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1.  Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys 
Journal of Medical Genetics  2005;42(4):e21.
Background: The melanocortin-4-receptor gene (MC4R) is part of the melanocortinergic pathway that controls energy homeostasis. In a recent meta-analysis, the MC4R V103I (rs2229616) polymorphism was shown to be associated with body weight regulation. Although no functional differences between the isoleucine comprising receptor and the wild type receptor have been detected as yet, this meta-analysis of 14 case–control studies reported a mild negative association with obesity (odds ratio (OR) 0.69, p = 0.03). However, evidence in a large population based study in a homogeneous population and a significant estimate of the change in quantitative measures of obesity is still lacking.
Methods: We analysed the data of two surveys of a white population with the same high quality study protocol, giving a total of 7937 participants.
Results: By linear regression, we found a significant decrease of 0.52 body mass index (BMI) units (95% confidence interval (CI) –0.02 to –1.03, p = 0.043) for carriers of the heterozygote rs2229616G/A genotype, which was observed in 3.7% of the participants. Logistic regression yielded a significantly negative association of the MC4R variant with "above average weight" (BMI ⩾ median BMI) yielding an OR of 0.75 (95% CI 0.59 to 0.95 p = 0.017). We obtained similar results comparing obese (BMI ⩾30 kg/m2, World Health Organization results for 1997) with non-obese (BMI <30 kg/m2) participants. The results were found for both sexes and each survey separately, and did not depend on the modelling of age, sex, or survey effects.
Conclusions: Our study confirms previous findings of a meta-analysis that the relatively infrequent G/A genotype of the V103I MC4R polymorphism is negatively associated with above average weight and obesity in population based original data of 7937 participants, and extends previous findings by showing for the first time a significantly lower BMI in individuals carrying the infrequent allele of this MC4R variant.
PMCID: PMC1736034  PMID: 15805150
2.  Association between Common Polymorphism near the MC4R Gene and Obesity Risk: A Systematic Review and Meta-Analysis 
PLoS ONE  2012;7(9):e45731.
Genome-wide association studies on Europeans have shown that two polymorphisms (rs17782313, rs12970134) near the melanocortin 4 receptor (MC4R) gene were associated with increased risk of obesity. Subsequently studies among different ethnic populations have shown mixed results with some confirming and others showing inconsistent results, especially among East Asians and Africans. We performed a comprehensive meta-analysis of various studies from different ethnic populations to assess the association of the MC4R polymorphism with obesity risk.
We retrieved all published literature that investigated association of MC4R variants with obesity from PubMed and Embase. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model.
A total of 61 studies (80,957 cases/220,223 controls) for rs17782313 polymorphism (or proxy) were included in the meta-analysis. The results suggested that rs17782313 polymorphism was significantly associated with obesity risk (OR = 1.18, 95%CI = 1.15–1.21, p<0.001). Similar trends were observed among subgroups of Europeans and East Asians, adults and children, studies with high quality score, and for each five MC4R polymorphisms independently.
The present meta-analysis confirms the significant association of MC4R polymorphism with risk of obesity. Further studies should be conducted to identify the causal variant and the underlying mechanisms of the identified association.
PMCID: PMC3458070  PMID: 23049848
3.  Meta-analysis on the effect of the N363S polymorphism of the glucocorticoid receptor gene (GRL) on human obesity 
BMC Medical Genetics  2006;7:50.
Since both excess glucocorticoid secretion and central obesity are clinical features of some obese patients, it is worthwhile to study a possible association of glucocorticoid receptor gene (GRL) variants with obesity. Previous studies have linked the N363S variant of the GRL gene to increased glucocorticoid effects such as higher body fat, a lower lean-body mass and a larger insulin response to dexamethasone. However, contradictory findings have been also reported about the association between this variant and obesity phenotypes. Individual studies may lack statistical power which may result in disparate results. This limitation can be overcome using meta-analytic techniques.
We conducted a meta-analysis to assess the association between the N363S polymorphism of the GRL gene and obesity risk. In addition to published research, we included also our own unpublished data -three novel case-control studies- in the meta-analysis The new case-control studies were conducted in German and Spanish children, adolescents and adults (total number of subjects: 1,117). Genotype was assessed by PCR-RFLP (Tsp509I). The final formal meta-analysis included a total number of 5,909 individuals.
