FTO polymorphisms are associated with obesity but not diabetes risk in postmenopausal women

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/m(2) 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.     

Association of the FTO gene with BMI

Variants in the FTO gene have been strongly associated with obesity in a very large sample (38,759) of diabetic and control subjects. To replicate these findings, the previously reported SNP in the FTO gene (rs9939609, T/A) was genotyped in 5,607 subjects from five different Utah studies. The studies included a random sample of the Utah population, families selected for aggregation of extreme thinness, families selected for severe obesity, a series of unrelated severe obesity subjects, and families participating in a 25-year longitudinal study of cardiovascular disease and aging. Results show a strong significant increase in the rs9939609 A allele frequency with increasing BMI (P < 0.0001). In the longitudinal study, FTO genotypes were significantly associated with BMI at a baseline exam, a 2(1/2)-year follow-up exam and a 25-year follow-up exam using an additive genetic model. The mean genotype difference in BMI ranged from 1.3 to 2.1 kg/m(2) across exams. The genotype difference in BMI means was established in youth, and at-risk subjects under age 20 at baseline had a significantly larger 25-year BMI increase (10.0 for A/A; 9.7 for A/T, and 8.5 kg/m(2) for T/T, P = 0.05). We conclude that the BMI increases associated with FTO genotypes begin in youth and are maintained throughout adulthood.     

Increased prevalence of the CVD-associated ANRIL allele in the Roma/Gypsy population in comparison with the majority Czech population

Cardiovascular disease (CVD) is a major cause of death around the world, with highest prevalence reported in minority Roma/Gypsy populations living in developed countries. Whether these differences are caused by unhealthy lifestyles or genetic factors remain unknown. The aim of our study was to examine the genotype frequencies of the rs10757274 polymorphism in the 9p.21 locus within ANRIL (antisense non-coding RNA in the INK4 locus), a long non-coding RNA located in the vicinity of the CDKN2A/2B inhibitors loci. ANRIL is understood to be the strongest genetic determinant of CVD in Caucasians. Using PCR-RFLP, we analysed the ANRIL rs10757274 polymorphism in 298 non-Roma (50% male) and 302 Roma/Gypsy (50% male) adult (39.5 ± 15.1 years and 39.2 ± 12.8 years, respectively) subjects. We found that frequencies of the ANRIL GG, GA and AA genotypes were 20.1%, 52.4% and 27.5% in the majority population and 32.9%, 47.9% and 19.2% in Roma/Gypsy subjects, respectively. The distribution of genotypes was deemed significantly different at P < 0.001. Within the Roma/Gypsy population, we detected increased prevalence of the CVD-associated GG genotype. Increased prevalence of CVD among Roma/Gypsies subjects may be significantly linked to genetic background.     

The FTO gene and obesity in a large Eastern European population sample: the HAPIEE study

Variants in the FTO (oxoglutarate-dependent nucleic acid demethylase) gene have been associated with the BMI determination in Western European and North American populations. To widen the geographical coverage of the FTO studies, we have analyzed the association between the FTO gene variant rs17817449 (G>C) and obesity in a Slavic Eastern European population. A total of 3,079 males and 3,602 females 45-69 years old were randomly selected from population registers of seven Czech cities. We examined three indices of obesity: BMI (kg/m(2)), waist circumference, and waist-to-hip ratio (WHR). The FTO rs17817449 variant was significantly associated with BMI both in males (GG 28.7 +/- 4.1; GT 28.3 +/- 3.9; TT 28.0 +/- 3.9; P = 0.003) and females (GG 28.7 +/- 5.2; GT 28.2 +/- 5.1; TT 27.2 +/- 4.9; P < 0.001); the associations were not affected by adjustment for age, smoking, socioeconomic status, and physical activity. The FTO variant was also associated with waist circumference (difference between GG and TT was 1.1 cm (P = 0.043) in men and 2.4 cm (P < 0.001) in women) but this relationship disappeared after adjustment for BMI. Similarly, BMI explained the weak association of FTO with WHR and C-reactive protein. FTO was not associated with plasma total and high-density lipoprotein cholesterol, triglycerides, blood glucose, and blood pressure. These results confirm that in a Slavic population the FTO variant is strongly associated with BMI but not with other risk factors.     

