available for the same genetic variant. Eventually 60 studies were found that looked at the association between eight specific gene variants and stroke. The only data that could be included in a combined analysis came from Chinese, Japanese, and Korean populations. Three of the eight gene variants were associated with an increased risk of stroke. Those three gene variants were ACE I/D (a variant in the gene coding for angiotensin 1-converting enzyme, which is involved in controlling blood pressure); a variant in MTHFR (which codes for the enzyme methylenetetrahydrofolate reductase, and which converts certain amino acids within cells); and a variant in the gene APOE, which codes for a protein that plays a role in breaking down fats. The researchers then compared their findings from this study with the findings of a previous systematic review they had carried out among people of European origin. Overall, each gene studied seemed to have a similar effect in the different populations, with the exception of APOE, which seemed to be associated with stroke in the Asian studies but not in the studies from people of non-European origin. The researchers also found that generally the Asian studies suggested a slightly greater effect of each gene variant than the studies in people of non-European origin did.
What Do These Findings Mean?
These findings suggest that, with the possible exception of APOE, similar gene variants play a role in determining stroke risk in people of European origin and Asian populations. Although generally the studies examined here suggested a slightly greater effect of these gene variants in Asian populations, this is not necessarily a real finding. This greater effect may just be due to small-study bias. Small-study bias describes the observation that small research studies are more likely to produce a false positive result than are large research studies. Therefore, future studies that examine the genetic basis of stroke should recruit much larger numbers of participants from populations made up of people of non-European origin than has previously been the case.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040131.
Health Encyclopedia entry on stroke from NHS Direct (UK National Health Service patient information)
Stroke Information page from the National Institute of Neurological Disorders and Stroke (provided by the US National Institutes of Health)
The Stroke Association, a UK charity funding this study
Information from the World Health Organization on the distribution and burden of stroke worldwide
The WHO has a world atlas of heart disease and stroke
doi:10.1371/journal.pmed.0040131
PMCID: PMC1876409  PMID: 17455988
3.  Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream 
PLoS Medicine  2008;5(8):e155.
Background
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.
Methods and Findings
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29–1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52–0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007–0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25–0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.
Conclusions
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.
Using a Mendelian randomization approach, Eric Brunner and colleagues show that the associations between serum C-reactive protein and insulin resistance, glycemia, and diabetes are likely to be noncausal.
Editors' Summary
Background.
Diabetes—a common, long-term (chronic) disease that causes heart, kidney, nerve, and eye problems and shortens life expectancy—is characterized by high levels of sugar (glucose) in the blood. In people without diabetes, blood sugar levels are controlled by the hormone insulin. Insulin is released by the pancreas after eating and “instructs” insulin-responsive muscle and fat cells to take up the glucose from the bloodstream that is produced by the digestion of food. In the early stages of type 2 diabetes (the commonest type of diabetes), the muscle and fat cells become nonresponsive to insulin (a condition called insulin resistance), and blood sugar levels increase. The pancreas responds by making more insulin—people with insulin resistance have high blood levels of both insulin and glucose. Eventually, however, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and frank diabetes develops.
Why Was This Study Done?
Globally, about 200 million people have diabetes, but experts believe this number will double by 2030. Ways to prevent or delay the onset of diabetes are, therefore, urgently needed. One major risk factor for insulin resistance and diabetes is being overweight. According to one theory, increased body fat causes mild, chronic tissue inflammation, which leads to insulin resistance. Consistent with this idea, people with higher than normal amounts of the inflammatory protein C-reactive protein (CRP) in their blood have a high risk of developing diabetes. If inflammation does cause diabetes, then drugs that inhibit CRP might prevent diabetes. However, simply measuring CRP and determining whether the people with high levels develop diabetes cannot prove that CRP causes diabetes. Those people with high blood levels of CRP might have other unknown factors in common (confounding factors) that are the real causes of diabetes. In this study, the researchers use “Mendelian randomization” to examine whether increased blood CRP causes diabetes. Some variants of CRP (the gene that encodes CRP) increase the amount of CRP in the blood. Because these variants are inherited randomly, there is no likelihood of confounding factors, and an association between these variants and the development of insulin resistance and diabetes indicates, therefore, that increased CRP levels cause diabetes.
What Did the Researchers Do and Find?
The researchers measured blood CRP levels in more than 5,000 people enrolled in the Whitehall II study, which is investigating factors that affect disease development. They also used the “homeostasis model assessment-insulin resistance” (HOMA-IR) method to estimate insulin sensitivity from blood glucose and insulin measurements, and measured levels of hemoglobin A1c (HbA1c, hemoglobin with sugar attached—a measure of long-term blood sugar control) in these people. Finally, they looked at three “single polynucleotide polymorphisms” (SNPs, single nucleotide changes in a gene's DNA sequence; combinations of SNPs that are inherited as a block are called haplotypes) in CRP in each study participant. Common haplotypes of CRP were related to blood serum CRP levels and, as previously reported, increased blood CRP levels were associated with diabetes and with HOMA-IR and HbA1c values indicative of insulin resistance and poor blood sugar control, respectively. By contrast, CRP haplotypes were not related to HOMA-IR or HbA1c values. Similarly, pooled analysis of CRP haplotypes and diabetes in Whitehall II and another large study on health determinants (the Northwick Park Heart Study II) showed no association between CRP variants and diabetes risk. Finally, data from the Wellcome Trust Case Control Consortium also showed no association between CRP haplotypes and diabetes risk.
What Do These Findings Mean?
Together, these findings suggest that increased blood CRP levels are not responsible for the development of insulin resistance or diabetes, at least in European populations. It may be that there is a causal relationship between CRP levels and diabetes risk in other ethnic populations—further Mendelian randomization studies are needed to discover whether this is the case. For now, though, these findings suggest that drugs targeted against CRP are unlikely to prevent or delay the onset of diabetes. However, they do not discount the possibility that proteins involved earlier in the inflammatory process might cause diabetes and might thus represent good drug targets for diabetes prevention.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050155.
This study is further discussed in a PLoS Medicine Perspective by Bernard Keavney
The MedlinePlus encyclopedia provides information about diabetes and about C-reactive protein (in English and Spanish)
US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on all aspects of diabetes, including information on insulin resistance (in English and Spanish)
The International Diabetes Federation provides information about diabetes, including information on the global diabetes epidemic
The US Centers for Disease Control and Prevention provides information for the public and professionals on all aspects of diabetes (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050155
PMCID: PMC2504484  PMID: 18700811
4.  Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases 
Perry, John R. B. | Voight, Benjamin F. | Yengo, Loïc | Amin, Najaf | Dupuis, Josée | Ganser, Martha | Grallert, Harald | Navarro, Pau | Li, Man | Qi, Lu | Steinthorsdottir, Valgerdur | Scott, Robert A. | Almgren, Peter | Arking, Dan E. | Aulchenko, Yurii | Balkau, Beverley | Benediktsson, Rafn | Bergman, Richard N. | Boerwinkle, Eric | Bonnycastle, Lori | Burtt, Noël P. | Campbell, Harry | Charpentier, Guillaume | Collins, Francis S. | Gieger, Christian | Green, Todd | Hadjadj, Samy | Hattersley, Andrew T. | Herder, Christian | Hofman, Albert | Johnson, Andrew D. | Kottgen, Anna | Kraft, Peter | Labrune, Yann | Langenberg, Claudia | Manning, Alisa K. | Mohlke, Karen L. | Morris, Andrew P. | Oostra, Ben | Pankow, James | Petersen, Ann-Kristin | Pramstaller, Peter P. | Prokopenko, Inga | Rathmann, Wolfgang | Rayner, William | Roden, Michael | Rudan, Igor | Rybin, Denis | Scott, Laura J. | Sigurdsson, Gunnar | Sladek, Rob | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Tuomilehto, Jaakko | Uitterlinden, Andre G. | Vivequin, Sidonie | Weedon, Michael N. | Wright, Alan F. | Hu, Frank B. | Illig, Thomas | Kao, Linda | Meigs, James B. | Wilson, James F. | Stefansson, Kari | van Duijn, Cornelia | Altschuler, David | Morris, Andrew D. | Boehnke, Michael | McCarthy, Mark I. | Froguel, Philippe | Palmer, Colin N. A. | Wareham, Nicholas J. | Groop, Leif | Frayling, Timothy M. | Cauchi, Stéphane
PLoS Genetics  2012;8(5):e1002741.
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10−9, OR = 1.13 [95% CI 1.09–1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00–1.06]). A variant in HMG20A—previously identified in South Asians but not Europeans—was associated with type 2 diabetes in obese cases (P = 1.3×10−8, OR = 1.11 [95% CI 1.07–1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10–1.17], P = 3.2×10−14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05–1.08], P = 2.2×10−16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
Author Summary
Individuals with Type 2 diabetes (T2D) can present with variable clinical characteristics. It is well known that obesity is a major risk factor for type 2 diabetes, yet patients can vary considerably—there are many lean diabetes patients and many overweight people without diabetes. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). Specifically, as lean T2D patients had lower risk than obese patients, they must have been more genetically susceptible. Using genetic data from multiple genome-wide association studies, we tested genetic markers across the genome in 2,112 lean type 2 diabetes cases (BMI<25 kg/m2), 4,123 obese cases (BMI≥30 kg/m2), and 54,412 healthy controls. We confirmed our results in an additional 2,881 lean cases, 8,702 obese cases, and 18,957 healthy controls. Using these data we found differences in genetic enrichment between lean and obese cases, supporting our original hypothesis. We also searched for genetic variants that may be risk factors only in lean or obese patients and found two novel gene regions not previously reported in European individuals. These findings may influence future study design for type 2 diabetes and provide further insight into the biology of the disease.
doi:10.1371/journal.pgen.1002741
PMCID: PMC3364960  PMID: 22693455
5.  Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study 
PLoS Biology  2013;11(9):e1001661.
A multi-ethnic study demonstrates that the extrapolation of genetic disease risk models from European populations to other ethnicities is compromised more strongly by genetic structure than by environmental or global genetic background in differential genetic risk associations across ethnicities.
The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
Author Summary
The number of known associations between human diseases and common genetic variants has grown dramatically in the past decade, most being identified in large-scale genetic studies of people of Western European origin. But because the frequencies of genetic variants can differ substantially between continental populations, it's important to assess how well these associations can be extended to populations with different continental ancestry. Are the correlations between genetic variants, disease endpoints, and risk factors consistent enough for genetic risk models to be reliably applied across different ancestries? Here we describe a systematic analysis of disease outcome and risk-factor–associated variants (tagSNPs) identified in European populations, in which we test whether the effect size of a tagSNP is consistent across six populations with significant non-European ancestry. We demonstrate that although nearly all such tagSNPs have effects in the same direction across all ancestries (i.e., variants associated with higher risk in Europeans will also be associated with higher risk in other populations), roughly a quarter of the variants tested have significantly different magnitude of effect (usually lower) in at least one non-European population. We therefore advise caution in the use of tagSNP-based genetic disease risk models in populations that have a different genetic ancestry from the population in which original associations were first made. We then show that this differential strength of association can be attributed to population-dependent variations in the correlation between tagSNPs and the variant that actually determines risk—the so-called functional variant. Risk models based on functional variants are therefore likely to be more robust than tagSNP-based models.
doi:10.1371/journal.pbio.1001661
PMCID: PMC3775722  PMID: 24068893
6.  Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study 
PLoS Medicine  2014;11(5):e1001647.