The meta-analysis revealed a higher body mass index (BMI) with an overall estimation of +0.18 kg/m2 (95% CI: +0.004 to +0.35) for homo-/heterozygous carriers of the 363S allele of the GRL gene in comparison to non-carriers. Moreover, differences in pooled BMI were statistically significant and positive when considering one-group studies from the literature in which participants had a BMI below 27 kg/m2 (+ 0.41 kg/m2 [95% CI +0.17 to +0.66]), but the differences in BMI were negative when only our novel data from younger (aged under 45) and normal weight subjects were pooled together (-0.50 kg/m2 [95% CI -0.84 to -0.17]). The overall risk for obesity for homo-/heterozygous carriers of the 363S allele was not statistically significant in the meta-analysis (pooled OR = 1.02; 95% CI: 0.56–1.87).
Although certain genotypic effects could be population-specific, we conclude that there is no compelling evidence that the N363S polymorphism of the GRL gene is associated with either average BMI or obesity risk.
PMCID: PMC1481544  PMID: 16725041
4.  Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study 
Human Molecular Genetics  2009;18(18):3496-3501.
Recently, the rs6232 (N221D) and rs6235 (S690T) SNPs in the PCSK1 gene were associated with obesity in a meta-analysis comprising more than 13 000 individuals of European ancestry. Each additional minor allele of rs6232 or rs6235 was associated with a 1.34- or 1.22-fold increase in the risk of obesity, respectively. So far, only one relatively small study has aimed to replicate these findings, but could not confirm the association of the rs6235 SNP and did not study the rs6232 variant. In the present study, we examined the associations of the rs6232 and rs6235 SNPs with obesity in a population-based cohort consisting of 20 249 individuals of European descent from Norfolk, UK. Logistic regression and generalized linear models were used to test the associations of the risk alleles with obesity and related quantitative traits, respectively. Neither of the SNPs was significantly associated with obesity, BMI or waist circumference under the additive genetic model (P > 0.05). However, we observed an interaction between rs6232 and age on the level of BMI (P = 0.010) and risk of obesity (P = 0.020). The rs6232 SNP was associated with BMI (P = 0.021) and obesity (P = 0.022) in the younger individuals [less than median age (59 years)], but not among the older age group (P = 0.81 and P = 0.68 for BMI and obesity, respectively). In conclusion, our data suggest that the PCSK1 rs6232 and rs6235 SNPs are not major contributors to common obesity in the general population. However, the effect of rs6232 may be age-dependent.
PMCID: PMC2729665  PMID: 19528091
5.  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.
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.
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
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
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
PMCID: PMC3206047  PMID: 22069379
6.  Replication and Meta-analysis of the Gene-Environment Interaction between Body Mass Index and the Interleukin-6 Promoter Polymorphism with Higher Insulin Resistance 
Insulin resistance (IR) is a complex disorder caused by an interplay of both genetic and environmental factors. Recent studies identified a significant interaction between body mass index (BMI) and the rs1800795 polymorphism of the Interleukin-6 (IL-6) gene that influences both IR and onset of type 2 diabetes mellitus (T2DM) with obese individuals homozygous for the C allele demonstrating the highest level of IR and greatest risk for T2DM. Replication of a gene-environment interaction is important to confirm the validity of the initial finding and extends the generalizability of the results to other populations. Thus, the objective of this study was to replicate this gene-environment interaction on IR in a hypertensive population and perform a meta-analysis with prior published results.
Material and Methods
The replication analysis was performed using Caucasian individuals with hypertension (HTN) from the HyperPATH cohort (N=311), genotyped for rs1800795. Phenotype studies were conducted after participants consumed two diets: high sodium (HS) (200mmol/day) and low sodium (LS) (10mmol/day) for 7 days each. Measurements for plasma glucose, insulin, and IL-6 were obtained after 8 hours of fasting. IR was characterized by the homeostatic model assessment (HOMA-IR).
In HyperPATH, BMI was a significant effect modifier of the relationship between rs1800795 and HOMA-IR; higher BMI was associated with higher HOMA-IR among homozygote CC individuals when compared to major allele G carriers (p=0.003). Further, the meta-analysis in 1028 individuals confirmed the result demonstrating the same significant interaction between rs1800795 and BMI on HOMA-IR (p=1.05×10−6).
