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1.  An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference 
Aims
A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians.
Methods
We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥ 40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case–control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies.
Results
In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95% CI 0.24–0.67) kg/m2 per A-allele (P = 3.0× 10−5) and with waist circumference was 0.88 (95% CI 0.36–1.41) cm per A-allele (P = 0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95% CI) 1.18 (1.07–1.30); P = 0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95% CI 1.14–1.31); P = 1.07× 10−8] even after adjusting for BMI [1.18 (95% CI 1.10–1.27); P = 1.02× 10−5] or waist circumference [1.18 (95% CI 1.10–1.27); P = 3.97× 10−5].
Conclusions
The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.
doi:10.1111/j.1464-5491.2011.03257.x
PMCID: PMC3095685  PMID: 21294771
2.  FTO, Type 2 Diabetes, and Weight Gain Throughout Adult Life 
Diabetes  2011;60(5):1637-1644.
OBJECTIVE
FTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span.
RESEARCH DESIGN AND METHODS
Through regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malmö Diet and Cancer (MDC) and Malmö Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians.
RESULTS
The meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 × 10−8) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 × 10−8). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/m2 per risk allele; P = 2.0 × 10−26), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (∆BMI = 0.0 [−0.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults.
CONCLUSIONS
We have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter.
doi:10.2337/db10-1340
PMCID: PMC3292341  PMID: 21398525
3.  FTO Polymorphisms Are Associated With Obesity but Not Diabetes Risk in Postmenopausal Women 
Obesity (Silver Spring, Md.)  2008;16(11):2472-2480.
The FTO gene was recently identified as a susceptibility locus for both obesity and type 2 diabetes by whole-genome association analyses of several European populations. We tested for an association between FTO risk alleles and obesity and diabetes in a well-characterized multiethnic cohort of postmenopausal women in the United States. We genotyped two most significantly associated single-nucleotide polymorphisms (SNPs) (rs9939609 and rs8050136) in intron 1 of FTO gene in a nested case–control study of 1,517 diabetes cases and 2,123 controls from the Women’s Health Initiative–Observational Study (WHI-OS). The allelic frequencies of either rs9939609 or rs8050136 differed widely across four ethnic groups. The frequency of the rare allele A of rs9939609 among controls was much lower in Asians/Pacific Islanders (17%) than in blacks (45%), whites (40%), and Hispanics (31%). We found significant associations of rs9939609 with BMI and waist circumference in white and Hispanic women, but not among black and Asian/Pacific Islander women. On average, each copy of the risk-allele A at rs9939609 was significantly associated with 0.45 kg/m2 increase in BMI (95% confidence interval (CI): 0.16–0.74; P = 0.004) and 0.97 cm increase in waist circumference (95% CI: 0.21–0.65; P = 0.0002). Similar results were observed for rs8050136. However, we found no significant genetic associations with diabetes risk, either within the full study sample or in any ethnic group. In conclusion, common genetic variants in the intron 1 of FTO gene may confer a modest susceptibility to obesity in an ethnicity-specific manner, but may be unlikely to contribute to a clinically significant diabetes risk.
doi:10.1038/oby.2008.408
PMCID: PMC2732012  PMID: 18787525
4.  FTO Gene Variants are Strongly Associated with Type 2 Diabetes but only weakly with Obesity in South Asian Indians 
Diabetologia  2008;52(2):247-252.
Background
Variants in FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes (T2D) in white Europeans. These associations are not consistent in Asians and there are few reports in South Asian Indians who develop T2D at a much lower body mass index (BMI) than that in the white Europeans.
Aims and hypothesis
We studied the association of FTO variants with T2D and measures of obesity in South Asian Indians in Pune, India.
Methods
We genotyped by sequencing, two SNPs rs9939609 and rs7191344, in the FTO gene in 1453 type 2 diabetes patients and 1361 controls and a further 961 population based individuals from India .
Results
We observed a strong association of the minor allele A at rs9939609 with T2D (OR per allele =1.26 [95% CI, 1.13-1.40], P=3×10-5). The variant was also associated with BMI but this association appeared to be weaker (0.06SDs; 95%CIs:0.01-0.10, p=0.017) than the previously reported effect in Europeans (0.10SDs 95%CIs:0.09-0.12). Unlike in the Europeans, the association with T2D remained when adjusting for BMI (OR per allele for T2D=1.21 (95% CI, 1.06-1.37); P=4.0 × 10-3). Similar results were obtained when using waist circumference and other anthropometric parameters.