In this study, Wareham and colleagues quantified the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. The authors found that the relative effect of a type 2 diabetes genetic risk score is greater in younger and leaner participants, and the high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Please see later in the article for the Editors' Summary
Background
Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.
Methods and Findings
The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10−4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10−3) and waist circumference (p for interaction  = 7.49×10−9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score.
Conclusions
The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 380 million people currently have diabetes, and the condition is becoming increasingly common. Diabetes is characterized by high levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest type of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing excess sugar from the blood become less responsive to insulin. Type 2 diabetes can often initially be controlled with diet and exercise (lifestyle changes) and with antidiabetic drugs such as metformin and sulfonylureas, but patients may eventually need insulin injections to control their blood sugar levels. Long-term complications of diabetes, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about ten years compared to people without diabetes.
Why Was This Study Done?
Type 2 diabetes is thought to originate from the interplay between genetic and lifestyle factors. But although rapid progress is being made in understanding the genetic basis of type 2 diabetes, it is not known whether the consequences of adverse lifestyles (for example, being overweight and/or physically inactive) differ according to an individual's underlying genetic risk of diabetes. It is important to investigate this question to inform strategies for prevention. If, for example, obese individuals with a high level of genetic risk have a higher risk of developing diabetes than obese individuals with a low level of genetic risk, then preventative strategies that target lifestyle interventions to obese individuals with a high genetic risk would be more effective than strategies that target all obese individuals. In this case-cohort study, researchers from the InterAct consortium quantify the combined effects of genetic and lifestyle factors on the risk of type 2 diabetes. A case-cohort study measures exposure to potential risk factors in a group (cohort) of people and compares the occurrence of these risk factors in people who later develop the disease with those who remain disease free.
What Did the Researchers Do and Find?
The InterAct study involves 12,403 middle-aged individuals who developed type 2 diabetes after enrollment (incident cases) into the European Prospective Investigation into Cancer and Nutrition (EPIC) and a sub-cohort of 16,154 EPIC participants. The researchers calculated a genetic type 2 diabetes risk score for most of these individuals by determining which of 49 gene variants associated with type 2 diabetes each person carried, and collected baseline information about exposure to lifestyle risk factors for type 2 diabetes. They then used various statistical approaches to examine the combined effects of the genetic risk score and lifestyle factors on diabetes development. The effect of the genetic score was greater in younger individuals than in older individuals and greater in leaner participants than in participants with larger amounts of body fat. The absolute risk of type 2 diabetes, expressed as the ten-year cumulative incidence of type 2 diabetes (the percentage of participants who developed diabetes over a ten-year period) increased with increasing genetic score in normal weight individuals from 0.25% in people with the lowest genetic risk scores to 0.89% in those with the highest scores; in obese people, the ten-year cumulative incidence rose from 4.22% to 7.99% with increasing genetic risk score.
What Do These Findings Mean?
These findings show that in this middle-aged cohort, the relative association with type 2 diabetes of a genetic risk score comprised of a large number of gene variants is greatest in individuals who are younger and leaner at baseline. This finding may in part reflect the methods used to originally identify gene variants associated with type 2 diabetes, and future investigations that include other genetic variants, other lifestyle factors, and individuals living in other settings should be undertaken to confirm this finding. Importantly, however, this study shows that young, lean individuals with a high genetic risk score have a low absolute risk of developing type 2 diabetes. Thus, this sub-group of individuals is not a logical target for preventative interventions. Rather, suggest the researchers, the high absolute risk of type 2 diabetes associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001647.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals and the general public, including detailed information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes and about living with diabetes; it also provides people's stories about diabetes
The charity Diabetes UK provides detailed information for patients and carers in several languages, including information on healthy lifestyles for people with diabetes
The UK-based non-profit organization Healthtalkonline has interviews with people about their experiences of diabetes
The Genetic Landscape of Diabetes is published by the US National Center for Biotechnology Information
More information on the InterAct study is available
MedlinePlus provides links to further resources and advice about diabetes and diabetes prevention (in English and Spanish)
doi:10.1371/journal.pmed.1001647
PMCID: PMC4028183  PMID: 24845081
7.  Mendelian Randomization Study of B-Type Natriuretic Peptide and Type 2 Diabetes: Evidence of Causal Association from Population Studies 
PLoS Medicine  2011;8(10):e1001112.
Using mendelian randomization, Roman Pfister and colleagues demonstrate a potentially causal link between low levels of B-type natriuretic peptide (BNP), a hormone released by damaged hearts, and the development of type 2 diabetes.
Background
Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.
Methods and Findings
We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%–36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91–0.97) was similar to that expected (0.96, 0.93–0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74–0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15–0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.
Conclusions
Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, nearly 250 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone that the pancreas releases after meals (digestion of food produces glucose). In people with type 2 diabetes (the most common form of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. The long-term complications of diabetes, which include kidney failure and an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Because the causes of type 2 diabetes are poorly understood, it is hard to devise ways to prevent the condition. Recently, B-type natriuretic peptide (BNP, a hormone released by damaged hearts) has been implicated in type 2 diabetes development in cross-sectional studies (investigations in which data are collected at a single time point from a population to look for associations between an illness and potential risk factors). Although these studies suggest that high levels of BNP may protect against type 2 diabetes, they cannot prove a causal link between BNP levels and diabetes because the study participants with low BNP levels may share some another unknown factor (a confounding factor) that is the real cause of both diabetes and altered BNP levels. Here, the researchers use an approach called “Mendelian randomization” to examine whether reduced BNP levels contribute to causing type 2 diabetes. It is known that a common genetic variant (rs198389) within the genome region that encodes BNP is associated with a reduced risk of type 2 diabetes. Because gene variants are inherited randomly, they are not subject to confounding. So, by investigating the association between BNP gene variants that alter NT-pro-BNP (a molecule created when BNP is being produced) levels and the development of type 2 diabetes, the researchers can discover whether BNP is causally involved in this chronic condition.
What Did the Researchers Do and Find?
The researchers analyzed the association between blood levels of NT-pro-BNP at baseline in 440 participants of the EPIC-Norfolk study (a prospective population-based study of lifestyle factors and the risk of chronic diseases) who subsequently developed diabetes and in 740 participants who did not develop diabetes. In this prospective case-cohort study, the risk of developing type 2 diabetes was associated with lower NT-pro-BNP levels. They also genotyped (sequenced) rs198389 in the participants of three case-control studies of type 2 diabetes (studies in which potential risk factors for type 2 diabetes were examined in people with type 2 diabetes and matched controls living in the East of England), and combined these results with those of eight similar published case-control studies. Finally, the researchers showed that the association between rs198389 and type 2 diabetes measured in the case-control studies was similar to the expected association calculated from the association between NT-pro-BNP level and type 2 diabetes obtained from the prospective case-cohort study and the association between rs198389 and BNP levels obtained from the EPIC-Norfolk study and other published studies.
What Do These Findings Mean?
The results of this Mendelian randomization study provide evidence for a causal, protective role of the BNP hormone system in the development of type 2 diabetes. That is, these findings suggest that low levels of BNP are partly responsible for the development of type 2 diabetes. Because the participants in all the individual studies included in this analysis were of European descent, these findings may not be generalizable to other ethnicities. Moreover, they provide no explanation of how alterations in the BNP hormone system might affect the development of type 2 diabetes. Nevertheless, the demonstration of a causal link between the BNP hormone system and type 2 diabetes suggests that BNP may be a potential target for interventions designed to prevent type 2 diabetes, particularly since the feasibility of altering BNP levels with drugs has already been proven in patients with cardiovascular disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001112.
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health-care professionals, and the general public (in English and Spanish)
The UK National Health Service Choices website also provides information for patients and carers about type 2 diabetes and includes people's stories about diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
Wikipedia has pages on BNP and on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The charity Healthtalkonline has interviews with people about their experiences of diabetes; the charity Diabetes UK has a further selection of stories from people with diabetes
doi:10.1371/journal.pmed.1001112
PMCID: PMC3201934  PMID: 22039354
8.  Transethnic Meta-Analysis of Genomewide Association Studies 
Genetic Epidemiology  2011;35(8):809-822.
The detection of loci contributing effects to complex human traits, and their subsequent fine-mapping for the location of causal variants, remains a considerable challenge for the genetics research community. Meta-analyses of genomewide association studies, primarily ascertained from European-descent populations, have made considerable advances in our understanding of complex trait genetics, although much of their heritability is still unexplained. With the increasing availability of genomewide association data from diverse populations, transethnic meta-analysis may offer an exciting opportunity to increase the power to detect novel complex trait loci and to improve the resolution of fine-mapping of causal variants by leveraging differences in local linkage disequilibrium structure between ethnic groups. However, we might also expect there to be substantial genetic heterogeneity between diverse populations, both in terms of the spectrum of causal variants and their allelic effects, which cannot easily be accommodated through traditional approaches to meta-analysis. In order to address this challenge, I propose novel transethnic meta-analysis methodology that takes account of the expected similarity in allelic effects between the most closely related populations, while allowing for heterogeneity between more diverse ethnic groups. This approach yields substantial improvements in performance, compared to fixed-effects meta-analysis, both in terms of power to detect association, and localization of the causal variant, over a range of models of heterogeneity between ethnic groups. Furthermore, when the similarity in allelic effects between populations is well captured by their relatedness, this approach has increased power and mapping resolution over random-effects meta-analysis. Genet. Epidemiol. 2011. © 2011 Wiley Periodicals, Inc.35: 809–;822, 2011.
doi:10.1002/gepi.20630
PMCID: PMC3460225  PMID: 22125221
meta-analysis; transethnic; genomewide association study; diverse populations; Bayesian partition model; fine-mapping
9.  Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study 
PLoS Medicine  2010;7(8):e1000332.
Shengxu Li and colleagues use data from a large prospective observational cohort to examine the extent to which a genetic predisposition toward obesity may be modified by living a physically active lifestyle.
Background
We have previously shown that multiple genetic loci identified by genome-wide association studies (GWAS) increase the susceptibility to obesity in a cumulative manner. It is, however, not known whether and to what extent this genetic susceptibility may be attenuated by a physically active lifestyle. We aimed to assess the influence of a physically active lifestyle on the genetic predisposition to obesity in a large population-based study.