This rare replication of a gene-environment interaction extends the generalizability of the results to HTN while highlighting this polymorphism as a marker of IR in obese individuals.
PMCID: PMC3461261  PMID: 22075267
Interleukin-6 gene; Hypertension; Obesity; Insulin Resistance
7.  Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees 
Diabetes  2008;57(9):2511-2518.
OBJECTIVE— Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.
RESEARCH DESIGN AND METHODS— We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations.
RESULTS— Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 × 10−10). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years).
CONCLUSIONS— We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an “obesogenic” environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.
PMCID: PMC2518504  PMID: 18559663
8.  Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design? 
PLoS Genetics  2009;5(10):e1000694.
The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.
Author Summary
A polymorphism of the INSIG2 gene was identified as being associated with obesity in one of the first genome-wide association studies. However, this association has since then been highly debated upon inconsistent subsequent reports. We collected association information from 34 studies including a total of 74,000 participants. In a meta-analysis of the 27 studies including 66,000 Caucasian adults, we found no overall association of this polymorphism rs7566605 with obesity, comparing subjects with a body-mass-index (BMI)≥30 kg/m2 with normal BMI subjects (BMI<30 kg/m2). Our data suggested an association of this polymorphism with extreme obesity (e.g., BMI≥37.5 kg/m2) compared to normal controls. Such an association with extreme obesity might induce heterogeneous effects from different study designs depending on the proportion of extreme obesity included by the design. However, further studies would be required to substantiate this finding. The importance of study design might be under-recognized in gene discovery and association replication so far.
PMCID: PMC2757909  PMID: 19851442
9.  Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups 
PLoS Genetics  2010;6(4):e1000916.
Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
Author Summary
Genome-wide association studies (GWAS) have successfully contributed to the detection of genetic variants involved in body-weight regulation. We jointly analysed two GWAS for early-onset extreme obesity in 2,258 individuals of European origin and followed-up the findings in 3,141 individuals. Evidence for association of markers in two new genetic loci was shown (SDCCAG8 on chromosome 1q43–q44 and between TNKS/MSRA on chromosome 8p23.1). We also re-identified variants in or near FTO, MC4R, and TMEM18 to be associated with extreme obesity. In addition, we assessed the effect of the markers in 31,182 obese, lean, normal weight, and unselected individuals from population-based samples and showed that the variants near FTO, MC4R, TMEM18, and SDCCAG8 were consistently associated with obesity. For variants of TNKS/MSRA, the obesity association was limited to children and adolescents. In summary, we detected two new obesity loci and confirmed that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
PMCID: PMC2858696  PMID: 20421936
10.  Association between Variants of the Leptin Receptor Gene (LEPR) and Overweight: A Systematic Review and an Analysis of the CoLaus Study 
PLoS ONE  2011;6(10):e26157.
Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex.
Methodology/Principal Findings
We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions.
Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.
PMCID: PMC3196514  PMID: 22028824
11.  Mutation screen and association studies for the fatty acid amide hydrolase (FAAH) gene and early onset and adult obesity 
BMC Medical Genetics  2010;11:2.
The orexigenic effects of cannabinoids are limited by activation of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH). The aim of this study was to analyse whether FAAH alleles are associated with early and late onset obesity.
We initially assessed association of five single nucleotide polymorphisms (SNPs) in FAAH with early onset extreme obesity in up to 521 German obese children and both parents. SNPs with nominal p-values ≤ 0.1 were subsequently analysed in 235 independent German obesity families. SNPs associated with childhood obesity (p-values ≤ 0.05) were further analysed in 8,491 adult individuals of a population-based cohort (KORA) for association with adult obesity. One SNP was further analysed in 985 German obese adults and 588 normal and underweight controls. In parallel, we screened the FAAH coding region for novel sequence variants in 92 extremely obese children using single-stranded-conformation-polymorphism-analysis and denaturing HPLC and assessed the implication of the identified new variants for childhood obesity.