Conclusions
Our study replicates the strong association of FTO variants with type 2 diabetes in South Asian Indians but suggests that the association of FTO with T2D in them might operate through mechanisms other than obesity. This could imply a fundamental difference between Indians and Europeans in the mechanisms linking body size with T2D.
doi:10.1007/s00125-008-1186-6
PMCID: PMC2658005  PMID: 19005641
FTO; type 2 diabetes mellitus; polymorphisms; ethnicity; body mass index
5.  The FTO Gene rs9939609 Polymorphism Predicts Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(8):e71901.
Objective
Genome-wide association studies have shown that variance in the fat mass- and obesity- associated gene (FTO) is associated with risk of obesity in Europeans and Asians. Since obesity is associated with an increased risk of cardiovascular disease (CVD), several studies have investigated the association between variant in the FTO gene and CVD risk, with inconsistent results. In this study, we performed a meta-analysis to clarify the association of rs9939609 variant (or its proxies [r2>0.90]) in the FTO gene with CVD risk.
Methods
Published literature from PubMed and Embase was retrieved. Pooled odds ratios with 95% confidence intervals were calculated using the fixed- or random- effects model.
Results
A total of 10 studies (comprising 19,153 CVD cases and 103,720 controls) were included in the meta-analysis. The results indicated that the rs9939609 variant was significantly associated with CVD risk (odds ratio = 1.18, 95% confidence interval = 1.07–1.30, p = 0.001 [Z test], I2 = 80.6%, p<0.001 [heterogeneity]), and there was an insignificant change after adjustment for body mass index (BMI) and other conventional CVD risk factors (odds ratio = 1.16, 95% confidence interval = 1.05–1.27, p = 0.003 [Z test], I2 = 75.4%, p<0.001 [heterogeneity]).
Conclusions
The present meta-analysis confirmed the significant association of the rs9939609 variant in the FTO gene with CVD risk, which was independent of BMI and other conventional CVD risk factors.
doi:10.1371/journal.pone.0071901
PMCID: PMC3747067  PMID: 23977173
6.  The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China 
BMC Medical Genetics  2010;11:107.
Background
Previous genome-wide association studies for type 2 diabetes susceptibility genes have confirmed that a common variant, rs9939609, in the fat mass and obesity associated (FTO) gene region is associated with body mass index (BMI) in European children and adults. A significant association of the same risk allele has been described in Asian adult populations, but the results are conflicting. In addition, no replication studies have been conducted in children and adolescents of Asian ancestry.
Methods
A population-based survey was carried out among 3503 children and adolescents (6-18 years of age) in Beijing, China, including 1229 obese and 2274 non-obese subjects. We investigated the association of rs9939609 with BMI and the risk of obesity. In addition, we tested the association of rs9939609 with weight, height, waist circumference, waist-to-height ratio, fat mass percentage, birth weight, blood pressure and related metabolic traits.
Results
We found significant associations of rs9939609 variant with weight, BMI, BMI standard deviation score (BMI-SDS), waist circumference, waist-to-height ratio, and fat mass percentage in children and adolescents (p for trend = 3.29 × 10-5, 1.39 × 10-6, 3.76 × 10-6, 2.26 × 10-5, 1.94 × 10-5, and 9.75 × 10-5, respectively). No significant associations were detected with height, birth weight, systolic and diastolic blood pressure and related metabolic traits such as total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol and fasting plasma glucose (all p > 0.05). Each additional copy of the rs9939609 A allele was associated with a BMI increase of 0.79 [95% Confidence interval (CI) 0.47 to 1.10] kg/m2, equivalent to 0.25 (95%CI 0.14 to 0.35) BMI-SDS units. This rs9939609 variant is significantly associated with the risk of obesity under an additive model [Odds ratio (OR) = 1.29, 95% CI 1.11 to 1.50] after adjusting for age and gender. Moreover, an interaction between the FTO rs9939609 genotype and physical activity (p < 0.001) was detected on BMI levels, the effect of rs9939609-A allele on BMI being (0.95 ± 0.10), (0.77 ± 0.08) and (0.67 ± 0.05) kg/m2, for subjects who performed low, moderate and severe intensity physical activity.
Conclusion
The FTO rs9939609 variant is strongly associated with BMI and the risk of obesity in a population of children and adolescents in Beijing, China.
doi:10.1186/1471-2350-11-107
PMCID: PMC2914647  PMID: 20598163
7.  The Common FTO Genetic Polymorphism rs9939609 is Associated with Increased BMI in Type 1 Diabetes but not with Diabetic Nephropathy 
Biomarker Insights  2010;5:29-32.
The fat mass and obesity associated (FTO) gene has an important genetic effect on body mass index (BMI) and risk of obesity, and obesity contributes to the progression of renal diseases, including diabetic nephropathy. We thus conducted a genetic association study to evaluate whether the FTO gene confers the risk susceptibility to the development of diabetic nephropathy. Genotyping experiments of the common FTO polymorphism, rs9939609, in 1170 type 1 diabetes patients with (n = 597) or without diabetic nephropathy (n = 573) were performed with TaqMan allelic discrimination. All subjects are of European descent and selected from the Genetics of Kidney Diseases in Diabetes (GoKinD) study. The frequency of T allele of this polymorphism was 0.414 in the studied population. There was no allelic association of this polymorphism with diabetic nephropathy. But, the risk susceptibility of A allele conferring to the increased BMI among type 1 diabetes patients was observed. The subjects carrying with AA genotype had higher BMI compared to the carriers with TA and/or TT genotype(s) (P ≤ 0.019). The present study provides evidence that the common FTO genetic polymorphism, rs9939609, is associated with increased BMI in type 1 diabetes but not with diabetic nephropathy.