Methods and Findings
We genotyped 12 SNPs in obesity-susceptibility loci in a population-based sample of 20,430 individuals (aged 39–79 y) from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with an average follow-up period of 3.6 y. A genetic predisposition score was calculated for each individual by adding the body mass index (BMI)-increasing alleles across the 12 SNPs. Physical activity was assessed using a self-administered questionnaire. Linear and logistic regression models were used to examine main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time, assuming an additive effect for each additional BMI-increasing allele carried. Each additional BMI-increasing allele was associated with 0.154 (standard error [SE] 0.012) kg/m2 (p = 6.73×10−37) increase in BMI (equivalent to 445 g in body weight for a person 1.70 m tall). This association was significantly (pinteraction = 0.005) more pronounced in inactive people (0.205 [SE 0.024] kg/m2 [p = 3.62×10−18; 592 g in weight]) than in active people (0.131 [SE 0.014] kg/m2 [p = 7.97×10−21; 379 g in weight]). Similarly, each additional BMI-increasing allele increased the risk of obesity 1.116-fold (95% confidence interval [CI] 1.093–1.139, p = 3.37×10−26) in the whole population, but significantly (pinteraction = 0.015) more in inactive individuals (odds ratio [OR] = 1.158 [95% CI 1.118–1.199; p = 1.93×10−16]) than in active individuals (OR = 1.095 (95% CI 1.068–1.123; p = 1.15×10−12]). Consistent with the cross-sectional observations, physical activity modified the association between the genetic predisposition score and change in BMI during follow-up (pinteraction = 0.028).
Conclusions
Our study shows that living a physically active lifestyle is associated with a 40% reduction in the genetic predisposition to common obesity, as estimated by the number of risk alleles carried for any of the 12 recently GWAS-identified loci.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In the past few decades, the global incidence of obesity—defined as a body mass index (BMI, a simple index of weight-for-height that uses the weight in kilograms divided by the square of the height in meters) of 30 and over, has increased so much that this growing public health concern is now commonly referred to as the “obesity epidemic.” Once considered prevalent only in high-income countries, obesity is an increasing health problem in low- and middle-income countries, particularly in urban settings. In 2005, at least 400 million adults world-wide were obese, and the projected figure for 2015 is a substantial increase of 300 million to around 700 million. Childhood obesity is also a growing concern. Contributing factors to the obesity epidemic are a shift in diet to an increased intake of energy-dense foods that are high in fat and sugars and a trend towards decreased physical activity due to increasingly sedentary lifestyles.
However, genetics are also thought to play a critical role as genetically predisposed individuals may be more prone to obesity if they live in an environment that has abundant access to energy-dense food and labor-saving devices.
Why Was This Study Done?
Although recent genetic studies (genome-wide association studies) have identified 12 alleles (a DNA variant that is located at a specific position on a specific chromosome) associated with increased BMI, there has been no convincing evidence of the interaction between genetics and lifestyle. In this study the researchers examined the possibility of such an interaction by assessing whether individuals with a genetic predisposition to increased obesity risk could modify this risk by increasing their daily physical activity.
What Did the Researchers Do and Find?
The researchers used a population-based cohort study of 25,631 people living in Norwich, UK (The EPIC-Norfolk study) and identified individuals who were 39 to 79 years old during a health check between 1993 and 1997. The researchers invited these people to a second health examination. In total, 20,430 individuals had baseline data available, of which 11,936 had BMI data at the second health check. The researchers used genotyping methods and then calculated a genetic predisposition score for each individual and their occupational and leisure-time physical activities were assessed by using a validated self-administered questionnaire. Then, the researchers used modeling techniques to examine the main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time. The researchers found that each additional BMI-increasing allele was associated with an increase in BMI equivalent to 445 g in body weight for a person 1.70 m tall and that the size of this effect was greater in inactive people than in active people. In individuals who have a physically active lifestyle, this increase was only 379 g/allele, or 36% lower than in physically inactive individuals in whom the increase was 592 g/allele. Furthermore, in the total sample each additional obesity-susceptibility allele increased the odds of obesity by 1.116-fold. However, the increased odds per allele for obesity risk were 40% lower in physically active individuals (1.095 odds/allele) compared to physically inactive individuals (1.158 odds/allele).
What Do These Findings Mean?
The findings of this study indicate that the genetic predisposition to obesity can be reduced by approximately 40% by having a physically active lifestyle. The findings of this study suggest that, while the whole population benefits from increased physical activity levels, individuals who are genetically predisposed to obesity would benefit more than genetically protected individuals. Furthermore, these findings challenge the deterministic view of the genetic predisposition to obesity that is often held by the public, as they show that even the most genetically predisposed individuals will benefit from adopting a healthy lifestyle. The results are limited by participants self-reporting their physical activity levels, which is less accurate than objective measures of physical activity.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000332.
This study relies on the results of previous genome-wide association studies The National Human Genome Research Institute provides an easy-to-follow guide to understanding such studies
The International Association for the Study of Obesity aims to improve global health by promoting the understanding of obesity and weight-related diseases through scientific research and dialogue
The International Obesity Taskforce is the research-led think tank and advocacy arm of the International Association for the Study of Obesity
The Global Alliance for the Prevention of Obesity and Related Chronic Disease is a global action program that addresses the issues surrounding the prevention of obesity
The National Institutes of Health has its own obesity task force, which includes 26 institutes
doi:10.1371/journal.pmed.1000332
PMCID: PMC2930873  PMID: 20824172
10.  Muscle-Strengthening and Conditioning Activities and Risk of Type 2 Diabetes: A Prospective Study in Two Cohorts of US Women 
PLoS Medicine  2014;11(1):e1001587.
Anders Grøntved and colleagues examined whether women who perform muscle-strengthening and conditioning activities have an associated reduced risk of type 2 diabetes mellitus.
Please see later in the article for the Editors' Summary
Background
It is well established that aerobic physical activity can lower the risk of type 2 diabetes (T2D), but whether muscle-strengthening activities are beneficial for the prevention of T2D is unclear. This study examined the association of muscle-strengthening activities with the risk of T2D in women.
Methods and Findings
We prospectively followed up 99,316 middle-aged and older women for 8 years from the Nurses' Health Study ([NHS] aged 53–81 years, 2000–2008) and Nurses' Health Study II ([NHSII] aged 36–55 years, 2001–2009), who were free of diabetes, cancer, and cardiovascular diseases at baseline. Participants reported weekly time spent on resistance exercise, lower intensity muscular conditioning exercises (yoga, stretching, toning), and aerobic moderate and vigorous physical activity (MVPA) at baseline and in 2004/2005. Cox regression with adjustment for major determinants for T2D was carried out to examine the influence of these types of activities on T2D risk. During 705,869 person years of follow-up, 3,491 incident T2D cases were documented. In multivariable adjusted models including aerobic MVPA, the pooled relative risk (RR) for T2D for women performing 1–29, 30–59, 60–150, and >150 min/week of total muscle-strengthening and conditioning activities was 0.83, 0.93, 0.75, and 0.60 compared to women reporting no muscle-strengthening and conditioning activities (p<0.001 for trend). Furthermore, resistance exercise and lower intensity muscular conditioning exercises were each independently associated with lower risk of T2D in pooled analyses. Women who engaged in at least 150 min/week of aerobic MVPA and at least 60 min/week of muscle-strengthening activities had substantial risk reduction compared with inactive women (pooled RR = 0.33 [95% CI 0.29–0.38]). Limitations to the study include that muscle-strengthening and conditioning activity and other types of physical activity were assessed by a self-administered questionnaire and that the study population consisted of registered nurses with mostly European ancestry.
Conclusions
Our study suggests that engagement in muscle-strengthening and conditioning activities (resistance exercise, yoga, stretching, toning) is associated with a lower risk of T2D. Engagement in both aerobic MVPA and muscle-strengthening type activity is associated with a substantial reduction in the risk of T2D in middle-aged and older women.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 370 million people have diabetes mellitus, a disorder characterized by poor glycemic control—dangerously high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas. In people with type 2 diabetes (the commonest form of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing excess sugar from the blood become less responsive to insulin. Type 2 diabetes, which was previously known as adult-onset diabetes, can often initially be controlled with diet and exercise, and with antidiabetic drugs such as metformin and sulfonylureas. However, as the disease progresses, the pancreatic beta cells, which make insulin, become impaired and patients may eventually need insulin injections. Long-term complications of diabetes, which include an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Type 2 diabetes is becoming increasingly common worldwide so better preventative strategies are essential. It is well-established that regular aerobic exercise—physical activity in which the breathing and heart rate increase noticeably such as jogging, brisk walking, and swimming—lowers the risk of type 2 diabetes. The World Health Organization currently recommends that adults should do at least 150 min/week of moderate-to-vigorous aerobic physical activity to reduce the risk of diabetes and other non-communicable diseases. It also recommends that adults should undertake muscle-strengthening and conditioning activities such as weight training and yoga on two or more days a week. However, although studies have shown that muscle-strengthening activity improves glycemic control in people who already have diabetes, it is unclear whether this form of exercise prevents diabetes. In this prospective cohort study (a study in which disease development is followed up over time in a group of people whose characteristics are recorded at baseline), the researchers investigated the association of muscle-strengthening activities with the risk of type 2 diabetes in women.
What Did the Researchers Do and Find?
The researchers followed up nearly 100,000 women enrolled in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHSII), two prospective US investigations into risk factors for chronic diseases in women, for 8 years. The women provided information on weekly participation in muscle-strengthening exercise (for example, weight training), lower intensity muscle-conditioning exercises (for example, yoga and toning), and aerobic moderate and vigorous physical activity (aerobic MVPA) at baseline and 4 years later. During the study 3,491 women developed diabetes. After allowing for major risk factors for type 2 diabetes (for example, diet and a family history of diabetes) and for aerobic MVPA, compared to women who did no muscle-strengthening or conditioning exercise, the risk of developing type 2 diabetes among women declined with increasing participation in muscle-strengthening and conditioning activity. Notably, women who did more than 150 min/week of these types of exercise had 40% lower risk of developing diabetes as women who did not exercise in this way at all. Muscle-strengthening and muscle-conditioning exercise were both independently associated with reduced diabetes risk, and women who engaged in at least 150 min/week of aerobic MVPA and at least 60 min/week of muscle-strengthening exercise were a third as likely to develop diabetes as inactive women.
What Do These Findings Mean?
These findings show that, among the women enrolled in NHS and NHSII, engagement in muscle-strengthening and conditioning activities lowered the risk of type 2 diabetes independent of aerobic MVPA. That is, non-aerobic exercise provided protection against diabetes in women who did no aerobic exercise. Importantly, they also show that doing both aerobic exercise and muscle-strengthening exercise substantially reduced the risk of type 2 diabetes. Because nearly all the participants in NHS and NHSII were of European ancestry, these results may not be generalizable to women of other ethnic backgrounds. Moreover, the accuracy of these findings may be limited by the use of self-administered questionnaires to determine how much exercise the women undertook. Nevertheless, these findings support the inclusion of muscle-strengthening and conditioning exercises in strategies designed to prevent type 2 diabetes in women, a conclusion that is consistent with current guidelines for physical activity among adults.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001587.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals and the general public, including information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes and explains the benefits of regular physical activity
The World Health Organization provides information about diabetes and about physical activity and health (in several languages); its 2010 Global Recommendations on Physical Activity for Health are available in several languages
The US Centers for Disease Control and Prevention provides information on physical activity for different age groups; its Physical Activity for Everyone web pages include guidelines, instructional videos and personal success stories
More information about the Nurses Health Study and the Nurses Health Study II is available
The UK charity Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes and about physical exercise and fitness (in English and Spanish)
doi:10.1371/journal.pmed.1001587
PMCID: PMC3891575  PMID: 24453948
11.  Transferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic Cohorts from Southeast Asia 
PLoS Genetics  2011;7(4):e1001363.