Association of the FTO rs9939609 single nucleotide polymorphism with C-reactive protein levels

Adipose tissue is a key factor determining C-reactive protein (CRP) plasma levels. Variation at the fat-mass and obesity-associated (FTO) gene locus has been reported to be associated with increased body fat. We investigated whether the FTO rs9939609 T>A single nucleotide polymorphism might alter CRP levels in a population-based sample of 2,415 participants from a large prospective cohort study. Genotype/phenotype relationships were studied by linear trend analysis stratified by sex. The rs9939609 A-allele was significantly associated with CRP levels in both genders (men, +21%, P = 0.002; women, +14%, P = 0.01 per A-allele). The association was attenuated, but remained statistically significant after additional adjustment for BMI, waist-to-hip ratio, and other potential confounding factors (men, +14%, P = 0.03; women, +12%, P = 0.02; per A-allele). Similar results were obtained when subjects with CRP levels higher then 10 mg/l were excluded. Our data provide preliminary evidence that the FTO rs9939609 T>A polymorphism contributes to variation in plasma CRP levels independently of obesity indices.     

Effects of FTO genotype on weight loss and metabolic risk factors in response to calorie restriction among Japanese women

Effects of gene variants in the fat-mass and obesity-associated (FTO) gene (primarily rs9939609) on weight loss induced by lifestyle intervention are controversial. The aim of this study was to investigate whether FTO gene variations are associated with weight-reduction and changes in metabolic risk factors in response to a 14-week calorie restriction. In total, 204 Japanese women (aged 24-66 years; BMI ≥ 25 kg/m(2)) enrolled as subjects and attended dietary lectures instructing them on how to consume a nutritionally balanced diet of 1,200 kcal/day. Fat mass, both at baseline (P = 0.100) and after the intervention (P = 0.020), was higher in subjects with the AA genotype (n = 15; 7.3%) than in those with TT (n = 114; 55.9%) and TA (n = 75; 36.8%) genotypes. The change in fat-mass tended to be smaller in subjects with the AA genotype than in those with other genotypes (P = 0.065). However, the subjects with the risk allele could still decrease their body weight and improve metabolic risk factors significantly. Our data suggest that the impact of FTO rs9939609 in Japanese women may not be great enough to change body weight or metabolic risk factors in response to calorie restriction. Environmental and behavioral factors may overcome the effects of genes on weight reduction.     

Genome-wide association study of anthropometric traits and evidence of interactions with age and study year in Filipino women

Increased values of multiple adiposity-related anthropometric traits are important risk factors for many common complex diseases. We performed a genome-wide association (GWA) study for four quantitative traits related to body size and adiposity (BMI, weight, waist circumference, and height) in a cohort of 1,792 adult Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). This is the first GWA study of anthropometric traits in Filipinos, a population experiencing a rapid transition into a more obesogenic environment. In addition to identifying suggestive evidence of additional single-nucleotide polymorphism (SNP) association signals (P < 10(-5)), we replicated (P < 0.05, same direction of additive effect) associations previously reported in European populations of both BMI and weight with MC4R and FTO, of BMI with BDNF, and of height with EFEMP1, ZBTB38, and NPPC, but none with waist circumference. We also replicated loci reported in Japanese or Korean populations as associated with BMI (OTOL1) and height (HIST1H1PS2, C14orf145, GPC5). A difference in local linkage disequilibrium (LD) between European and Asian populations suggests a narrowed association region for BDNF, while still including a proposed functional nonsynonymous amino acid substitution variant (rs6265, Val66Met). Finally, we observed significant evidence (P < 0.0042) for age-by-genotype interactions influencing BMI for rs17782313 (MC4R) and rs9939609 (FTO), and for a study year-by-genotype interaction for rs4923461 (BDNF). Our results show that several genetic risk factors are associated with anthropometric traits in Filipinos and provide further insight into the effects of BDNF, FTO, and MC4R on BMI.     

FTO influences on longitudinal BMI over childhood and adulthood and modulation on relationship between birth weight and longitudinal BMI

SNP rs9939609 within the fat mass and obesity associated gene (FTO) is strongly associated with adult body mass index (BMI). However, influences of FTO on longitudinal BMI change from childhood to adulthood have not been examined. Knowledge is limited on FTO, modulating the association between birth weight and longitudinal change of BMI. This longitudinal study examined SNPs of FTO in 658 white subjects from childhood (3–17 years) to adulthood (18–45 years). No significant associations of FTO SNPs with either birth weight or longitudinal BMI over childhood were noted after multiple-test adjustment. However, three SNPs (rs9939609, rs17820875 and rs860713) with different inheritance patterns were identified to be associated with longitudinal BMI over adulthood after Bonferroni adjustment (P = 5.3 × 10⁻⁵, 2.0 × 10⁻⁴ and 0.001). In addition, interactions were discovered between birth weight and SNPs of rs17820875 (P = 0.001) and rs860713 (0.002). A negative association between birth weight and adult BMI were found in risk genotype AG of rs17820875 and GG of rs860713 in contrast to positive associations in other genotypes. These findings led to the conclusion that lower birth weight predisposes to higher adult BMI depending on FTO risk genotypes. Our studies underscore the importance of FTO influences on obesity and provide insights into the evolution of the long-term burden of obesity.     