PMCID: PMC2867633  PMID: 20467478
diabetic nephropathy; fat mass and obesity associated; genetic association; single nucleotide polymorphism
8.  Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children 
Kilpeläinen, Tuomas O. | Qi, Lu | Brage, Soren | Sharp, Stephen J. | Sonestedt, Emily | Demerath, Ellen | Ahmad, Tariq | Mora, Samia | Kaakinen, Marika | Sandholt, Camilla Helene | Holzapfel, Christina | Autenrieth, Christine S. | Hyppönen, Elina | Cauchi, Stéphane | He, Meian | Kutalik, Zoltan | Kumari, Meena | Stančáková, Alena | Meidtner, Karina | Balkau, Beverley | Tan, Jonathan T. | Mangino, Massimo | Timpson, Nicholas J. | Song, Yiqing | Zillikens, M. Carola | Jablonski, Kathleen A. | Garcia, Melissa E. | Johansson, Stefan | Bragg-Gresham, Jennifer L. | Wu, Ying | van Vliet-Ostaptchouk, Jana V. | Onland-Moret, N. Charlotte | Zimmermann, Esther | Rivera, Natalia V. | Tanaka, Toshiko | Stringham, Heather M. | Silbernagel, Günther | Kanoni, Stavroula | Feitosa, Mary F. | Snitker, Soren | Ruiz, Jonatan R. | Metter, Jeffery | Larrad, Maria Teresa Martinez | Atalay, Mustafa | Hakanen, Maarit | Amin, Najaf | Cavalcanti-Proença, Christine | Grøntved, Anders | Hallmans, Göran | Jansson, John-Olov | Kuusisto, Johanna | Kähönen, Mika | Lutsey, Pamela L. | Nolan, John J. | Palla, Luigi | Pedersen, Oluf | Pérusse, Louis | Renström, Frida | Scott, Robert A. | Shungin, Dmitry | Sovio, Ulla | Tammelin, Tuija H. | Rönnemaa, Tapani | Lakka, Timo A. | Uusitupa, Matti | Rios, Manuel Serrano | Ferrucci, Luigi | Bouchard, Claude | Meirhaeghe, Aline | Fu, Mao | Walker, Mark | Borecki, Ingrid B. | Dedoussis, George V. | Fritsche, Andreas | Ohlsson, Claes | Boehnke, Michael | Bandinelli, Stefania | van Duijn, Cornelia M. | Ebrahim, Shah | Lawlor, Debbie A. | Gudnason, Vilmundur | Harris, Tamara B. | Sørensen, Thorkild I. A. | Mohlke, Karen L. | Hofman, Albert | Uitterlinden, André G. | Tuomilehto, Jaakko | Lehtimäki, Terho | Raitakari, Olli | Isomaa, Bo | Njølstad, Pål R. | Florez, Jose C. | Liu, Simin | Ness, Andy | Spector, Timothy D. | Tai, E. Shyong | Froguel, Philippe | Boeing, Heiner | Laakso, Markku | Marmot, Michael | Bergmann, Sven | Power, Chris | Khaw, Kay-Tee | Chasman, Daniel | Ridker, Paul | Hansen, Torben | Monda, Keri L. | Illig, Thomas | Järvelin, Marjo-Riitta | Wareham, Nicholas J. | Hu, Frank B. | Groop, Leif C. | Orho-Melander, Marju | Ekelund, Ulf | Franks, Paul W. | Loos, Ruth J. F. | Lewis, Cathryn
PLoS Medicine  2011;8(11):e1001116.
Ruth Loos and colleagues report findings from a meta-analysis of multiple studies examining the extent to which physical activity attenuates effects of a specific gene variant, FTO, on obesity in adults and children. They report a fairly substantial attenuation by physical activity on the effects of this genetic variant on the risk of obesity in adults.
Background
The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).
Methods and Findings
All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (pinteraction  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents.
Conclusions
The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
Please see later in the article for the Editors' Summary
Editors’ Summary
Background
Two in three Americans are overweight, of whom half are obese, and the trend towards increasing obesity is now seen across developed and developing countries. There has long been interest in understanding the impact of genes and environment when it comes to apportioning responsibility for obesity. Carrying a change in the FTO gene is common (found in three-quarters of Europeans and North Americans) and is associated with a 20%–30% increased risk of obesity. Some overweight or obese individuals may feel that the dice are loaded and there is little point in fighting the fat; it has been reported that those made aware of their genetic susceptibility to obesity may still choose a poor diet. A similar fatalism may occur when overweight and obese people consider physical activity. But disentangling the influence of physical activity on those genetically susceptible to obesity from other factors that might impact weight is not straightforward, as it requires large sample sizes, could be subject to publication bias, and may rely on less than ideal self-reporting methods.