Recent large genome-wide association studies (GWAS) have identified multiple loci which harbor genetic variants associated with type 2 diabetes mellitus (T2D), many of which encode proteins not previously suspected to be involved in the pathogenesis of T2D. Most GWAS for T2D have focused on populations of European descent, and GWAS conducted in other populations with different ancestry offer a unique opportunity to study the genetic architecture of T2D. We performed genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945 controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians (977 cases, 1,169 controls). In addition to the search for novel variants implicated in T2D, these multi-ethnic cohorts serve to assess the transferability and relevance of the previous findings from European descent populations in the three major ethnic populations of Asia, comprising half of the world's population. Of the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis including all three ethnic groups. However, consistent direction of effect was observed for many of the other SNPs in our study and in those carried out in European populations. Close examination of the associations at both the CDKAL1 and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity in relation to the associations with T2D. We also detected variation in linkage disequilibrium between populations for most of these loci that have been previously identified. These factors, combined with limited statistical power, may contribute to the failure to detect associations across populations of diverse ethnicity. These findings highlight the value of surveying across diverse racial/ethnic groups towards the fine-mapping efforts for the casual variants and also of the search for variants, which may be population-specific.
Author Summary
Type 2 diabetes mellitus (T2D) is a chronic disease which can lead to complications such as heart disease, stroke, hypertension, blindness due to diabetic retinopathy, amputations from peripheral vascular diseases, and kidney disease from diabetic nephropathy. The increasing prevalence and complications of T2D are likely to increase the health and economic burden of individuals, families, health systems, and countries. Our study carried out in three major Asian ethnic groups (Chinese, Malays, and Indians) in Singapore suggests that the findings of studies carried out in populations of European ancestry (which represents most studies to date) may be relevant to populations in Asia. However, our study also raises the possibility that different genes, and within the genes different variants, may confer susceptibility to T2D in these populations. These findings are particularly relevant in Asia, where the greatest growth of T2D is expected in the coming years, and emphasize the importance of studying diverse populations when trying to localize the regions of the genome associated with T2D. In addition, we may need to consider novel methods for combining data across populations.
doi:10.1371/journal.pgen.1001363
PMCID: PMC3072366  PMID: 21490949
12.  IL28B, HLA-C, and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort: A Cross-Sectional Study 
PLoS Medicine  2011;8(9):e1001092.
Vijayaprakash Suppiah and colleagues show that genotyping hepatitis C patients for the IL28B, HLA-C, and KIR genes improves the ability to predict whether or not patients will respond to antiviral treatment.
Background
To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%–50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control.
Methods and Findings
We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 “G” was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10−8, 1.67–2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10−14, 2.67–5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05–2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10−6, 2.03–7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B.
Conclusions
Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 170 million people harbor long-term (chronic) infections with the hepatitis C virus (HCV) and 3–4 million people are newly infected with the virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread though contact with infected blood. Transmission can occur during medical procedures (for example, transfusions with unscreened blood or reuse of inadequately sterilized medical instruments) but in developed countries, where donated blood is routinely screened for HCV, the most common transmission route is needle-sharing among intravenous drug users. HCV infection can cause a short-lived illness characterized by tiredness and jaundice (yellow skin and eyes) but 70%–80% of newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs—pegylated interferon-alpha and ribavirin (PegIFN/R). However, PegIFN/R is expensive, causes unpleasant side-effects, and is ineffective in about half of people infected with HCV genotype 1, the commonest HCV strain.
Why Was This Study Done?
It would be extremely helpful to be able to identify which patients will respond to PegIFN/R before starting treatment. An individual's genetic make-up plays a key role in the safety and effectiveness of drugs. Thus, pharmacogenomics—the study of how genetic variants affects the body's response to drugs—has the potential to alter the clinical management of many diseases by allowing clinicians to provide individually tailored drug treatments. In 2009, scientists reported that certain single nucleotide polymorphisms (SNPs, a type of genetic variant) lying near the IL28B gene (which encodes an immune system protein made in response to viral infections) strongly influence treatment outcomes and spontaneous clearance in HCV-infected people. This discovery is now being used to predict treatment responses to PegIFN/R in clinical practice but genotyping (analysis of variants of) IL28B only correctly predicts treatment failure two-thirds of the time. Here, the researchers investigate whether genotyping two additional regions of the genome—the HLA-C and KIR gene loci—can improve the predictive value of IL28B genotyping. Human leukocyte antigen C (HLA-C) and the killer immunoglobulin-like receptors (KIRs) are interacting proteins that have been implicated in HCV viral control.
What Did the Researchers Do and Find?
The researchers genotyped 417 patients chronically infected with HCV genotype 1 whose infection had been cleared by PegIFN/R treatment, 493 patients whose infection had not responded to treatment, and 234 patients whose infection had cleared spontaneously for two HLA-C variants (C1 and C2), the presence of several KIR genes (individuals carry different combinations of KIR genes), and two IL28B SNPs (rs8099917 and rs12979860). Carriage of “variants” of either IL28B SNP was associated with absence of treatment-induced clearance and absence of spontaneous clearance. That is, these variant SNPs were found more often in patients who did not respond to treatment than in those who did respond, and more often in patients who did not have spontaneous clearance of their infection than those who did. The HLA-C C2C2 genotype (there are two copies of most genes in the genome) was also more common in patients who failed treatment than in those who responded but was not associated with spontaneous clearance. The rate of correct prediction of treatment failure increased from 66% with IL28B genotyping alone to 80% with combined IL28B and HLA-C genotyping. Finally, carriage of specific KIR genes in combination with specific HLA-C and IL28B variants was also associated with an altered HCV treatment response.
What Do These Findings Mean?
These findings show that the addition of HCL-C and KIR genotyping to IL28B genotyping improved the prediction of HCV treatment response in the patients investigated in this study. Because all these patients were European or of European descent, these findings need confirming in people of other ethnic backgrounds. They also need confirming in other groups of Europeans before being used in a clinical setting. However, the discovery that the addition of HLA-C genotyping to IL28B genotyping raises the rate of correct prediction of PegIFN/R treatment failure to 80% is extremely promising and should improve the clinical management of patients infected with HCV genotype 1. In addition, these results provide new insights into how PegIFN/R clears HCV infections that may lead to improved therapies in the future.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001092.
The World Health Organization provides detailed information about hepatitis C (in several languages)
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
The Hepatitis C Trust is a patient-led, patient-run UK charity that provides detailed information about hepatitis C and support for patients and their families; a selection of personal stories about patients' experiences with hepatitis C is available, including Phil's treatment story, which details the ups and downs of treatment with PegIFN/R
MedlinePlus provides links to further resources on hepatitis C
The Human Genome Project provides information about medicine and the new genetics, including a primer on pharmacogenomics
doi:10.1371/journal.pmed.1001092
PMCID: PMC3172251  PMID: 21931540
13.  Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study 
Human Reproduction (Oxford, England)  2013;28(6):1695-1706.
STUDY QUESTION
Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?
SUMMARY ANSWER
We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.
WHAT IS KNOWN ALREADY
Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.
STUDY DESIGN, SIZE, DURATION
A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.
MATERIALS, SETTING, METHODS
SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.
MAIN RESULTS AND THE ROLE OF CHANCE
We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.
LIMITATIONS, REASONS FOR CAUTION
Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.
WIDER IMPLICATIONS OF THE FINDINGS
The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.
STUDY FUNDING/COMPETING INTEREST(S)
The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The authors report no conflicts of interest.
doi:10.1093/humrep/det071
PMCID: PMC3657124  PMID: 23508249
menopause; menarche; genome-wide association study; race/ethnicity; single nucleotide polymorphism
14.  Combining Information from Common Type 2 Diabetes Risk Polymorphisms Improves Disease Prediction 
PLoS Medicine  2006;3(10):e374.
Background
A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (~20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed.
Methods and Findings
Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles.
Conclusions
Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases.
Combining information from several known common risk polymorphisms allows the identification of subgroups of the population with markedly differing risks of developing type 2 diabetes.
Editors' Summary
Background.
Diabetes is an important and increasingly common global health problem; the World Health Organization has estimated that about 170 million people currently have diabetes worldwide. One particular form, type 2 diabetes, develops when cells in the body become unable to respond to a hormone called insulin. Insulin is normally released by the pancreas and controls the ability of body cells to take in glucose (sugar). Therefore, when cells become insensitive to insulin as in people with type 2 diabetes, glucose levels in the body are not well controlled and may become dangerously high in the blood. These high levels can have long-term damaging effects on various organs in the body, particularly the eyes, nerves, heart, and kidneys. There are many different factors that affect whether someone is likely to develop type 2 diabetes. These factors can be broadly grouped into two categories: environmental and genetic. Environmental factors such as obesity, a diet high in sugar, and a sedentary lifestyle are all risk factors for developing type 2 diabetes in later life. Genetically, a number of variants in many different genes may affect the risk of developing the disease. Generally, these gene variants are common in human populations but each gene variant only mildly increases the risk that a person possessing it will get type 2 diabetes.
Why Was This Study Done?
The investigators performing this study wanted to understand how different gene variants combine to affect an individual's risk of getting type 2 diabetes. That is, if a person carries many different variants, does their overall risk increase a lot or only a little?
What Did the Researchers Do and Find?
First, the researchers surveyed the published reports to identify those gene variants for which there was strong evidence of an association with type 2 diabetes. They found mutations in three genes that had been shown reproducibly to be associated with type 2 diabetes in different studies: PPARG (whose product is involved in regulation of fat tissue), KCNJ11 (whose product is involved in insulin production), and TCF7L2 (whose product is thought to be involved in controlling sugar levels). Then, they compared two groups of white people in the UK: 2,409 people with type 2 diabetes (“cases”), and 3,668 people from the general population (“controls”). The researchers compared the two groups to see which individuals possessed which gene variants, and did statistical testing to work out to what extent having particular combinations of the gene variants affected an individual's chance of being a “case” versus a “control.” Their results showed that in the groups studied, having an ever-increasing number of gene variants increased the risk of developing diabetes. The risk that someone with none of the gene variants would develop type 2 diabetes was about 2%, while the chance for someone with all gene variants was about10%.
What Do These Findings Mean?
These results show that the risk of developing type 2 diabetes is greater if an individual possesses all of the gene variants that were examined in this study. The analysis also suggests that using information on all three variants, rather than just one, is likely to be more accurate in predicting future risk. How this genetic information should be used alongside other well-known preventative measures such as altered lifestyle requires further study.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030374.
NHS Direct patient information on diabetes
National Diabetes Information Clearinghouse information on type 2 diabetes
World Health Organization Diabetes Programme
Centers for Disease ControlDiabetes Public Health Resource
doi:10.1371/journal.pmed.0030374
PMCID: PMC1584415  PMID: 17020404
15.  Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth 
PLoS Medicine  2010;7(5):e1000284.
Ken Ong and colleagues genotyped children from the ALSPAC birth cohort and showed an association between greater early infancy gains in weight and length and genetic markers for adult obesity risk.
Background
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.
Methods and Findings
Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an “obesity-risk-allele score” comprising the total number of risk alleles (range: 2–15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00–0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023–0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004–0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032–0.284) and with reduced risk of early infancy failure to thrive (odds ratio  = 0.92 per allele; 0.86–0.98; p = 0.009).