The trio analysis revealed some evidence for an association of three SNPs in FAAH (rs324420 rs324419 and rs873978) with childhood obesity (two-sided p-values between 0.06 and 0.10). Although analyses of these variants in 235 independent obesity families did not result in statistically significant effects (two-sided p-values between 0.14 and 0.75), the combined analysis of all 603 obesity families supported the idea of an association of two SNPs in FAAH (rs324420 and rs2295632) with early onset extreme obesity (p-values between 0.02 and 0.03). No association was, however, found between these variants and adult obesity. The mutation screen revealed four novel variants, which were not associated with early onset obesity (p > 0.05).
As we observed some evidence for an association of the FAAH variants rs2295632 rs324420 with early onset but not adult obesity, we conclude that the FAAH variants analyzed here at least do not seem to play a major role in the etiology of obesity within our samples.
PMCID: PMC2830932  PMID: 20044928
12.  Frequencies of obesity susceptibility alleles among ethnically and racially diverse bariatric patient populations 
Genetic factors likely play a role in obesity and the outcomes after bariatric surgery. Single nucleotide polymorphisms in or near the insulin-induced gene 2 (INSIG-2), fat mass and obesity-associated gene (FTO), melanocortin 4 receptor gene (MC4R), and proprotein convertase subtilisn/kexin type 1 gene (PCSK-1) have been associated with class III obesity in whites. Minimal data are available regarding the genetic susceptibility to obesity in class III obese nonwhites, especially Hispanics. Our objective was to perform a comparative analysis of 4 common genetic variants (INSIG-2, FTO, MC4R, and PCSK-1) associated with obesity in a diverse population of bariatric surgery patients to determine whether a difference exists by ethnicity (white versus Hispanic). The setting of the study was 2 university hospitals in the United States.
Bariatric surgery patients from 2 different institutions were enrolled prospectively, and genotyping was performed. Differences in the distribution of INSIG-2, FTO, MC4R, and PCSK-1 single nucleotide polymorphisms among the different ethnicities (whites and Hispanics) were compared using an additive model (0, 1, or 2 risk alleles). A propensity-matched analysis was used to account for cohort differences.
A total of 1276 bariatric patients were genotyped for the INSIG-2, FTO, MC4R, and PCSK-1 obesity single nucleotide polymorphisms. Statistically significant differences in FTO, INSIG-2, MC4R, and PCSK-1 were seen using an additive model. FTO, PCSK-1, and MC4R (test for trend) remained significantly different in the propensity analysis.
Significant differences in the frequencies of several common obesity susceptibility variants in or near FTO, PCSK-1, and MC4R were found in white and Hispanic patients with class III obesity undergoing bariatric surgery. Larger studies in more class III obese Hispanics of different nationalities are needed.
PMCID: PMC3685296  PMID: 22695173
Obesity; Genes; Genetics; Hispanics; Genotyping; Alleles; Frequency; Bariatric surgery
13.  A salmonid EST genomic study: genes, duplications, phylogeny and microarrays 
BMC Genomics  2008;9:545.
Salmonids are of interest because of their relatively recent genome duplication, and their extensive use in wild fisheries and aquaculture. A comprehensive gene list and a comparison of genes in some of the different species provide valuable genomic information for one of the most widely studied groups of fish.
298,304 expressed sequence tags (ESTs) from Atlantic salmon (69% of the total), 11,664 chinook, 10,813 sockeye, 10,051 brook trout, 10,975 grayling, 8,630 lake whitefish, and 3,624 northern pike ESTs were obtained in this study and have been deposited into the public databases. Contigs were built and putative full-length Atlantic salmon clones have been identified. A database containing ESTs, assemblies, consensus sequences, open reading frames, gene predictions and putative annotation is available. The overall similarity between Atlantic salmon ESTs and those of rainbow trout, chinook, sockeye, brook trout, grayling, lake whitefish, northern pike and rainbow smelt is 93.4, 94.2, 94.6, 94.4, 92.5, 91.7, 89.6, and 86.2% respectively. An analysis of 78 transcript sets show Salmo as a sister group to Oncorhynchus and Salvelinus within Salmoninae, and Thymallinae as a sister group to Salmoninae and Coregoninae within Salmonidae. Extensive gene duplication is consistent with a genome duplication in the common ancestor of salmonids. Using all of the available EST data, a new expanded salmonid cDNA microarray of 32,000 features was created. Cross-species hybridizations to this cDNA microarray indicate that this resource will be useful for studies of all 68 salmonid species.