Why Was This Study Done?
The public health ramifications of understanding the interaction between genetic susceptibility to obesity and physical activity are considerable. Tackling the rising prevalence of obesity will inevitably include interventions principally aimed at changing dietary intake and/or increasing physical activity, but the evidence for these with regards to those genetically susceptible has been lacking to date. The authors of this paper set out to explore the interaction between the commonest genetic susceptibility trait and physical activity using a rigorous meta-analysis of a large number of studies.
What Did the Researchers Do and Find?
The authors were concerned that a meta-analysis of published studies would be limited both by the data available to them and by possible bias. Instead of this more widely used approach, they took the literature search as their starting point, identified other studies through their collaborators’ network, and then undertook a meta-analysis of all available studies using a new and standardized analysis plan. This entailed an extremely large number of authors mining their data afresh to extract the relevant data points to enable such a meta-analysis. Physical activity was identified in the original studies in many different ways, including by self-report or by using an external measure of activity or heart rate. In order to perform the meta-analysis, participants were labeled as physically active or inactive in each study. For studies that had used a continuous scale, the authors decided that the bottom 20% of the participants were inactive (10% for children and adolescents). Using data from over 218,000 adults, the authors found that carrying a copy of the susceptibility gene increased the odds of obesity by 1.23-fold. But the size of this influence was 27% less in the genetically susceptible adults who were physically active (1.22-fold) compared to those who were physically inactive (1.30-fold). In a smaller study of about 19,000 children, no such effect of physical activity was seen.
What Do these Findings Mean?
This study demonstrates that people who carry the susceptibility gene for obesity can benefit from physical activity. This should inform health care professionals and the wider public that the view of genetically determined obesity not being amenable to exercise is incorrect and should be challenged. Dissemination, implementation, and ensuring uptake of effective physical activity programs remains a challenge and deserves further consideration. That the researchers treated “physically active” as a yes/no category, and how they categorized individuals, could be criticized, but this was done for pragmatic reasons, as a variety of means of assessing physical activity were used across the studies. It is unlikely that the findings would have changed if the authors had used a different method of defining physically active. Most of the studies included in the meta-analysis looked at one time point only; information about the influence of physical activity on weight changes over time in genetically susceptible individuals is only beginning to emerge.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001116.
This study is further discussed in a PLoS Medicine Perspective by Lennert Veerman
The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States
A more worldwide view is given by the World Health Organization
The UK National Health Service website gives information on physical activity guidelines for different age groups, while similar information can also be found from US sources
doi:10.1371/journal.pmed.1001116
PMCID: PMC3206047  PMID: 22069379
9.  FTO Variants Are Associated With Obesity in the Chinese and Malay Populations in Singapore 
Diabetes  2008;57(10):2851-2857.
OBJECTIVE— Association between genetic variants at the FTO locus and obesity has been consistently observed in populations of European ancestry and inconsistently in non-Europeans. The aim of this study was to examine the effects of FTO variants on obesity and type 2 diabetes in Southeast Asian populations.
RESEARCH DESIGN AND METHODS— We examined associations between nine previously reported FTO single nucleotide polymorphisms (SNPs) with obesity, type 2 diabetes, and related traits in 4,298 participants (2,919 Chinese, 785 Malays, and 594 Asian Indians) from the 1998 Singapore National Health Survey (NHS98) and 2,996 Malays from the Singapore Malay Eye Study (SiMES).
RESULTS— All nine SNPs exhibited strong linkage disequilibrium (r2 = 0.6–0.99), and minor alleles were associated with obesity in the same direction as previous studies with effect sizes ranging from 0.42 to 0.68 kg/m2 (P < 0.0001) in NHS98 Chinese, 0.65 to 0.91 kg/m2 (P < 0.02) in NHS98 Malays, and 0.52 to 0.64 kg/m2 (P < 0.0001) in SiMES Malays after adjustment for age, sex, smoking, alcohol consumption, and exercise. The variants were also associated with type 2 diabetes, though not after adjustment for BMI (with the exception of the SiMES Malays: odds ratio 1.17–1.22; P ≤ 0.026).
CONCLUSIONS— FTO variants common among European populations are associated with obesity in ethnic Chinese and Malays in Singapore. Our data do not support the hypothesis that differences in allele frequency or genetic architecture underlie the lack of association observed in some populations of Asian ancestry. Examination of gene-environment interactions involving variants at this locus may provide further insights into the role of FTO in the pathogenesis of human obesity and diabetes.
doi:10.2337/db08-0214
PMCID: PMC2551698  PMID: 18599522
10.  Common Variation in the FTO Gene Alters Diabetes-Related Metabolic Traits to the Extent Expected Given Its Effect on BMI 
Diabetes  2008;57(5):1419-1426.
OBJECTIVE
Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.
RESEARCH DESIGN AND METHODS
We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.