Conclusions
The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The proportion of overweight and obese children is increasing across the globe. In the US, the Surgeon General estimates that, compared with 1980, twice as many children and three times the number of adolescents are now overweight. Worldwide, 22 million children under five years old are considered by the World Health Organization to be overweight.
Being overweight or obese in childhood is associated with poor physical and mental health. In addition, childhood obesity is considered a major risk factor for adult obesity, which is itself a major risk factor for cancer, heart disease, diabetes, osteoarthritis, and other chronic conditions.
The most commonly used measure of whether an adult is a healthy weight is body mass index (BMI), defined as weight in kilograms/(height in metres)2. However, adult categories of obese (>30) and overweight (>25) BMI are not directly applicable to children, whose BMI naturally varies as they grow. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information.
Why Was This Study Done?
As the numbers of obese and overweight children increase, a corresponding rise in future numbers of overweight and obese adults is also expected. This in turn is expected to lead to an increasing incidence of poor health. As a result, there is great interest among health professionals in possible pathways between childhood and adult obesity. It has been proposed that certain periods in childhood may be critical for the development of obesity.
In the last few years, ten genetic variants have been found to be more common in overweight or obese adults. Eight of these have also been linked to childhood BMI and/or obesity. The authors wanted to identify the timing of childhood weight changes that may be associated with adult obesity. Knowledge of obesity risk genetic variants gave them an opportunity to do so now, without following a set of children to adulthood.
What Did the Researchers Do and Find?
The authors analysed data gathered from a subset of 7,146 singleton white European children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, which is investigating associations between genetics, lifestyle, and health outcomes for a group of children in Bristol whose due date of birth fell between April 1991 and December 1992. They used knowledge of the children's genetic makeup to find associations between an obesity risk allele score—a measure of how many of the obesity risk genetic variants a child possessed—and the children's weight, height, BMI, levels of body fat (at nine years old), and rate of weight gain, up to age 11 years.
They found that, at birth, children with a higher obesity risk allele score were not any heavier, but in the immediate postnatal period they were less likely to be in the bottom 5% of the population for weight gain (adjusted for birthweight), often termed “failure to thrive.” At six weeks of age, children with a higher obesity risk allele score tended to be longer and heavier, even allowing for weight at birth.
After six weeks of age, the obesity risk allele score was not associated with any further increase in length/height, but it was associated with a more rapid weight gain between birth and age 11 years. BMI is derived from height and weight measurements, and the association between the obesity risk allele score and BMI was weak between birth and age three-and-a-half years, but after that age the association with BMI increased rapidly. By age nine, children with a higher obesity risk allele score tended to be heavier and taller, with more fat on their bodies.
What Do These Findings Mean?
The combined obesity allele risk score is associated with higher rates of weight gain and adult obesity, and so the authors conclude that weight gain and growth even in the first few weeks after birth may be the beginning of a pathway of greater adult obesity risk.
A study that tracks a population over time can find associations but it cannot show cause and effect. In addition, only a relatively small proportion (1.7%) of the variation in BMI at nine years of age is explained by the obesity risk allele score.
The authors' method of finding associations between childhood events and adult outcomes via genetic markers of risk of disease as an adult has a significant advantage: the authors did not have to follow the children themselves to adulthood, so their findings are more likely to be relevant to current populations. Despite this, this research does not yield advice for parents how to reduce their children's obesity risk. It does suggest that “failure to thrive” in the first six weeks of life is not simply due to a lack of provision of food by the baby's caregiver but that genetic factors also contribute to early weight gain and growth.
The study looked at the combined obesity risk allele score and the authors did not attempt to identify which individual alleles have greater or weaker associations with weight gain and overweight or obesity. This would require further research based on far larger numbers of babies and children. The findings may also not be relevant to children in other types of setting because of the effects of different nutrition and lifestyles.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000284.
Further information is available on the ALSPAC study
The UK National Health Service and other partners provide guidance on establishing a healthy lifestyle for children and families in their Change4Life programme
The International Obesity Taskforce is a global network of expertise and the advocacy arm of the International Association for the Study of Obesity. It works with the World Health Organization, other NGOs, and stakeholders and provides information on overweight and obesity
The Centers for Disease Control and Prevention (CDC) in the US provide guidance and tips on maintaining a healthy weight, including BMI calculators in both metric and Imperial measurements for both adults and children. They also provide BMI growth charts for boys and girls showing how healthy ranges vary for each sex at with age
The Royal College of Paediatrics and Child Health provides growth charts for weight and length/height from birth to age 4 years that are based on WHO 2006 growth standards and have been adapted for use in the UK
The CDC Web site provides information on overweight and obesity in adults and children, including definitions, causes, and data
The CDC also provide information on the role of genes in causing obesity.
The World Health Organization publishes a fact sheet on obesity, overweight and weight management, including links to childhood overweight and obesity
Wikipedia includes an article on childhood obesity (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000284
PMCID: PMC2876048  PMID: 20520848
16.  Long-Term Risk of Incident Type 2 Diabetes and Measures of Overall and Regional Obesity: The EPIC-InterAct Case-Cohort Study 
PLoS Medicine  2012;9(6):e1001230.
A collaborative re-analysis of data from the InterAct case-control study conducted by Claudia Langenberg and colleagues has established that waist circumference is associated with risk of type 2 diabetes, independently of body mass index.
Background
Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI).
Methods and Findings
The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5–22.4 kg/m2) with a low WC (<94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI≥35 kg/m2) and a high WC (>102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50–103 per 1,000 person-years in men and 28–74 per 1,000 person-years in women).
Conclusions
WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 350 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone that the pancreas releases after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. The long-term complications of diabetes, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
A high body mass index (BMI, a measure of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is a strong predictor of type 2 diabetes. Although the risk of diabetes is greatest in obese people (who have a BMI of greater than 30 kg/m2), many of the people who develop diabetes are overweight—they have a BMI of 25–30 kg/m2. Healthy eating and exercise reduce the incidence of diabetes in high-risk individuals, but it is difficult and expensive to provide all overweight and obese people with individual lifestyle advice. Ideally, a way is needed to distinguish between people with high and low risk of developing diabetes at different levels of BMI. Waist circumference is a measure of fat distribution that has the potential to quantify diabetes risk among people with different BMIs because it estimates the amount of fat around the abdominal organs, which also predicts diabetes development. In this case-cohort study, the researchers use data from the InterAct study (which is investigating how genetics and lifestyle interact to affect diabetes risk) to estimate the long-term risk of type 2 diabetes associated with BMI and waist circumference. A case-cohort study measures exposure to potential risk factors in a group (cohort) of people and compares the occurrence of these risk factors in people who later develop the disease and in a randomly chosen subcohort.
What Did the Researchers Do and Find?
The researchers estimated the association of BMI and waist circumference with type 2 diabetes from baseline measurements of the weight, height, and waist circumference of 12,403 people who subsequently developed type 2 diabetes and a subcohort of 16,154 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC). Both risk factors were independently associated with type 2 diabetes risk, but waist circumference was a stronger risk factor in women than in men. Obese men (BMI greater than 35 kg/m2) with a high waist circumference (greater than 102 cm) were 22 times more likely to develop diabetes than men with a low normal weight (BMI 18.5–22.4 kg/m2) and a low waist circumference (less than 94 cm); obese women with a waist circumference of more than 88 cm were 31.8 times more likely to develop type 2 diabetes than women with a low normal weight and waist circumference (less than 80 cm). Importantly, among overweight people, waist circumference measurements identified a subgroup of overweight people (those with a high waist circumference) whose 10-year cumulative incidence of type 2 diabetes was similar to that of obese people.
What Do These Findings Mean?
These findings indicate that, among people of European descent, waist circumference is independently and strongly associated with type 2 diabetes, particularly among women. Additional studies are needed to confirm this association in other ethnic groups. Targeted measurement of waist circumference in overweight individuals (who now account for a third of the US and UK adult population) could be an effective strategy for the prevention of diabetes because it would allow the identification of a high-risk subgroup of people who might benefit from individualized lifestyle advice.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001230.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health care professionals, and the general public, including detailed information on diabetes prevention (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (including some information in Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes, about the prevention of type 2 diabetes, and about obesity; it also includes peoples stories about diabetes and about obesity
The charity Diabetes UK also provides detailed information for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the charity Healthtalkonline has interviews with people about their experiences of diabetes
More information on the InterAct study is available
MedlinePlus provides links to further resources and advice about diabetes and diabetes prevention and about obesity (in English and Spanish)
doi:10.1371/journal.pmed.1001230
PMCID: PMC3367997  PMID: 22679397
17.  The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis 
Fall, Tove | Hägg, Sara | Mägi, Reedik | Ploner, Alexander | Fischer, Krista | Horikoshi, Momoko | Sarin, Antti-Pekka | Thorleifsson, Gudmar | Ladenvall, Claes | Kals, Mart | Kuningas, Maris | Draisma, Harmen H. M. | Ried, Janina S. | van Zuydam, Natalie R. | Huikari, Ville | Mangino, Massimo | Sonestedt, Emily | Benyamin, Beben | Nelson, Christopher P. | Rivera, Natalia V. | Kristiansson, Kati | Shen, Huei-yi | Havulinna, Aki S. | Dehghan, Abbas | Donnelly, Louise A. | Kaakinen, Marika | Nuotio, Marja-Liisa | Robertson, Neil | de Bruijn, Renée F. A. G. | Ikram, M. Arfan | Amin, Najaf | Balmforth, Anthony J. | Braund, Peter S. | Doney, Alexander S. F. | Döring, Angela | Elliott, Paul | Esko, Tõnu | Franco, Oscar H. | Gretarsdottir, Solveig | Hartikainen, Anna-Liisa | Heikkilä, Kauko | Herzig, Karl-Heinz | Holm, Hilma | Hottenga, Jouke Jan | Hyppönen, Elina | Illig, Thomas | Isaacs, Aaron | Isomaa, Bo | Karssen, Lennart C. | Kettunen, Johannes | Koenig, Wolfgang | Kuulasmaa, Kari | Laatikainen, Tiina | Laitinen, Jaana | Lindgren, Cecilia | Lyssenko, Valeriya | Läärä, Esa | Rayner, Nigel W. | Männistö, Satu | Pouta, Anneli | Rathmann, Wolfgang | Rivadeneira, Fernando | Ruokonen, Aimo | Savolainen, Markku J. | Sijbrands, Eric J. G. | Small, Kerrin S. | Smit, Jan H. | Steinthorsdottir, Valgerdur | Syvänen, Ann-Christine | Taanila, Anja | Tobin, Martin D. | Uitterlinden, Andre G. | Willems, Sara M. | Willemsen, Gonneke | Witteman, Jacqueline | Perola, Markus | Evans, Alun | Ferrières, Jean | Virtamo, Jarmo | Kee, Frank | Tregouet, David-Alexandre | Arveiler, Dominique | Amouyel, Philippe | Ferrario, Marco M. | Brambilla, Paolo | Hall, Alistair S. | Heath, Andrew C. | Madden, Pamela A. F. | Martin, Nicholas G. | Montgomery, Grant W. | Whitfield, John B. | Jula, Antti | Knekt, Paul | Oostra, Ben | van Duijn, Cornelia M. | Penninx, Brenda W. J. H. | Davey Smith, George | Kaprio, Jaakko | Samani, Nilesh J. | Gieger, Christian | Peters, Annette | Wichmann, H.-Erich | Boomsma, Dorret I. | de Geus, Eco J. C. | Tuomi, TiinaMaija | Power, Chris | Hammond, Christopher J. | Spector, Tim D. | Lind, Lars | Orho-Melander, Marju | Palmer, Colin Neil Alexander | Morris, Andrew D. | Groop, Leif | Järvelin, Marjo-Riitta | Salomaa, Veikko | Vartiainen, Erkki | Hofman, Albert | Ripatti, Samuli | Metspalu, Andres | Thorsteinsdottir, Unnur | Stefansson, Kari | Pedersen, Nancy L. | McCarthy, Mark I. | Ingelsson, Erik | Prokopenko, Inga
PLoS Medicine  2013;10(6):e1001474.