An extensive collection and analysis of salmonid RNA putative transcripts indicate that Pacific salmon, Atlantic salmon and charr are 94–96% similar while the more distant whitefish, grayling, pike and smelt are 93, 92, 89 and 86% similar to salmon. The salmonid transcriptome reveals a complex history of gene duplication that is consistent with an ancestral salmonid genome duplication hypothesis. Genome resources, including a new 32 K microarray, provide valuable new tools to study salmonids.
PMCID: PMC2628678  PMID: 19014685
14.  Copy number variations associated with obesity related traits in African Americans: a joint analysis between GENOA and HyperGEN 
Obesity (Silver Spring, Md.)  2012;20(12):2431-2437.
Obesity is a highly heritable trait and a growing public health problem. African Americans are a genetically diverse, yet understudied population with a high prevalence of obesity (body mass index (BMI) greater than 30 kg/m2). Recent studies based upon single nucleotide polymorphisms (SNPs) have identified genetic markers associated with obesity. However, a large proportion of the heritability of obesity remains unexplained. Copy number variation (CNV) has been cited as a possible source of missing heritability in common diseases such as obesity. We conducted a CNV genome-wide association study of BMI in two African American cohorts from GENOA and HyperGEN. We performed independent and identical association analyses in each study, then combined the results in a meta-analysis. We identified three CNVs associated with BMI, obesity, and other obesity-related traits after adjusting for multiple testing. These CNVs overlap the PARK2, GYPA and SGCZ genes. Our results suggest that CNV may play a role in the etiology of obesity in African Americans.
PMCID: PMC3484176  PMID: 22836685
Obesity; CNVs; Meta-analysis; BMI; African Americans
15.  Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity 
Journal of Clinical Investigation  2000;106(2):253-262.
By integrating an agonist satiety signal, provided by alpha–melanocyte-stimulating hormone (α-MSH), and an antagonist signal, provided by agouti-related protein (AGRP), the melanocortin-4 receptor (MC4-R) is a key element in the hypothalamic control of food intake. Inactivation of the gene encoding this G protein–coupled receptor causes obesity in mice. In humans, frameshift mutations in MC4-R cause an early-onset dominant form of obesity in two families. In this study we find a high frequency (4%) of rare heterozygous MC4-R mutations in a large population of morbidly obese patients. No such mutations were found in controls. By analyzing the phenotypes of the probands carrying these mutations, we demonstrate that these patients display a common, nonsyndromic form of obesity. Interestingly, functional analysis of the mutant receptors indicates that obesity-associated defects in MC4-R range from loss of function to constitutive activation. Transmission of these mutations in the families of the carriers indicates a variable expressivity that is not related to the functional severity of the mutations. This variable expressivity of MC4-R–associated obesity is not due to variations in genes for α-MSH or AGRP. Taken together, these results demonstrate that MC4-R mutations are a frequent but heterogeneous genetic cause of morbid obesity.
PMCID: PMC314306  PMID: 10903341
16.  Association of the melanocortin-4 receptor V103I polymorphism with dietary intake in severely obese individuals 
Several studies have reported that carriers of the 103I allele of the MC4R gene had lower body weight when compared to the wild-type genotype. A recent study found an association of the MC4R 103I variant with carbohydrate intake which possibly mediates some of the association of this variant with leanness.
The purpose of our study was to investigate the association between the MC4R V103I polymorphism and dietary intake derived by the Willett food frequency questionnaire in individuals with severe obesity.
The MC4R V103I polymorphism was genotyped in a group of 1029 severely obese white subjects with an average BMI of 46.0 kg/m² (range 33–92 kg/m²).
Carriers of the 103I allele showed a significantly higher daily energy (+364 kcal/day or +19%, p=0.03) and carbohydrate intake (+57 g/day or +27%, p=0.01), but there was no relationship with BMI. No notable association of this polymorphism with lipid and glucose parameters of the metabolic syndrome was observed as indicated in a previous study.
The higher dietary intake of carbohydrates in severely obese individuals with the MC4R 103I variant is in line with previous findings and might indicate a differential consequence on body size measures in extremely obese subjects when compared to the general population.