RESULTS
Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% CI 0.013–0.064]; P = 0.003), glucose (0.024 [0.001– 0.048]; P = 0.044), and triglycerides (0.028 [0.003– 0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008 – 0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, γ-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10 –1.25]; P = 3 × 10−6).
CONCLUSIONS
FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of >12,000 individuals were needed to detect associations at P < 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.
doi:10.2337/db07-1466
PMCID: PMC3073395  PMID: 18346983
11.  Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis 
Diabetologia  2012;55(10):2636-2645.
Aims/hypothesis
FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS.
Methods
A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis.
Results
A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10−11) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10−10). This translated into an approximately 3.3 kg/m2 increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations.
Conclusions/interpretation
The effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS.
doi:10.1007/s00125-012-2638-6
PMCID: PMC3433670  PMID: 22801903
BMI; FTO; Meta-analysis; Polycystic ovary syndrome; Systematic review; Weight
12.  The FTO A/T Polymorphism and Elite Athletic Performance: A Study Involving Three Groups of European Athletes 
PLoS ONE  2013;8(4):e60570.
Objective
The FTO A/T polymorphism (rs9939609) is a strong candidate to influence obesity-related traits. Elite athletes from many different sporting disciplines are characterized by low body fat. Therefore, the aim of this study was to assess whether athletic status is associated with the FTO A/T polymorphism.
Subjects and Methods
A large cohort of European Caucasians from Poland, Russia and Spain were tested to examine the association between FTO A/T polymorphism (rs9939609) and athletic status. A total of 551 athletes were divided by type of sport (endurance athletes, n = 266 vs. sprint/power athletes, n = 285) as well as by level of competition (elite-level vs. national-level). The control group consisted of 1,416 ethnically-matched, non-athletic participants, all Europeans. Multinomial logistic regression analyses were conducted to assess the association between FTO A/T genotypes and athletic status/competition level.
Results
There were no significantly greater/lesser odds of harbouring any type of genotype when comparing across athletic status (endurance athletes, sprint/power athletes or control participants). These effects were observed after controlling for sex and nationality. Furthermore, no significantly greater/lesser odds ratios were observed for any of the genotypes in respect to the level of competition (elite-level vs. national-level).
Conclusion
The FTO A/T polymorphism is not associated with elite athletic status in the largest group of elite athletes studied to date. Large collaborations and data sharing between researchers, as presented here, are strongly recommended to enhance the research in the field of exercise genomics.
doi:10.1371/journal.pone.0060570
PMCID: PMC3616005  PMID: 23573268
13.  Common Variant of FTO Gene, rs9939609, and Obesity in Pakistani Females 
BioMed Research International  2013;2013:324093.
Numerous studies confirmed the association of FTO (fat mass and obesity associated gene) common variant, rs9939609, with obesity in European populations. However, studies in Asian populations revealed conflicting results. We examined the association of rs9939609 variant of FTO gene with obesity and obesity-related anthropometric and metabolic parameters in Pakistani population. Body weight, height, waist circumference, hip circumference, and blood pressure (BP) were measured. BMI and waist-to-hip ratio (WHR) were calculated. Levels of fasting blood glucose (FBG), insulin, leptin, and leptin receptors were measured by enzyme linked immunosorbent assay (ELISA), and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The results showed association of FTO gene, rs9939609, with obesity in females (>18 years of age). FTO minor allele increased the risk of obesity by 2.8 times (95% CI = 1.3–6.0) in females. This allele showed association with body weight, BMI, waist circumference, hip circumference, WHR, BP, plasma FBG levels, HOMA-IR, plasma insulin levels, and plasma leptin levels. In conclusion, FTO gene, rs9939609, is associated with BMI and risk of obesity in adult Pakistani females. Association of rs9939609 variant with higher FBG, plasma insulin, and leptin levels indicates that this polymorphism may disturb the metabolism in adult females and predispose them to obesity and type 2 diabetes. However, the above-mentioned findings were not seen in children or males.
doi:10.1155/2013/324093
PMCID: PMC3775403  PMID: 24102053
14.  The genetics of obesity: FTO leads the way 
Trends in Genetics  2010;26(6):266-274.
In 2007, an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) gene region with body mass index (BMI) and risk of obesity was identified in multiple populations, making FTO the first locus unequivocally associated with adiposity. At the time, FTO was a gene of unknown function and it was not known whether these SNPs exerted their effect on adiposity by affecting FTO or neighboring genes. Therefore, this breakthrough association inspired a wealth of in silico, in vitro, and in vivo analyses in model organisms and humans to improve knowledge of FTO function. These studies suggested that FTO plays a role in controlling feeding behavior and energy expenditure. Here, we review the approaches taken that provide a blueprint for the study of other obesity-associated genes in the hope that this strategy will result in increased understanding of the biological mechanisms underlying body weight regulation.
doi:10.1016/j.tig.2010.02.006
PMCID: PMC2906751  PMID: 20381893
15.  Fat Mass and Obesity Associated Gene (FTO) Expression Is Regulated Negatively by the Transcription Factor Foxa2 
PLoS ONE  2012;7(12):e51082.