In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Please see later in the article for the Editors' Summary
Background
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
Methods and Findings
We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.
Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).
Conclusions
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Globally, both the incidence of CVD (the number of new cases in a population every year) and its prevalence (the proportion of the population with CVD) are increasing, particularly in low- and middle-income countries. This increasing burden of CVD is occurring in parallel with a global increase in the incidence and prevalence of obesity—having an unhealthy amount of body fat (adiposity)—and of metabolic diseases—conditions such as diabetes in which metabolism (the processes that the body uses to make energy from food) is disrupted, with resulting high blood sugar and damage to the blood vessels.
Why Was This Study Done?
Epidemiological studies—investigations that record the patterns and causes of disease in populations—have reported an association between adiposity (indicated by an increased body mass index [BMI], which is calculated by dividing body weight in kilograms by height in meters squared) and cardiometabolic traits such as coronary heart disease, stroke, heart failure (a condition in which the heart is incapable of pumping sufficient amounts of blood around the body), diabetes, high blood pressure (hypertension), and high blood cholesterol (dyslipidemia). However, observational studies cannot prove that adiposity causes any particular cardiometabolic trait because overweight individuals may share other characteristics (confounding factors) that are the real causes of both obesity and the cardiometabolic disease. Moreover, it is possible that having CVD or a metabolic disease causes obesity (reverse causation). For example, individuals with heart failure cannot do much exercise, so heart failure may cause obesity rather than vice versa. Here, the researchers use “Mendelian randomization” to examine whether adiposity is causally related to various cardiometabolic traits. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Thus, an investigation of the associations between rs9939609 and cardiometabolic traits can indicate whether obesity is causally related to these traits.
What Did the Researchers Do and Find?
The researchers analyzed the association between rs9939609 (the “instrumental variable,” or IV) and BMI, between rs9939609 and 24 cardiometabolic traits, and between BMI and the same traits using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent. They then quantified the strength of the causal association between BMI and the cardiometabolic traits by calculating “IV estimators.” Higher BMI showed a causal relationship with heart failure, metabolic syndrome (a combination of medical disorders that increases the risk of developing CVD), type 2 diabetes, dyslipidemia, hypertension, increased blood levels of liver enzymes (an indicator of liver damage; some metabolic disorders involve liver damage), and several other cardiometabolic traits. All the IV estimators were similar to the BMI–cardiovascular trait associations (observational estimates) derived from the same individuals, with the exception of diabetes, where the causal estimate was higher than the observational estimate, probably because the observational estimate is based on a single BMI measurement, whereas the causal estimate considers lifetime changes in BMI.
What Do These Findings Mean?
Like all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. Nevertheless, these findings provide support for many previously suspected and biologically plausible causal relationships, such as that between adiposity and hypertension. They also provide new insights into the causal effect of obesity on liver enzyme levels and on heart failure. In the latter case, these findings suggest that a one-unit increase in BMI might increase the incidence of heart failure by 17%. In the US, this corresponds to 113,000 additional cases of heart failure for every unit increase in BMI at the population level. Although additional studies are needed to confirm and extend these findings, these results suggest that global efforts to reduce the burden of obesity will likely also reduce the occurrence of CVD and metabolic disorders.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001474.
The American Heart Association provides information on all aspects of cardiovascular disease and tips on keeping the heart healthy, including weight management (in several languages); its website includes personal stories about stroke and heart attacks
The US Centers for Disease Control and Prevention has information on heart disease, stroke, and all aspects of overweight and obesity (in English and Spanish)
The UK National Health Service Choices website provides information about cardiovascular disease and obesity, including a personal story about losing weight
The World Health Organization provides information on obesity (in several languages)
The International Obesity Taskforce provides information about the global obesity epidemic
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides links to other sources of information on heart disease, on vascular disease, on obesity, and on metabolic disorders (in English and Spanish)
The International Association for the Study of Obesity provides maps and information about obesity worldwide
The International Diabetes Federation has a web page that describes types, complications, and risk factors of diabetes
doi:10.1371/journal.pmed.1001474
PMCID: PMC3692470  PMID: 23824655
18.  Evaluation of Common Type 2 Diabetes Risk Variants in a South Asian Population of Sri Lankan Descent 
PLoS ONE  2014;9(6):e98608.
Introduction
Most studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka.
Methodology
Lead single nucleotide polymorphism (SNPs) at 37 T2D-risk loci attaining genome-wide significance in Europeans were genotyped in 878 T2D cases and 1523 normoglycaemic controls from Sri Lanka. Association testing was performed by logistic regression adjusting for age and sex and by the Cochran-Mantel-Haenszel test after stratifying according to self-identified ethnolinguistic subgroup. A weighted genetic risk score was generated to examine the combined effect of these SNPs on T2D-risk in the Sri Lankan population.
Results
Of the 36 SNPs passing quality control, sixteen showed nominal (p<0.05) association in Sri Lankan samples, fifteen of those directionally-consistent with the original signal. Overall, these association findings were robust to analyses that accounted for membership of ethnolinguistic subgroups. Overall, the odds ratios for 31 of the 36 SNPs were directionally-consistent with those observed in Europeans (p = 3.2×10−6). Allelic odds ratios and risk allele frequencies in Sri Lankan subjects were not systematically different to those reported in Europeans. Genetic risk score and risk of T2D were strongly related in Sri Lankans (per allele OR 1.10 [95%CI 1.08–1.13], p = 1.2×10−17).
Conclusion
Our data indicate that most T2D-risk variants identified in Europeans have similar effects in South Asians from Sri Lanka, and that systematic difference in common variant associations are unlikely to explain inter-ethnic differences in prevalence or presentation of T2D.
doi:10.1371/journal.pone.0098608
PMCID: PMC4057178  PMID: 24926958
19.  A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap 
PLoS Genetics  2011;7(12):e1002406.
In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non–Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10−06) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non–MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.
Author Summary
It is well known that multiple autoimmune disorders cluster in families. However, all of the genetic variants that explain this clustering have not been discovered, and the specific genetic variants shared between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) are not known. In order to better understand the genetic factors that explain this predisposition to autoimmunity, we performed a comprehensive evaluation of shared autoimmune genetic variants. First we considered results from 17 ADs and compiled a list with 446 significant genetic variants from these studies. We identified some genetic variants extensively shared between ADs, as well as the ADs that share the most variants. The genetic overlap between SLE and other ADs was modest. Next we tested how important all the 446 genetic variants were in our collection with a minimum of 1,500 SLE patients. Among the most significant variants in SLE, the majority had already been identified in previous studies, but we also discovered variants in two important immune genes. In summary, our data identified diseases with common genetic risk factors and novel SLE effects, and this supports a relatively distinct genetic susceptibility for SLE. This study helps delineate the genetic architecture of ADs.
doi:10.1371/journal.pgen.1002406
PMCID: PMC3234215  PMID: 22174698
20.  Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits 
PLoS Genetics  2007;3(7):e115.
The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 ×10−7), hip circumference (p = 3.4 × 10−8), and weight (p = 9.1 × 10−7). In Sardinia, homozygotes for the rare “G” allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common “A” allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 × 10−6). Homozygotes for the rare “A” allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common “G” allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare “A” allele were, on average, 1.0–3.0 BMI units heavier than homozygotes for the more common “G” allele. In summary, we have completed a whole genome–association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.
Author Summary
Although twin and family studies have clearly shown that genes play a role in obesity, it has proven quite difficult to identify the specific genetic variants involved. Here, we take advantage of recent technical and methodological advances to examine the role of common genetic variants on several obesity-related traits. By examining >4,000 Sardinians, we show that a specific genetic variant, rs9930506, and other nearby variants on human Chromosome 16 are associated with body mass index, hip circumference, and total body weight. The variants overlap FTO, a gene with poorly understood function. Further studies of the region may implicate new biological pathways affecting susceptibility to obesity. We also show that the association is not restricted to Sardinia but is also seen in independent samples of European Americans and Hispanic Americans. This finding is particularly important because obesity is associated with increased risk of cardiovascular disease and diabetes.
doi:10.1371/journal.pgen.0030115
PMCID: PMC1934391  PMID: 17658951
21.  Early Emergence of Ethnic Differences in Type 2 Diabetes Precursors in the UK: The Child Heart and Health Study in England (CHASE Study) 
PLoS Medicine  2010;7(4):e1000263.
Peter Whincup and colleagues carry out a cross-sectional study examining ethnic differences in precursors of of type 2 diabetes among children aged 9–10 living in three UK cities.
Background
Adults of South Asian origin living in the United Kingdom have high risks of type 2 diabetes and central obesity; raised circulating insulin, triglyceride, and C-reactive protein concentrations; and low HDL-cholesterol when compared with white Europeans. Adults of African-Caribbean origin living in the UK have smaller increases in type 2 diabetes risk, raised circulating insulin and HDL-cholesterol, and low triglyceride and C-reactive protein concentrations. We examined whether corresponding ethnic differences were apparent in childhood.
Methods and Findings
We performed a cross-sectional survey of 4,796 children aged 9–10 y in three UK cities who had anthropometric measurements (68% response) and provided blood samples (58% response); ethnicity was based on parental definition. In age-adjusted comparisons with white Europeans (n = 1,153), South Asian children (n = 1,306) had higher glycated haemoglobin (HbA1c) (% difference: 2.1, 95% CI 1.6 to 2.7), fasting insulin (% difference 30.0, 95% CI 23.4 to 36.9), triglyceride (% difference 12.9, 95% CI 9.4 to 16.5), and C-reactive protein (% difference 43.3, 95% CI 28.6 to 59.7), and lower HDL-cholesterol (% difference −2.9, 95% CI −4.5 to −1.3). Higher adiposity levels among South Asians (based on skinfolds and bioimpedance) did not account for these patterns. Black African-Caribbean children (n = 1,215) had higher levels of HbA1c, insulin, and C-reactive protein than white Europeans, though the ethnic differences were not as marked as in South Asians. Black African-Caribbean children had higher HDL-cholesterol and lower triglyceride levels than white Europeans; adiposity markers were not increased.