PMCID: PMC3246117  PMID: 18779298
melanocortin-4 receptor (MC4R); genetic association; obesity; lipoprotein metabolism; dietary intake
17.  Genome Wide Association (GWA) Study for Early Onset Extreme Obesity Supports the Role of Fat Mass and Obesity Associated Gene (FTO) Variants 
PLoS ONE  2007;2(12):e1361.
Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.
Methodology/Principal Findings
a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency ≥10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13×10−7, corrected p = 0.0494; odds ratio (OR)CT 1.67, 95% confidence interval (CI) 1.22–2.27; ORTT 2.76, 95% CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.
Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.
PMCID: PMC2137937  PMID: 18159244
18.  UCP2 -866G/A, Ala55Val and UCP3 -55C/T Polymorphisms in Association with Obesity Susceptibility — A Meta-Analysis Study 
PLoS ONE  2013;8(4):e58939.
Variants of UCP2 and UCP3 genes have been reported to be associated with obesity, but the available data on the relationship are inconsistent. A meta-analysis was performed to determine whether there are any associations between the UCP2 -866G/A, Ala55Val, and UCP3 -55C/T polymorphisms and obesity susceptibility.
The PubMed, Embase, Web of Science and CNKI, CBMdisc databases were searched for all relevant case-control studies. The fixed or random effect pooled measure was determined on the bias of heterogeneity test among studies. Publication bias was examined by the modified Begg's and Egger's test.
Twenty-two published articles with thirty-two outcomes were included in the meta-analysis: 12 studies with a total of 7,390 cases and 9,860 controls were analyzed for UCP2 -866G/A polymorphism with obesity, 9 studies with 1,483 cases and 2,067 controls for UCP2 Ala55Val and 8 studies with 2,180 cases and 2,514 controls for UCP3 -55C/T polymorphism. Using an additive model, the UCP2 -866G/A polymorphism showed no significant association with obesity risk in Asians (REM OR = 0.81, 95% CI: 0.65–1.01). In contrast, a statistically significant association was observed in subjects of European descent (FEM OR = 1.06, 95% CI: 1.01–1.12). But neither the UCP2 Ala55Val nor the UCP3 -55C/T polymorphism showed any significant association with obesity risk in either subjects of Asian (REM OR = 0.84, 95% CI: 0.67–1.06 for Ala55Val; REM OR = 0.94, 95% CI: 0.55–1.28 for -55C/T) or of European descent (REM OR = 1.04, 95% CI: 0.80-1.36 for Ala55Val; FEM OR = 1.08, 95% CI: 0.97–1.20 for -55C/T).
Conclusions and Interpretation
Our meta-analysis revealed that the UCP2 -866G/A polymorphism may be a risk factor for susceptibility to obesity in subjects of European descent, but not in individuals of Asian descent. And our results did not support the association between UCP2 Ala55Val, UCP3 -55C/T polymorphisms and obesity in the populations investigated. This conclusion warrants confirmation by further studies.
PMCID: PMC3613358  PMID: 23560041
19.  Strong Association of 677 C>T Substitution in the MTHFR Gene with Male Infertility - A Study on an Indian Population and a Meta-Analysis 
PLoS ONE  2011;6(7):e22277.
Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies.
Methodology/Principal Findings
We undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522) and confirmed fertile (N = 315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included ‘Pubmed’, ‘Ovid’ and ‘Google Scholar’. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p = 0.0025) and genotypes (CT+TT) (p = 0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p = 0.000), 1.310 (p = 0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility.
677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.
PMCID: PMC3140509  PMID: 21799811
20.  Association of apolipoprotein B XbaI gene polymorphism and lipid profile in northern Indian obese 
Over the last few decades, obesity, diabetes, and hypertension have become main health evils. The health problems of obesity are well-recognized. However, the fact that all obese individuals are not at the same risk of developing a disease is also recognized. The apolipoprotein B (APOB) plays a central role in lipid metabolism. So we compare the association of APOB XbaI gene polymorphism and lipid profile total in obese north Indian population.
A total of 132 obese (body mass index [BMI] >25 kg/m2) and 132 age matched non-obese (BMI ≤ 25 kg/m2) subjects were studied after taking detailed clinical profile. Lipid profile in serum/plasma was done using commercial kits. Genetic analysis of APOB XbaI was done using Polymerase Chain Reaction-Restriction Fragment Leanth polymorphism (PCR-RFLP).