Fat mass and obesity associated gene (FTO) is the first gene associated with body mass index (BMI) and risk for diabetes. FTO is highly expressed in the brain and pancreas, and is involved in regulating dietary intake and energy expenditure. To investigate the transcriptional regulation of FTO expression, we created 5′-deletion constructs of the FTO promoter to determine which transcription factors are most relevant to FTO expression. The presence of an activation region at −201/+34 was confirmed by luciferase activity analysis. A potential Foxa2 (called HNF-3β) binding site and an upstream stimulatory factor (USF)-binding site was identified in the −100 bp fragment upstream of the transcription start site (TSS). Furthermore, using mutagenesis, we identified the Foxa2 binding sequence (−26/−14) as a negative regulatory element to the activity of the human FTO promoter. The USF binding site did not affect the FTO promoter activity. Chromatin immunoprecipitation (ChIP) assays were performed to confirm Foxa2 binding to the FTO promoter. Overexpression of Foxa2 in HEK 293 cells significantly down-regulated FTO promoter activity and expression. Conversely, knockdown of Foxa2 by siRNA significantly up-regulated FTO expression. These findings suggest that Foxa2 negatively regulates the basal transcription and expression of the human FTO gene.
doi:10.1371/journal.pone.0051082
PMCID: PMC3517585  PMID: 23236435
16.  Genetic variant in fat mass and obesity-associated gene associated with type 2 diabetes risk in Han Chinese 
BMC Genetics  2013;14:86.
Background
Genome-wide association study (GWAS) has identified that rs8050136 C/A polymorphism in fat mass and obesity-associated gene (FTO) was associated with the risk of type 2 diabetes (T2D) in Europeans. But this association was abolished after adjustment for body mass index (BMI), suggesting that the effect of rs8050136 on T2D risk might be mediated by BMI in Europeans. However, the findings in subsequent studies were inconsistent among Asian populations. To determine whether rs8050136 polymorphism in FTO is independently associated with the risk of T2D in Chinese, we conducted a case–control study with 2,925 T2D patients and 3,281 controls in Han Chinese.
Results
Logistic regression revealed that the A allele of rs8050136 was significantly associated with an increased risk of T2D, independent of BMI (odds ratio (OR) = 1.17, 95% confidence interval (95% CI) = 1.03-1.32, p = 0.016). Meta-analysis containing 10 reported studies and our data with a total of 15,819 cases and 18,314 controls further confirmed the association between rs8050136 polymorphism and T2D risk in East Asians (OR = 1.13, 95% CI = 1.07-1.19).
Conclusions
Our findings indicate that the genetic variant in FTO may contribute to T2D risk in Han Chinese and rs8050136 polymorphism may be a genetic marker for T2D susceptibility.
doi:10.1186/1471-2156-14-86
PMCID: PMC3848839  PMID: 24053193
Fat mass and obesity-associated Gene; Genome-wide association study; Genetic susceptibility; Single nucleotide polymorphism; Type 2 diabetes
17.  A multilevel linear mixed model of the association between candidate genes and weight and body mass index using the Framingham longitudinal family data 
BMC Proceedings  2009;3(Suppl 7):S115.
Obesity has become an epidemic in many countries and is one of the major risk conditions for disease including type 2 diabetes, coronary heart disease, stroke, dyslipidemia, and hypertension. Recent genome-wide association studies have identified two genes (FTO and near MC4R) that were unequivocally associated with body mass index (BMI) and obesity. For the Genetic Analysis Workshop 16, data from the Framingham Heart Study were made available, including longitudinal anthropometric and metabolic traits for 7130 Caucasian individuals over three generations, each with follow-up data at up to four time points. We explored the associations between four single-nucleotide polymorphisms (SNPs) on FTO (rs1121980, rs9939609) or near MC4R (rs17782313, rs17700633) with weight and BMI under an additive model. We applied multilevel linear mixed model for continuous outcomes, using the Affymetrix 500k genome-wide genotype data for the four SNPs. The results of the multilevel modeling in the entire sample indicated that the minor alleles of the four SNPs were associated with higher weight and higher BMI. The most significant associations were between rs9939609 and weight (p = 4.7 × 10-6) and BMI (p = 8.9 × 10-8). The results also showed that, for SNPs at FTO, the homozygotes for the minor allele had the most pronounced increase in weight and BMI, while the common allele homozygotes gained less weight and BMI during the follow-up period. Linkage disequilibrium (LD) between the two FTO SNPs was strong (D' = 0.997, r2 = 0.875) but their haplotype was not significantly associated with either weight or BMI. The two SNPs near MC4R were in weak LD (D' = 0.487, r2 = 0.166).
PMCID: PMC2795887  PMID: 20017980
18.  Association Analysis of the FTO Gene with Obesity in Children of Caucasian and African Ancestry Reveals a Common Tagging SNP 
PLoS ONE  2008;3(3):e1746.
Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI≥95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r2 = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08–1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91–1.21; P = 0.49) and of 1.31 (95% CI 1.050–1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact.
doi:10.1371/journal.pone.0001746
PMCID: PMC2262153  PMID: 18335027
19.  Common Variants of FTO Are Associated with Childhood Obesity in a Cross-Sectional Study of 3,126 Urban Indian Children 
PLoS ONE  2012;7(10):e47772.
Background
FTO variants are robustly associated with obesity and related traits in many population and shown to have variable impact during life course. Although studies have shown association of FTO variants with adiposity in adult Indian, its association in Indian children is yet to be confirmed.
Methods
Here we examined association of FTO variants (rs9939609 and rs8050136) with obesity and related anthropometric and biochemical traits in 3,126 Indian children (aged 11–17 years) including 2,230 normal-weight and 896 over-weight/obese children. We also compared effects observed in the present study with that observed in previous studies on South Asian adults and children of other ethnic groups.
Results
The variant rs9939609 showed significant association with risk of obesity [OR = 1.21, P = 2.5×10−3] and its measures BMI, weight, waist circumference and hip circumference [β range = 0.11 to 0.14 Z-score units; P range = 1.3×10−4 to 1.6×10−7] in children. The observed effect sizes in Indian children were similar to those reported for European children. Variant rs9939609 explained 0.88% of BMI variance in Indian children. The effect sizes of rs9939609 on BMI and WC were ∼2 fold higher in children than adults. Interestingly rs9939609 was also associated with serum levels of thyroid stimulating hormone (TSH) [β = 0.10 Z-score, P = 5.8×10−3]. The other variant rs8050136 was in strong linkage disequilibrium with rs9939609 (r2 = 0.97) and provided similar association results.
Conclusion
The study provides first report of association of FTO variants with obesity and related anthropometric traits in Indian children with higher impact in children compared to adults. We also demonstrated association of FTO variant with serum levels of TSH, indicating putative influence of FTO in hypothalamic-pituitary-thyroid axis.
doi:10.1371/journal.pone.0047772
PMCID: PMC3472993  PMID: 23091647
20.  Common Variation in the Fat Mass and Obesity-Associated (FTO) Gene Confers Risk of Obesity and Modulates BMI in the Chinese Population 
Diabetes  2008;57(8):2245-2252.
OBJECTIVE— Genetic variants in the fat mass and obesity-associated (FTO) gene have been linked with obesity and type 2 diabetes in European populations. We aimed to test the role of FTO genetic variants in obesity and type 2 diabetes in the Chinese population.
RESEARCH DESIGN AND METHODS— We genotyped 19 single-nucleotide polymorphisms (SNPs) spanning from the 3′ end of the neighboring RPGRIP1L gene to the 5′ flanking region of the FTO gene. We analyzed their associations with obesity (638 case and 1,610 control subjects), type 2 diabetes (759 case and 784 control subjects), and obesity-related traits in nondiabetic subjects.
RESULTS— Among the 19 SNPs, the rs9939609 A allele was strongly associated with obesity (P = 7.0 × 10−4) and BMI (P = 0.0024) in the Chinese population. The odds ratio for obesity was 2.60 (95% CI 1.24–5.46) (P = 0.011) for the AA genotype and 1.32 (1.05–1.66) (P = 0.018) for the AT genotype compared with the TT genotype. Each additional copy of the rs9936609 A allele was associated with a BMI increase of ∼0.37 kg/m2. The rs9939609 A allele was substantially less common in the Chinese population than in the European population (12.6 vs. 45%). We did not find significant associations of the 19 SNPs with type 2 diabetes or other obesity-related traits.
CONCLUSIONS— Genetic variation in the FTO gene is strongly associated with obesity and BMI in the Chinese population. The risk variant is less common in the Chinese population, but its effect size on BMI is comparable with that in the European population.
doi:10.2337/db08-0377
PMCID: PMC2494679  PMID: 18487448
21.  Risk of Type 2 Diabetes and Obesity Is Differentially Associated with Variation in FTO in Whites and African-Americans in the ARIC Study 
PLoS ONE  2010;5(5):e10521.