Conclusions
Ethnic differences in type 2 diabetes precursors, mostly following adult patterns, are apparent in UK children in the first decade. Some key determinants operate before adult life and may provide scope for early prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, nearly 250 million people have diabetes, and the number of people affected by this chronic disease is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone that the pancreas releases when blood sugar levels rise after eating (digestion of food produces glucose). In people with type 2 diabetes (the most common type of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing sugar from the blood become less responsive to insulin (insulin resistant). Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. Long-term complications of diabetes include kidney failure, blindness, nerve damage, and an increased risk of developing cardiovascular problems, including heart disease and stroke.
Why Was This Study Done?
South Asians and African-Caribbeans living in Western countries tend to have higher rates of type 2 diabetes than host populations. South Asian adults living in the UK, for example, have a 3-fold higher risk of developing type 2 diabetes than white Europeans. They also have higher fasting blood levels of glucose, insulin and triglycerides (a type of fat), higher blood levels of “glycated hemoglobin” (HbA1c; an indicator of average of blood-sugar levels over time), more body fat (increased adiposity), raised levels of a molecule called C-reactive protein, and lower levels of HDL-cholesterol (another type of fat) than white Europeans. Most of these “diabetes precursors” (risk factors) are also seen in black African-Caribbean adults living in the UK except that individuals in this ethnic group often have raised HDL-cholesterol levels and low triglyceride levels. Ethnic differences in type 2 diabetes precursors are also present in adolescents, but the extent to which they are present in childhood remains unclear. Knowing this information could have implications for diabetes prevention. In this population-based study, therefore, the researchers investigate patterns of diabetes precursors in 9- to 10-year-old UK children of white European, South Asian, and black African-Caribbean origin.
What Did the Researchers Do and Find?
The researchers enrolled nearly 5,000 children (including 1,153 white European, 1,306 South Asian and 1,215 black African-Caribbean children) from primary schools with high prevalences of ethnic minority pupils in London, Birmingham, and Leicester in the Child Heart and Health study in England (CHASE). They measured and weighed more than two-thirds of the enrolled children and determined their adiposity. They also took blood samples for measurement of diabetes precursors from nearly two-thirds of the children. The recorded ethnicity of each child was based on parental definition. The researchers' analysis of these data showed that, compared with white Europeans, South Asian children had higher levels of HbA1c, insulin, triglycerides, and C-reactive protein but lower HDL-cholesterol levels. In addition, they had higher adiposity levels than the white European children, but this did not account for the observed differences in the other diabetes precursors. Black African-Caribbean children also had higher levels of HbA1c, insulin, and C-reactive protein than white European children, although the differences were smaller than those between South Asians and white Europeans. Similar to black African-Caribbean adults, however, children of this ethnic origin had higher HDL-cholesterol and lower triglyceride levels than white Europeans.
What Do These Findings Mean?
These findings indicate that ethnic differences in diabetes precursors are already present in apparently healthy children before they are 10 years old. Furthermore, most of the ethnic differences in diabetes precursors seen among the children follow the pattern seen in adults. Although these findings need confirming in more children, they suggest that the ethnic differences in type 2 diabetes susceptibility first described in immigrants to the UK are persisting in UK-born South Asian and black African-Caribbean children. Most importantly, these findings suggest that some of the factors thought to be responsible for ethnic differences in type 2 diabetes—for example, varying levels of physical activity and dietary differences—are operating well before adult life. Interventions that target these factors early could, therefore, offer good opportunities for diabetes prevention in high-risk ethnic groups, provided such interventions are carefully tailored to the needs of these groups.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000263.
The International Diabetes Federation provides information about all aspects of diabetes (in English, French and Spanish)
The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health-care professionals and the general public, including information on diabetes in specific US populations (in English and Spanish)
The UK National Health Service also provides information for patients and carers about type 2 diabetes (in several languages)
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
The US Agency for Healthcare Research and Quality has a fact sheet on diabetes disparities among racial and ethnic minorities
doi:10.1371/journal.pmed.1000263
PMCID: PMC2857652  PMID: 20421924
22.  Genetic associations in diabetic nephropathy: a meta-analysis 
Diabetologia  2010;54(3):544-553.
Aims/hypothesis
This meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy.
Methods
PubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease [ESRD]) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group.
Results
The literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes).
Conclusions/interpretation
This meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-010-1996-1) contains supplementary material, which is available to authorised users.
doi:10.1007/s00125-010-1996-1
PMCID: PMC3034040  PMID: 21127830
Diabetes mellitus; Diabetic nephropathy; Genetic association studies; Genetic polymorphism; Meta-analysis
23.  SLC2A9 Is a High-Capacity Urate Transporter in Humans 
PLoS Medicine  2008;5(10):e197.
Background
Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man.
Methods and Findings
We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200–500 μM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 μM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case–control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size −0.12 mm Hg, 95% CI −0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size −0.03 mm Hg, 95% CI −0.39 to 0.31, p = 0.82).
Conclusions
This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.
Editors' Summary
Background.
Blood is continually pumped around the human body to deliver the chemicals needed to keep the body's cells alive and to take cellular waste products to the kidneys where they are filtered out of the blood and excreted in the urine. In healthy people, the levels of nutrients and waste products in serum (the liquid part of blood) fall within “normal” ranges but in ill people these levels can be very different. For example, serum uric acid (urate) levels are usually increased in people with gout. In this arthritic condition, uric acid crystallizes in the joints (often those in the big toe) and causes swelling and intense pain. Increased serum urate levels, which are also associated with high blood pressure, diabetes, and several other important conditions, can be caused by eating food that is rich in chemicals called purines (for example, liver, dried beans, and port). The body also converts its own purines into uric acid so genetic variations in the enzymes involved in purine breakdown can alter serum urate levels, as can variations in the rate of urate removal from the body by the kidneys. Urinary urate excretion is controlled by urate transporters, proteins that carry urate into and out of the kidney cells. Uricosuric drugs, which are used to treat gout, reduce serum urate levels by inhibiting a urate transporter that reabsorbs urate from urine.
Why Was This Study Done?
Several urate transporters have already been identified but recently, using an approach called genome-wide association scanning, scientists found that some genetic variants of a human gene called SLC2A9 are more common in people with high serum urate levels than in people with normal levels. SLC2A9 encodes a glucose transporter (a protein that helps to move the sugar glucose through cell membranes) and is highly expressed in the kidney's main urate handling site. Given these facts, could SLC2A9 (the protein made from SLC2A9) be a urate transporter as well as a glucose transporter? In this study, the researchers investigate this possibility and also ask whether genetic variations in SLC2A9 might be responsible for the association between serum urate levels and high blood pressure.
What Did the Researchers Do and Find?
The researchers first expressed SLC2A9 in frog eggs, a type of cell that does not have its own urate transporter. They found that urate rapidly moved into eggs expressing SLC2A9 but not into control eggs, that SLC2A9 transported urate about 50 times faster than glucose, and that glucose stimulated SLC2A9-mediated urate transport. Similarly, overexpression of SLC2A9 in human embryonic kidney cells more than doubled their urate uptake. Conversely, when the researchers used a technique called RNA interference to reduce the expression of mouse SLC2A9 in mouse cells that normally makes this protein, urate transport was reduced. Next, the researchers looked at two small parts of SLC2A9 that vary between individuals (so-called single polynucleotide polymorphisms) in nearly 900 men who had had their serum urate levels and urinary urate excretion rates measured. They found that certain genetic variations at these two sites were associated with increased serum urate levels and decreased urinary urate excretion. Finally, the researchers used a statistical technique called meta-analysis to look for an association between one of the SLC2A9 gene variants and blood pressure. In two separate meta-analyses that together involved more than 20, 000 participants in several studies, there was no association between this gene variant and blood pressure.
What Do These Findings Mean?
Overall, these findings indicate that SLCA9 is a high capacity urate transporter and suggest that this protein plays an important part in controlling serum urate levels. They provide confirmation that common genetic variants in SLC2A9 affect serum urate levels to a marked degree, although they do not show exactly which genetic variant is responsible for increasing serum urate levels. They also provide important new insights into how the kidneys normally handle urate and suggest ways in which this essential process may sometimes go wrong. Thus, these findings could eventually lead to new treatments for gout and possibly for other diseases that are associated with increased serum urate levels.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050197.
The UK National Health Service Direct health encyclopedia provides detailed information for patients about gout
MedlinePlus provides links to many sources of information about gout (in English and Spanish), including “What is gout?”, an easy-to-read guide from the US National Institutes of Arthritis and Musculoskeletal and Skin Diseases
Wikipedia also has pages on gout, uric acid, and SCL2A9 (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The Arthritis Research Campaign also has information on gout
Mark Caulfield and colleagues show that theSLC2A9 gene, which encodes a facilitative glucose transporter, is also a high-capacity urate transporter.
doi:10.1371/journal.pmed.0050197
PMCID: PMC2561076  PMID: 18842065
24.  Rotating Night Shift Work and Risk of Type 2 Diabetes: Two Prospective Cohort Studies in Women 
PLoS Medicine  2011;8(12):e1001141.
An Pan and colleagues examined data from two Nurses' Health Studies and found that extended periods of rotating night shift work were associated with a modestly increased risk of type 2 diabetes, partly mediated through body weight.
Background
Rotating night shift work disrupts circadian rhythms and has been associated with obesity, metabolic syndrome, and glucose dysregulation. However, its association with type 2 diabetes remains unclear. Therefore, we aimed to evaluate this association in two cohorts of US women.
Methods and Findings
We followed 69,269 women aged 42–67 in Nurses' Health Study I (NHS I, 1988–2008), and 107,915 women aged 25–42 in NHS II (1989–2007) without diabetes, cardiovascular disease, and cancer at baseline. Participants were asked how long they had worked rotating night shifts (defined as at least three nights/month in addition to days and evenings in that month) at baseline. This information was updated every 2–4 years in NHS II. Self-reported type 2 diabetes was confirmed by a validated supplementary questionnaire. We documented 6,165 (NHS I) and 3,961 (NHS II) incident type 2 diabetes cases during the 18–20 years of follow-up. In the Cox proportional models adjusted for diabetes risk factors, duration of shift work was monotonically associated with an increased risk of type 2 diabetes in both cohorts. Compared with women who reported no shift work, the pooled hazard ratios (95% confidence intervals) for participants with 1–2, 3–9, 10–19, and ≥20 years of shift work were 1.05 (1.00–1.11), 1.20 (1.14–1.26), 1.40 (1.30–1.51), and 1.58 (1.43–1.74, p-value for trend <0.001), respectively. Further adjustment for updated body mass index attenuated the association, and the pooled hazard ratios were 1.03 (0.98–1.08), 1.06 (1.01–1.11), 1.10 (1.02–1.18), and 1.24 (1.13–1.37, p-value for trend <0.001).
Conclusions
Our results suggest that an extended period of rotating night shift work is associated with a modestly increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight. Proper screening and intervention strategies in rotating night shift workers are needed for prevention of diabetes.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Around 346 million people worldwide have diabetes—a chronic disease affecting blood glucose levels, which over time may lead to serious damage in many body systems. In 2004, an estimated 3.4 million people died from consequences of high blood sugar, with more than 80% of deaths occurring in low-and middle-income countries. Type 2 diabetes accounts for 90% of people with diabetes and is largely the result of excess body weight and physical inactivity, which causes the body to use insulin ineffectively. One strategy in the public health response to the increasing prevalence and incidence of type 2 diabetes is to focus on the prevention and management of obesity by targeting risk factors of obesity.