Statistical analysis was performed by Statistical Package for the Social Sciences (SPSS) (version 11.5) software (IBM Corporation). All continuous variables were expressed as mean ± SD and tested by analysis of variance test. Comparisons of categorical variables were assessed using χ2 tests or Fisher's exact test. P < 0.05 was considered as significant.
Analysis showed that obese subjects had significantly higher value of the waist-to-hip ratio, blood pressure (systolic and diastolic), and lipid profile. In APOB XbaI gene polymorphism, we did not find significant differences in genotype or allele frequencies. Moreover, none of the studied metabolic parameters (lipid profile) showed any association with the gene polymorphism.
Study reveals no considerable association of APOB XbaI gene polymorphism with obesity and lipid profile in north Indians.
PMCID: PMC3722626  PMID: 23901190
Body mass index; lipid profile; obesity; polymorphism
21.  Association of Lung Function with Cognitive Decline and Dementia: The Atherosclerosis Risk in Communities (ARIC) Study 
Previous studies reported a higher risk of cognitive decline and dementia among individuals with impaired lung function. However, many did not adjust for important confounders or did not include women and nonwhites.
We studied 10,975 men and women aged 47–70 (23% African-Americans), enrolled in the Atherosclerosis Risk in Communities Study. Pulmonary function tests and a cognitive assessment, including the Delayed Word Recall, the Digit Symbol Substitution, and the World Fluency Tests, were done in 1990–92. Repeated cognitive assessments were performed in 1996–98 for the entire cohort, and in 1993–95 and 2004–06 in 904 eligible individuals. Dementia hospitalization was ascertained through 2005.
In analysis adjusted for lifestyles, APOE genotype, and cardiovascular risk factors, impaired lung function was associated with worse cognitive function at baseline. No association was found between lung function and cognitive decline over time. Impaired lung function at baseline was associated with higher risk of dementia hospitalization during follow-up, particularly among younger individuals. The hazard ratios (95% confidence intervals) of dementia hospitalization were 1.6 (0.9, 2.8) and 2.1 (1.2, 3.7) comparing the lowest to the highest quartile of forced expiratory volume in 1 second and forced vital capacity, respectively. Presence of a restrictive ventilatory pattern, but not of an obstructive pattern, was associated with reduced cognitive scores and higher dementia risk.
Reduced lung function was associated with worse performance in cognitive assessments and with an increased risk of dementia hospitalization. Future research should determine whether maintaining optimal pulmonary health might prevent cognitive impairment and dementia.
PMCID: PMC3092022  PMID: 21244584
Lung function; cognitive decline; dementia; prospective studies
22.  Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case–control study 
Breast Cancer Research  2004;6(4):R416-R422.
The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations.
We conducted a nested case–control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available.
Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (χ2 = 3.43, five degrees of freedom, P = 0.63).
There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk.
PMCID: PMC468661  PMID: 15217510
ataxia telangiectasia mutated gene; breast cancer; haplotype tagging single nucleotide polymorphisms
23.  Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis 
The gene ANK3 is implicated in bipolar disorder and schizophrenia. The present study investigated the influence of this gene on cognitive performance and brain structure among individuals with first-episode psychosis (FEP). The brief illness duration of an FEP sample makes it well suited for studying the effects of genetic variation.
We genotyped 2 single nucleotide polymorphisms (SNPs; rs1938526 and rs10994336) in ANK3 in patients with FEP. Multivariate analysis of variance compared risk allele carriers and noncarriers on 6 domains of cognition consistent with MATRICS consensus. A subsample of 82 patients was assessed using magnetic resonance imaging. We compared brain structure between carriers and noncarriers using cortical thickness analysis and voxel-based morphometry on white matter.
In the 173 patients with FEP included in our study, rs1938526 and rs10994336 were in very high linkage disequilibrium (d′ = 0.95), and analyses were therefore only carried out on the SNP (rs1938526) with the highest minor allele frequency (G). Allele G of rs1938526, was associated with lower cognitive performance across domains (F6,164 = 2.38, p = 0.030) and significantly lower scores on the domains of verbal memory (p = 0.015), working memory (p = 0.006) and attention (p = 0.019). The significant effects of this SNP on cognition were not maintained when controlling for IQ. Cortical thinning was observed in risk allele carriers at diverse sites across cortical lobes bilaterally at a threshold of p < 0.01, false discovery rate–corrected. Risk-allele carriers did not show any regions of reduced white matter volume.