FTO基因rs9939609 A/T多态与多囊卵巢综合征易感性的研究

目的:探讨FTO基因rs9939609 A/T单核苷酸多态性位点与多囊卵巢综合征易感性及其临床生化特征的相关性。方法:选择102例多囊卵巢综合征患者和96例健康女性作为研究对象并收集其病例临床信息,采用突变敏感性分子开关方法检测各受试者FTO基因rs9939609A/T多态,比较多囊卵巢综合征组与对照组基因型与基因频率的差异,分析基因型与临床生化特征的相关性。结果:rs9939609A/T多态位点共检测到TT、AT、AA三种基因型,其在多囊卵巢综合征组与对照组的频率分别为77.5%、21.5%、1.0%,77.1%12.5%10.4%,两者之间存在显著性差异(P=0.006);等位基因T、A的频率在多囊卵巢综合征组(88.2%、11.8%)与对照组(83.3%、16.7%)之间的分布不具有显著性差异;多囊卵巢综合征组与对照组中,TT与AT+AA两基因型群体的临床和生化特征比较均未发现显著性差异。结论:FTO基因rs9939609 A/T多态位点与PCOS易感性存在相关性。     

The common rs9939609 gene variant of the fat mass- and obesity-associated gene FTO is related to fat cell lipolysis

We investigated the rs9939609 single nucleotide polymorphism of the FTO gene in relation to fat cell function and adipose tissue gene expression in 306 healthy women with a wide range in body mass index (18-53 kg/m(2)). Subcutaneous adipose tissue biopsies were taken for fat cell metabolism studies and in a subgroup (n = 90) for gene expression analyses. In homozygous carriers of the T-allele, the in vitro basal (spontaneous) adipocyte glycerol release was increased by 22% (P = 0.007) and the in vivo plasma glycerol level was increased by approximately 30% (P = 0.037) compared with carriers of the A allele. In contrast, there were no genotype effects on catecholamine-stimulated lipolysis or basal or insulin-induced lipogenesis. We found no difference between genotypes for adipose tissue mRNA levels of FTO, hormone-sensitive lipase, adipose triglyceride lipase, perilipin, or CGI-58. Finally, the adipose tissue level of FTO mRNA was increased in obesity (P = 0.002), was similar in subcutaneous and omental adipose tissue, was higher in fat cells than in fat tissue (P = 0.0007), and was induced at an early stage in the differentiation process (P = 0.004). These data suggest a role of the FTO gene in fat cell lipolysis, which may be important in explaining why the gene is implicated in body weight regulation.     

Frequency distribution and association of Fat-mass and obesity (FTO) gene SNP rs-9939609 variant with Diabetes Mellitus Type-II population of Hyderabad,Sindh, Pakistan

Background/AimDiabetes Mellitus (DM) is one of the important public health issues worldwide. The Fat mass obesity (FTO) gene rs-9939609 variant identified single nucleotide polymorphism (SNP) with the T to A missense mutation, and has a strong association with T2DM. FTO gene is present on chromosome “16q12.2” comprising of nine exons. FTO gene rs-9939609 a variant is commonly found in the Pakistani Population. The purpose of the study was to alert the population about the rs-9939609 variant SNP, having a strong association with T2DM.Material and MethodsTotal of 190 participants were included in the present cross-sectional study. To collect the samples non-probability convenience technique was used. subjects were recruited and divided into three groups, normal healthy subjects, obese and T2DM. The patients were selected from the Medicine department Jamshoro/Hyderabad by filling the pre-designed proforma, as well as verbal and written consent taken from study participants. To analysed the data ANOVA Post hoc (Tukey-test) was applied for comparison among groups (P < 0.05) and “SNP-STAT” online software was used for frequencies.ResultsThe BMI, neck circumference, waist circumference and lipid profile, fasting blood sugar and HbA1c was found significant (p < 0.001) in both genders as compared to control. Homozygous and heterozygous distribution of allelic and genotyping frequency was found in study participants. 37.9 %T/A, 57.4% T/T, and A/A were 4.7%. The FTO gene rs-9939609 variant amplified and have an increased risk of developing T2DM in the Sindh population. Codominant model odd ratio of T/A showed 2.42 (CI)1.23–3.84, with significant p < 0.032.ConclusionThe present study concluded that the FTO gene SNP rs-9939609 variant was found in the population of Hyderabad, Sindh and having strong association with T2DM and obese individuals. Increase BMI, neck and waist circumference are the biomarkers of obesity and causative factors of T2DM.     