Single nucleotide polymorphisms (SNPs) in the fat mass and obesity associated (FTO) gene are associated with body mass index (BMI) in populations of European descent. The FTO rs9939609 variant, first detected in a genome-wide association study of diabetes, conferred an increased disease risk that was abolished after adjustment for BMI, suggesting that the association may be due to variation in adiposity. The relationship between diabetes, four previously identified FTO polymorphisms that span a 19.6-kb genomic region, and obesity was therefore evaluated in the biracial population-based Atherosclerosis Risk in Communities Study with the goal of further refining the association by comparing results between the two ethnic groups. The prevalence of diabetes and obesity (BMI ≥30 kg/m2) was established at baseline, and diabetes was determined by either self-report, a fasting glucose level ≥126 mg/dL, or non-fasting glucose ≥200 mg/dL. There were 1,004 diabetes cases and 10,038 non-cases in whites, and 670 cases and 2,780 non-cases in African-Americans. Differences in mean BMI were assessed by a general linear model, and multivariable logistic regression was used to predict the risk of diabetes and obesity. For white participants, the FTO rs9939609 A allele was associated with an increased risk of diabetes (odds ratio (OR)  = 1.19, p<0.001) and obesity (OR = 1.22, p<0.001) under an additive genetic model that was similar for all of the SNPs analyzed. In African-Americans, only the rs1421085 C allele was a determinant of obesity risk (OR = 1.17, p = 0.05), but was found to be protective against diabetes (OR = 0.79, p = 0.03). Adjustment for BMI did not eliminate any of the observed associations with diabetes. Significant statistical interaction between race and the FTO variants suggests that the effect on diabetes susceptibility may be context dependent.
doi:10.1371/journal.pone.0010521
PMCID: PMC2873943  PMID: 20502638
22.  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
23.  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
24.  Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children 
BMC Medical Genetics  2010;11:136.
Background
Fat-mass and obesity-associated (FTO) gene is a gene located in chromosome region 16q12.2. Genetic variants in FTO are associated with the obesity phenotype in European and Hispanic populations. However, this association still remains controversial in Asian population. We aimed to test the association of FTO genetic variants with obesity and obesity-related metabolic traits among children living in Beijing, China.
Methods
We genotyped FTO variants rs9939609 in 670 children (332 girls and 338 boys) aged 8-11 years living in Beijing, and analyzed its association with obesity and obesity-related metabolic traits. Overweight and obesity were defined by age- and sex-specific BMI reference for Chinese children. Obesity-related metabolic traits included fasting plasma glucose, lipid profiles, leptin, ghrelin, adiponectin and blood pressures.
Results
The frequency of rs9939609 A allele was 12.2%, which was 21.9% for the heterozygote and 1.2% for the homozygote of the A allele. The obesity prevalence among the carriers of AA/AT genotypes was significantly higher than that among those with TT genotype (36.4% vs. 22.6%, P = 0.004). Compared to the carrier of TT genotype, the likelihood of obesity was 1.79 (95% confidence interval (95% CI) 1.20-2.67, P = 0.004) for the carrier of AA/AT genotype, after adjustment of sex, age and puberty stages. The BMI Z-score of children with AA/AT genotype were significantly higher than that of their counterparts with the TT genotype (1.1 ± 0.1 vs. 0.8 ± 0.1, P = 0.02). The concentration of triglyceride was 1.03 ± 0.52 mmol/L among TT carrier and 1.13 ± 0.68 mmol/L among AA/AT carrier (P = 0.045). While, the concentrations of adiponectin were 18.0 ± 0.4 μg/ml among carriers of TT and 16.2 ± 0.7 μg/ml among subjects with AA/AT genotype (P = 0.03). The level of glucose marginally increased in the AA/AT genotype subjects (4.67 ± 0.40 mmol/L vs. 4.60 ± 0.35 mmol/L, P = 0.08). The evidence of association was reduced after adjustment for BMI (P = 0.38 for triglyceride, P = 0.20 for adiponectin and glucose). There was weak evidence of association between rs9939609 and other obesity-related metabolic traits including total cholesterol (3.92 ± 0.03 mmol/L vs. 4.02 ± 0.05 mmol/L, P = 0.10), insulin (2.69 ± 1.77 ng/ml vs. 3.12 ± 2.91 ng/ml, P = 0.14), and insulin resistance (HOMA-IR 0.56 ± 0.03 vs. 0.66 ± 0.05, P = 0.10).
Conclusions
Genetic variation in the FTO gene associates with obesity in Chinese children.
doi:10.1186/1471-2350-11-136
PMCID: PMC2955568  PMID: 20858286
25.  An Obesity-Related FTO Variant and the Risk of Preeclampsia in a Finnish Study Population 
Journal of Pregnancy  2011;2011:251470.
Previous studies have demonstrated a common variant of the obesity and fat mass-related FTO gene, rs9939609, to be associated with obesity, type 2 diabetes, and elevated blood pressure. We investigated whether the FTO SNP rs9939609 is associated with the risk of preeclampsia (PE) in a Finnish study population. 485 women with prior PE and 449 women who had given birth after a normotensive pregnancy were genotyped (TaqMan) for the SNP rs9939609. The prevalences of genotypes AA, AT, and TT were 15%, 53%, and 32%, respectively, among the PE cases, and 16%, 47%, and 37%, respectively, among the controls (P = 0.199). We found no evidence of an association between the FTO SNP rs9939609 and PE. However, our cases were dominated by severe, early-onset PE. Thus, we are unable to exclude an association with the milder, later-onset form of the disease in which the role of maternal metabolic predisposition could be more significant.
doi:10.1155/2011/251470
PMCID: PMC3216321  PMID: 22132335

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