The sample size is modest given that a low-frequency variant was being examined.
The ANK3 risk allele rs1938526 appears to be associated with general cognitive impairment and widespread cortical thinning in patients with FEP.
PMCID: PMC3868663  PMID: 24016415
24.  A Variant near the Interleukin-6 Gene Is Associated with Fat Mass in Caucasian Men 
Regulation of fat mass appears to be associated with immune functions. Studies of knockout mice show that endogenous interleukin (IL)-6 can suppress mature-onset obesity.
To systematically investigate associations of single nucleotide polymorphisms (SNPs) near the IL-6 (IL6) and IL-6 receptor (IL6R) genes with body fat mass, in support for our hypothesis that variants of these genes can be associated with obesity.
Design and Study Subjects
The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18-20 years old men (n=1 049), from the Gothenburg area (Sweden). Major findings were confirmed in two additional cohorts consisting of elderly men from the Osteoporotic Fractures in Men (MrOS) Sweden (n=2 851) and MrOS US (n=5 611) multicenter population-based studies.
Main Outcome
The genotype distributions and their association with fat mass in different compartments, measured with dual-energy X-ray absorptiometry (DXA).
Out of 18 evaluated tag single nucleotide polymorphisms (SNPs) near the IL6 and IL6R genes, a recently identified SNP rs10242595 G/A [minor allele frequency (MAF) = 29%] 3′ of the IL6 gene was negatively associated with the primary outcome total body fat mass (effect size -0.11 standard deviation (SD) units/A allele, P=0.02). This negative association with fat mass was also confirmed in the combined MrOS Sweden and MrOS US cohorts (effect size -0.05 SD units/A allele; P=0.002). When all three cohorts were combined (n= 8 927, Caucasian subjects), rs10242595*A showed a negative association with total body fat mass (effect size -0.05 SD units/A allele, P<0.0002). Furthermore, the rs10242595*A was associated with low body mass index [(BMI, effect size -0.03, P<0.001)] and smaller regional fat masses. None of the other SNPs investigated in the GOOD study were reproducibly associated with body fat.
The IL6 gene polymorphism rs10242595*A is associated with decreased fat mass in three combined cohorts of 8 927 Caucasian men.
PMCID: PMC2885503  PMID: 20157327
IL6; IL6R; obesity; SNP; rs10242595
25.  The -308G/A of Tumor Necrosis Factor (TNF)-α and 825C/T of Guanidine Nucleotide Binding Protein 3 (GNB3) are Associated with the Onset of Acute Myocardial Infarction and Obesity in Taiwan 
Acute myocardial infarction is a highly prevalent cardiovascular disease in Taiwan. Among several etiological risk factors, obesity and inflammation are strongly associated with the frequency of hypertension, cardiovascular disease, diabetes, and myocardial infarction. To discriminate obesity- and inflammation-related genes and the onset of acute myocardial infarction (AMI), a case-control study was conducted to investigate the association of the -308G/A polymorphisms of tumor necrosis factor (TNF)-α and the C825T polymorphism of guanidine nucleotide binding protein 3 (GNB3) with the onset of AMI among Taiwanese cohorts. A total of 103 AMI patients and 163 matched normal control samples were enrolled in the present study. The genomic DNA was extracted and subjected into polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. An association between the A homozygosity of the TNF-α-308G/A polymorphism and the onset of AMI was observed among the male subjects (p = 0.026; Spearman index = 0.200, p = 0.008). An association between the T homozygosity of GNB3 C825T polymorphism and obesity was also observed (Fisher’s exact, p = 0.009). The TT genotype has a protective effect against acquiring AMI among the obese female population in Taiwan (Fisher’s exact, p = 0.032). In conclusion, TNF-α-308G/A and the GNB3 C825T polymorphisms are associated with obesity and AMI in the Taiwanese population.
PMCID: PMC3291997  PMID: 22408428
acute myocardial infarction; gene polymorphisms; GNB-3; TNF-alpha

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