Common genetic variants and central adiposity among Asian-Indians

Recent studies have identified common genetic variants that are unequivocally associated with central adiposity, BMI, and/or fasting plasma glucose among individuals of European descent. Our objective was to evaluate these associations in a population of Asian-Indians. We examined 16 single-nucleotide polymorphisms (SNPs) from loci previously linked to waist circumference, BMI, or fasting glucose in 1,129 Asian-Indians from New Delhi and Trivandrum. Trained medical staff measured waist circumference, height, and weight. Fasting plasma glucose was measured from collected blood specimens. Genotype-phenotype associations were evaluated using linear regression, with adjustments for age, gender, religion, and study region. For gene-environment interaction tests, total physical activity (PA) during the past 7 days was assessed by the International Physical Activity Questionnaire (IPAQ). The T allele at the FTO rs3751812 locus was associated with increased waist circumference (per allele effect of +1.58 cm, P(trend) = 0.0015) after Bonferroni adjustment for multiple testing (P(adj) = 0.04). We also found a nominally statistically significant FTO-PA interaction (P(interaction) = 0.008). Among participants with <81 metabolic equivalent (MET)-h/wk of PA, the rs3751812 variant was associated with increased waist size (+2.68 cm; 95% confidence interval (CI) = 1.24, 4.12), but not among those with 212+ MET-h/wk (-1.79 cm; 95% CI = -4.17, 0.58). No other variant had statistically significant associations, although statistical power was modest. In conclusion, we confirmed that an FTO variant associated with central adiposity in European populations is associated with central adiposity among Asian-Indians and corroborated prior reports indicating that high PA attenuates FTO-related genetic susceptibility to adiposity.     

Interactions of anthropometric indices,rs9939609 FTO gene polymorphism and breast cancer: A case-control study

Contradictory results were reported on the effect of fat mass- and obesity-associated (FTO) gene and anthropometric measurements on breast cancer (BC). This study aimed to assess the interactions between rs9939609 polymorphism of FTO gene, anthropometric indices and BC risk in Iranian women. This case-control study was performed on 540 women including 180 women with BC and 360 healthy women in Tehran, Iran. Physical activity and dietary intakes were assessed by validated questionnaires. Data on sociodemographic and pathologic factors of the participants as well as their blood samples were collected. The rs9939609 FTO gene polymorphism was genotyped using the tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR). No significant association was found between BC and risk allele of FTO rs9939609 polymorphism after adjustments for the confounders. However, there was a significant association between rs9939609 polymorphism risk allele and BC risk in females with overweight, even after adjusting for age, family history of BC, abortion, BMI and the number of pregnancies (P < .05). The association was disappeared after further adjustments for lifestyle factors including smoking, alcohol consumption, calorie and macronutrients intake, and physical activity. The FTO gene polymorphism was associated with the risk of BC in overweight individuals. This association was influenced by environmental factors including diet, alcohol consumption and smoking. Future studies are required to confirm the association between the FTO gene and BC in overweight females and to identify the underlying mechanisms.     

The Effects of Genetic Variation in FTO rs9939609 on Obesity and Dietary Preferences in Chinese Han Children and Adolescents