Previous studies have suggested that rotating night shift work, which is common and becoming increasingly prevalent in countries worldwide, is associated with an increased risk of obesity and metabolic syndrome, conditions closely related to type 2 diabetes.
Why Was This Study Done?
Some studies have investigated the association between rotating night shift work and type 2 diabetes but have experienced methodological problems (such as minimal information on the rotating shift work, small sample sizes, and limited study populations), which make interpretation of the results difficult. In this study, the researchers attempted to overcome these methodological issues by prospectively examining the relationship between duration of rotating night shift work and risk of incident type 2 diabetes and, also if the duration of shift work was associated with greater weight gain, in two large cohorts of women in the United States.
What Did the Researchers Do and Find?
The researchers used data from the Nurses' Health Study I (NHS I, established in 1976 and included 121,704 women) and the Nurses' Health Study II (NHS II, established in 1989 and included 116,677 women), in which participating women completed regular questionnaires about their lifestyle practices and the development of chronic diseases. In both studies, the women also gave information about how long they had done rotating night shifts work (defined as at least three nights/month in addition to 19 days and evenings in that month), and this information was updated at regular intervals over the study follow-up period (18 years). The comparison group was women who did not report a history of rotating night shift work.
To assess the incidence of diabetes in both cohorts, the researchers sent a supplementary questionnaire to women who reported a diagnosis of diabetes, which asked about the symptoms, diagnostic tests, and medical management: if at least one of the National Diabetes Data Group criteria was reported, the researchers considered confirmed a diagnosis of type 2 diabetes. The researchers then used statistical methods (time-dependent Cox proportional hazards models) to estimate the hazard ratios of the chance of women working rotating shifts developing type 2 diabetes as a ratio of the chance of women not working rotating shifts developing diabetes.
The researchers found that in NHS I, 6,165 women developed type 2 diabetes and in NHS II 3,961 women developed type 2 diabetes. Using their statistical models, the researchers found that the duration of rotating night shift work was strongly associated with an increased risk of type 2 diabetes in both cohorts. The researchers found that in both cohorts, compared with women who reported no rotating night shift work, the HR of women developing type 2 diabetes, increased with the numbers of years working rotating shifts (the HRs of working rotating shifts for 1–2, 3–9, 10–19, and ≥20 years were 0.99, 1.17, 1.42, and 1.64, respectively, in NHS I, and in NHS II, 1.13, 1.34, 1.76, and 2.50, respectively). However, these associations were slightly weaker after the authors took other factors into consideration, except for body mass index (BMI).
What Do These Findings Mean?
These findings show that in these women, there is a positive association between rotating night shift work and the risk of developing type 2 diabetes. Furthermore, long duration of shift work may also be associated with greater weight gain. Although these findings need to be confirmed in men and other ethnic groups, because a large proportion of the working population is involved in some kind of permanent night and rotating night shift work, these findings are of potential public health significance. Additional preventative strategies in rotating night shift workers should therefore be considered.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001141.
This study is further discussed in a PLoS Medicine Perspective by Mika Kivimki and colleagues
Wikipedia has information about the Nurses’ Health study (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Detailed information about the Nurses’ Health Study is available
The World Health Organization provides comprehensive information about all kinds of diabetes
For more information about diabetes that is useful for patients see Diabetes UK
doi:10.1371/journal.pmed.1001141
PMCID: PMC3232220  PMID: 22162955
25.  Polymorphisms, Mutations, and Amplification of the EGFR Gene in Non-Small Cell Lung Cancers 
PLoS Medicine  2007;4(4):e125.
Background
The epidermal growth factor receptor (EGFR) gene is the prototype member of the type I receptor tyrosine kinase (TK) family and plays a pivotal role in cell proliferation and differentiation. There are three well described polymorphisms that are associated with increased protein production in experimental systems: a polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one (lower number of repeats) and two single nucleotide polymorphisms (SNPs) in the promoter region, −216 (G/T or T/T) and −191 (C/A or A/A). The objective of this study was to examine distributions of these three polymorphisms and their relationships to each other and to EGFR gene mutations and allelic imbalance (AI) in non-small cell lung cancers.
Methods and Findings
We examined the frequencies of the three polymorphisms of EGFR in 556 resected lung cancers and corresponding non-malignant lung tissues from 336 East Asians, 213 individuals of Northern European descent, and seven of other ethnicities. We also studied the EGFR gene in 93 corresponding non-malignant lung tissue samples from European-descent patients from Italy and in peripheral blood mononuclear cells from 250 normal healthy US individuals enrolled in epidemiological studies including individuals of European descent, African–Americans, and Mexican–Americans. We sequenced the four exons (18–21) of the TK domain known to harbor activating mutations in tumors and examined the status of the CA-SSR1 alleles (presence of heterozygosity, repeat number of the alleles, and relative amplification of one allele) and allele-specific amplification of mutant tumors as determined by a standardized semiautomated method of microsatellite analysis. Variant forms of SNP −216 (G/T or T/T) and SNP −191 (C/A or A/A) (associated with higher protein production in experimental systems) were less frequent in East Asians than in individuals of other ethnicities (p < 0.001). Both alleles of CA-SSR1 were significantly longer in East Asians than in individuals of other ethnicities (p < 0.001). Expression studies using bronchial epithelial cultures demonstrated a trend towards increased mRNA expression in cultures having the variant SNP −216 G/T or T/T genotypes. Monoallelic amplification of the CA-SSR1 locus was present in 30.6% of the informative cases and occurred more often in individuals of East Asian ethnicity. AI was present in 44.4% (95% confidence interval: 34.1%–54.7%) of mutant tumors compared with 25.9% (20.6%–31.2%) of wild-type tumors (p = 0.002). The shorter allele in tumors with AI in East Asian individuals was selectively amplified (shorter allele dominant) more often in mutant tumors (75.0%, 61.6%–88.4%) than in wild-type tumors (43.5%, 31.8%–55.2%, p = 0.003). In addition, there was a strong positive association between AI ratios of CA-SSR1 alleles and AI of mutant alleles.
Conclusions
The three polymorphisms associated with increased EGFR protein production (shorter CA-SSR1 length and variant forms of SNPs −216 and −191) were found to be rare in East Asians as compared to other ethnicities, suggesting that the cells of East Asians may make relatively less intrinsic EGFR protein. Interestingly, especially in tumors from patients of East Asian ethnicity, EGFR mutations were found to favor the shorter allele of CA-SSR1, and selective amplification of the shorter allele of CA-SSR1 occurred frequently in tumors harboring a mutation. These distinct molecular events targeting the same allele would both be predicted to result in greater EGFR protein production and/or activity. Our findings may help explain to some of the ethnic differences observed in mutational frequencies and responses to TK inhibitors.
Masaharu Nomura and colleagues examine the distribution ofEGFR polymorphisms in different populations and find differences that might explain different responses to tyrosine kinase inhibitors in lung cancer patients.
Editors' Summary
Background.
Most cases of lung cancer—the leading cause of cancer deaths worldwide—are “non-small cell lung cancer” (NSCLC), which has a very low cure rate. Recently, however, “targeted” therapies have brought new hope to patients with NSCLC. Like all cancers, NSCLC occurs when cells begin to divide uncontrollably because of changes (mutations) in their genetic material. Chemotherapy drugs treat cancer by killing these rapidly dividing cells, but, because some normal tissues are sensitive to these agents, it is hard to kill the cancer completely without causing serious side effects. Targeted therapies specifically attack the changes in cancer cells that allow them to divide uncontrollably, so it might be possible to kill the cancer cells selectively without damaging normal tissues. Epidermal growth factor receptor (EGRF) was one of the first molecules for which a targeted therapy was developed. In normal cells, messenger proteins bind to EGFR and activate its “tyrosine kinase,” an enzyme that sticks phosphate groups on tyrosine (an amino acid) in other proteins. These proteins then tell the cell to divide. Alterations to this signaling system drive the uncontrolled growth of some cancers, including NSCLC.
Why Was This Study Done?
Molecules that inhibit the tyrosine kinase activity of EGFR (for example, gefitinib) dramatically shrink some NSCLCs, particularly those in East Asian patients. Tumors shrunk by tyrosine kinase inhibitors (TKIs) often (but not always) have mutations in EGFR's tyrosine kinase. However, not all tumors with these mutations respond to TKIs, and other genetic changes—for example, amplification (multiple copies) of the EGFR gene—also affect tumor responses to TKIs. It would be useful to know which genetic changes predict these responses when planning treatments for NSCLC and to understand why the frequency of these changes varies between ethnic groups. In this study, the researchers have examined three polymorphisms—differences in DNA sequences that occur between individuals—in the EGFR gene in people with and without NSCLC. In addition, they have looked for associations between these polymorphisms, which are present in every cell of the body, and the EGFR gene mutations and allelic imbalances (genes occur in pairs but amplification or loss of one copy, or allele, often causes allelic imbalance in tumors) that occur in NSCLCs.
What Did the Researchers Do and Find?
The researchers measured how often three EGFR polymorphisms (the length of a repeat sequence called CA-SSR1, and two single nucleotide variations [SNPs])—all of which probably affect how much protein is made from the EGFR gene—occurred in normal tissue and NSCLC tissue from East Asians and individuals of European descent. They also looked for mutations in the EGFR tyrosine kinase and allelic imbalance in the tumors, and then determined which genetic variations and alterations tended to occur together in people with the same ethnicity. Among many associations, the researchers found that shorter alleles of CA-SSR1 and the minor forms of the two SNPs occurred less often in East Asians than in individuals of European descent. They also confirmed that EGFR kinase mutations were more common in NSCLCs in East Asians than in European-descent individuals. Furthermore, mutations occurred more often in tumors with allelic imbalance, and in tumors where there was allelic imbalance and an EGFR mutation, the mutant allele was amplified more often than the wild-type allele.
What Do These Findings Mean?
The researchers use these associations between gene variants and tumor-associated alterations to propose a model to explain the ethnic differences in mutational frequencies and responses to TKIs seen in NSCLC. They suggest that because of the polymorphisms in the EGFR gene commonly seen in East Asians, people from this ethnic group make less EGFR protein than people from other ethnic groups. This would explain why, if a threshold level of EGFR is needed to drive cells towards malignancy, East Asians have a high frequency of amplified EGFR tyrosine kinase mutations in their tumors—mutation followed by amplification would be needed to activate EGFR signaling. This model, though speculative, helps to explain some clinical findings, such as the frequency of EGFR mutations and of TKI sensitivity in NSCLCs in East Asians. Further studies of this type in different ethnic groups and in different tumors, as well as with other genes for which targeted therapies are available, should help oncologists provide personalized cancer therapies for their patients.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040125.
US National Cancer Institute information on lung cancer and on cancer treatment for patients and professionals
MedlinePlus encyclopedia entries on NSCLC
Cancer Research UK information for patients about all aspects of lung cancer, including treatment with TKIs
Wikipedia pages on lung cancer, EGFR, and gefitinib (note that Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0040125
PMCID: PMC1876407  PMID: 17455987

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