The association of the rs9939609 single nucleotide polymorphism in FTO gene with obesity has been extensively investigated in studies of populations of European, African, and Asian ancestry. However, inconsistent results have been reported in Asian populations, and the relationship of FTO variation and dietary behaviors has only rarely been examined in Chinese children and adolescents. The aim of this study was to assess the association of rs9939609 with obesity and dietary preferences in childhood in a Chinese population. Epidemiological data including dietary preferences were collected in interviews using survey questionnaires, and rs9939609 genotype was determined by real-time PCR. The associations of rs9939609 genotypes with obesity and dietary preferences were analyzed by multivariate logistic regression using both additive and dominant models. The results showed that subjects with a TA or AA genotype had an increased risk of obesity compared with the TT participants; the odds ratios (ORs) were 1.47 (95% CI: 1.25–1.71, P = 1.73×10⁻⁶), and 3.32 (95% CI: 2.01–5.47, P = 2.68×10⁻⁶), respectively. After adjusting for age and gender, body mass index, waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol were higher, and high-density lipoprotein cholesterol was lower in TA and AA participants than in those with the TT genotype. After additionally controlling for body mass index, the association remained significant only for systolic blood pressure (P = 0.005). Compared with TT participants, those with the AA genotype were more likely to prefer a meat-based diet (OR = 2.81, 95% CI: 1.52–5.21). The combined OR for obesity in participants with TA/AA genotypes and preference for a meat-based diet was 4.04 (95% CI: 2.8–5.81) compared with the TT participants who preferred a plant-based diet. These findings indicate the genetic variation of rs9939609 is associated with obesity and dietary preferences in Chinese children and adolescents.     

Polymorphisms in the NPY2R gene show significant associations with BMI that are additive to FTO, MC4R, and NPFFR2 gene effects

Neuropeptide Y (NPY) is an appetite hormone that acts centrally to control feeding behavior. The 5' and exon 2 regions of NPY2R, one of five NPY receptor genes, have been weakly and inconsistently implicated with obesity. With the ATG start site of the gene at the beginning of exon 2, single-nucleotide polymorphisms (SNPs) across intron 1 may show stronger associations with obesity than expected. Two 5' SNPs, three intron 1 SNPs, and one synonymous exon 2 SNP were genotyped on 2,985 white Utah subjects. Previously associated FTO, NPY, NPY1R, MC4R, PPARGC1A, OR7D4, and four NPFFR2 SNPs were also genotyped and related to BMI. One NPY2R 5' SNP (rs12649641, P = 0.008), an exon 2 SNP (rs2880415, P = 0.009), and an intron 1 SNP (rs17376826, P = 7 × 10(-6)) were each significantly associated with BMI. All three SNPs, plus FTO (rs9939609, P = 1.5 × 10(-6)) and two NPFFR2 SNPs (rs4129733, P = 3.7 × 10(-13) and rs11940196, 4.2 × 10(-10)) remained significant in a multiple regression additive model. Diplotypes using the estimated haplotypes of NPY2R, NPFFR2, and MC4R were significantly associated with BMI (P = 1.0 × 10(-10), 3.2 × 10(-8), and 1.1 × 10(-4), respectively). Haplotypes of NPY2R, NPFFR2, and MC4R, plus the FTO SNP, explained 9.6% of the BMI variance. SNP effect sizes per allele for the four genes ranged from 0.8 to 3.5 kg/m(2). We conclude that haplotypes containing the rs17376826 SNP in intron 1 of NPY2R have strong associations with BMI, some NPFFR2 haplotypes are strongly protective against or increase risk of obesity, and both NPY2R and NPFFR2 play important roles in obesity predisposition independent of FTO and MC4R.     

Association of a common rs9939609 variant in the fat mass and obesity-associated (<Emphasis Type="Italic">FTO</Emphasis>) gene with obesity and metabolic phenotypes in a Taiwanese population: a replication study

It is a key challenge to conduct reproducibility in genetic research, especially association studies in obesity. While susceptibility of a single-nucleotide polymorphism (SNP), rs9939609, in the fat mass and obesity-associated (FTO) gene to obesity has been reported in various populations, data from Asians is less conclusive. This replication study was carried out to test whether the FTO rs9939609 SNP is a predictive factor for obesity and obesity-related metabolic traits in a Taiwanese population. A total of 1188 Taiwanese subjects were recruited for this study. The FTO rs9939609 SNP was genotyped by the Taqman assay. Obesity-related metabolic traits such as triglyceride, waist circumference, systolic and diastolic blood pressure, total cholesterol, creatinine, alanine aminotransferase and fasting glucose were measured. Our data revealed that the FTOrs9939609 SNP exhibited a significant association with obesity (BMI \(\geqq \) 30 kg/m ²) among the subjects (P= 0.026). However, the FTO rs9939609 SNP did not exhibit any significant association with obesity-related metabolic traits among the subjects. Our results indicated that the FTO rs9939609 SNP may be linked with the risk of obesity in Taiwanese subjects.     

Meta‐analysis Added Power to Identify Variants in FTO Associated With Type 2 Diabetes and Obesity in the Asian Population

Several common variants in the intron 1 of FTO (fat mass and associated obesity) gene have been reliably associated with BMI and obesity in European populations. We analyzed two variants (rs9939609 and rs8050136) in 4,189 Chinese Han individuals and conducted a meta‐analysis of published studies in Asian population to investigate whether these variants are associated with type 2 diabetes (T2D) and obesity in Asian population. In this study, both the minor allele A of rs9939609 and the minor allele A of rs805136 were associated with increased risk of T2D, independent of measures of BMI; the odds ratios (ORs) per copy of the risk allele were 1.19 for rs9939609 (95% confidence interval (CI), 1.04–1.37; P = 0.01) and 1.22 for rs8050136 (95% CI, 1.07–1.40; P = 0.004) after adjusting for age, sex, and BMI. Our results also showed association with risk of obesity (rs9939609: OR = 1.39 (95% CI 1.04–1.85), P = 0.02; rs8050136: OR = 1.45 (95% CI 1.09–1.93), P = 0.01) but no association with overweight. These results were consistent with the pooled results from our meta‐analysis study (for diabetes, rs8050136, P = 1.3 × 10^?3; rs9939609, P = 9.8 × 10^?4; for obesity, rs8050136, P = 2.2 × 10^?7; rs9939609, P = 9.0 × 10^?9). Our findings indicate that the two variants (rs9939609 and rs8050136) in the FTO gene contribute to obesity and T2D in the Asian populations.     

Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk

Observational studies suggest that obese men have a lower risk of incident prostate cancer, but an increased risk of advanced and fatal cancers. These observations could be due to confounding, detection bias, or a biological effect of obesity. Genetic studies are less susceptible to confounding than observational epidemiology and can suggest how associations between phenotypes (such as obesity) and diseases arise. To determine whether the associations between obesity and prostate cancer are causal, we conducted a genetic association study of the relationship between a single nucleotide polymorphism known to be associated with obesity (FTO rs9939609) and prostate cancer. Data are from a population-based sample of 1550 screen-detected prostate cancers, 1815 age- and general practice matched controls with unrestricted prostate specific antigen (PSA) values and 1175 low-PSA controls (PSA <0.5 ng/ml). The rs9939609 A allele, which was associated with higher BMI in the sample, was inversely associated with overall (odds ratio (OR) versus all controls = 0.93; 95% confidence interval (CI): 0.85-1.02 p = 0.12 per allele) and low-grade (OR = 0.90; 0.81-0.99 p = 0.03 per allele) prostate cancer risk, but positively associated with high-grade cancer among cases (OR high- versus low-grade cancer = 1.16; 0.99-1.37 p = 0.07 per allele). Although evidence for these effects was weak, they are consistent with observational data based on BMI phenotypes and suggest that the observed association between obesity and prostate cancer is not due to confounding. Further research should confirm these findings, extend them to other BMI-related genetic variants and determine whether they are due to detection bias or obesity-related hormonal changes. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN20141297.     

The Common Variant in the FTO Gene Did Not Modify the Effect of Lifestyle Changes on Body Weight: The Finnish Diabetes Prevention Study

The common single‐nucleotide polymorphism in the FTO (fat mass and obesity associated) gene is consistently associated with an increased risk of obesity. However, the knowledge of a potential modifying effect of the FTO gene on changes in body weight achieved by lifestyle intervention is limited. We examined whether the FTO gene variant (rs9939609, T/A) is associated with body weight and BMI and long‐term weight changes in the Finnish Diabetes Prevention Study (DPS). Altogether, 522 (aged 40–65 years; BMI ≥25 kg/m²) subjects with impaired glucose tolerance (IGT) were randomized to control and lifestyle intervention groups. SNP rs9939609 was genotyped from 502 subjects. At baseline, those with the AA genotype had higher BMI than subjects with other genotypes (P = 0.006). The association was observed in women (P = 0.016) but not in men. During the 4‐year follow‐up, the subjects with the AA genotype had consistently the highest BMI (P = 0.009) in the entire study population. The magnitude of weight reduction was greater in the intervention group, but the risk allele did not modify weight change in either of the groups. Our results confirm the association between the common FTO variant and BMI in a cross‐sectional setting and during the long‐term lifestyle intervention. We did not observe association between FTO variant and the magnitude of weight reduction achieved by long‐term lifestyle intervention. Based on the results from the DPS, it is unlikely that the common variant of the FTO gene affects the success of lifestyle modification on weight loss.