Homozygous Risk Allele Carriers Research Articles

FTO Gene Polymorphisms and Their Roles in Acromegaly.

The major causes of both morbidity and mortality in patients with acromegaly are cardiovascular diseases (CVDs). The polymorphisms of the fat mass and obesity-associated gene (FTO) are associated with obesity, as well as with an increased risk of CVDs. The aim of the study was to determine the relationship of risk alleles of four FTO gene polymorphisms with selected parameters of lipid and glucose metabolism as well as with IGF-1 and GH levels in the group of patients with acromegaly compared to the control group. The study group consisted of 104 patients with acromegaly and 64 healthy subjects constituting the control group. In the whole acromegaly group, the data reveal that the homozygous for risk allele carriers (rs1421085, rs9930506, rs9939609) as well as carriers of only one risk allele have lower IGF-1 concentrations. In the well-controlled acromegaly group, the homozygous for three risk allele carriers of FTO gene polymorphisms have lower HDL cholesterol concentration (rs1121980, rs1421085, rs993609). In the cured acromegaly group, homozygous risk allele carriers rs9930506 tend to have higher levels of total cholesterol and LDL cholesterol. These associations are not observed in the control group. Conclusion: there is an association between FTO gene polymorphisms and the metabolism of lipids, suggesting that the FTO gene may be associated with higher CVD risk in patients with acromegaly. In addition, there is an association between FTO gene polymorphisms and IGF-1, implying that FTO gene may influence/modify IGF-1 synthesis. Further investigation on a larger scale is required to provide more precise evidence.

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration.

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10-12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (-5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease.

Voluntary upregulation of heart rate variability through biofeedback is improved by mental contemplative training

Regulation of the parasympathetic nervous system, indexed through high frequency heart rate variability (HF-HRV), is indicative of physical and psychological health. However, little is known about the trainability of this capacity. We investigated the effects of a 9-month mental training program (the ReSource Project; n = 298) on voluntary HF-HRV upregulation, assessed with a novel biofeedback procedure. The program consisted of attentional, interoceptive, socio-affective and socio-cognitive training elements, all of which potentially influence parasympathetic regulation. Based on known links between oxytocin and parasympathetic activity, we also explored the relationship of HF-HRV upregulation to the oxytocin receptor system. We found that HF-HRV during the biofeedback session increased after 3 months of training, concomitant with prolonged respiration cycles. Breathing-controlled changes in HF-HRV upregulation, indicative of improved parasympathetic control, were significantly increased after 6 months of training. Homozygous risk allele carriers (AA) of the oxytocin receptor gene polymorphism rs53576 showed initially lower parasympathetic control, but fully compensated for their initial deficits through the training. No changes were found for HF-HRV at rest. Our data demonstrate that a mental training intervention extending over several months can increase the capacity for voluntary regulation of HF-HRV, with important implications for improving individual and societal health.

Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention.

A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention. The association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91-209) vs. 134 (85-194) AU⋅min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203 AU⋅min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08-2.68; P = 0.02). Bleeding risk was not altered. We conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.

Evaluation of FTO rs9939609 and MC4R rs17782313 Polymorphisms as Prognostic Biomarkers of Obesity: A Population-based Cross-sectional Study.

ObjectivesObesity is a significant risk factor for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity usually results from a combination of causes and contributing factors, including genetics and lifestyle choices. Many studies have shown an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) and the melanocortin-4 receptor (MC4R) genes with body mass index (BMI). Therefore, recognizing the main genes and their relevant genetic variants will aid prediction of obesity risk. The aim of our study was to investigate the frequency of rs9939609 and rs17782313 polymorphisms in FTO and MC4R genes in an Iranian population.MethodsWe enrolled 130 obese patients and 83 healthy weight controls and calculated their BMI. Genomic DNA was extracted from peripheral blood and the frequency of rs9939609 and rs17782313 polymorphisms in FTO and MC4R genes was determined using the tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR).ResultsSignificant associations were found between FTO rs9939609 and BMI. Where homozygous risk allele carriers (A-A) have significant higher odds ratio (OR) of being obese than individuals with normal BMI (OR = 6.927, p < 0.005, 95% confidence interval (CI): 3.48–13.78). No significant correlation between MC4R rs17782313 and obesity were observed when compared to healthy weight individuals. Although subjects with C-C genotype had higher odds of obesity (OR = 1.889, p = 0.077, 95%CI: 0.92–3.84).ConclusionsThis study shows a relationship between FTO polymorphism and increased BMI, therefore, SNP in the FTO gene influence changes in BMI and can be considered a prognostic marker of obesity risk.

Effect of Obesity-Linked FTO rs9939609 Variant on Physical Activity and Dietary Patterns in Physically Active Men and Women.

Single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) locus are associated with obesity, but lifestyle factors may modulate the obesity risk related to FTO. This study examined the physical activity and dietary patterns of 528 physically active white men and women (mean (SD): 34.9 (9.5) years, 26.6 (4.3) kg·m−2) carrying different risk variants of FTO SNP rs9939609. Sex, age, and anthropometric measurements (stature, body mass, and waist circumference) were self-reported using an online questionnaire, and body mass index and waist-to-height ratio were calculated. Physical activity and eating behaviour were assessed using the International Physical Activity Questionnaire (IPAQ) and Three-Factor Eating Questionnaire (TFEQ), respectively. Body mass, body mass index (BMI), waist circumference, and waist-to-height ratio were not significantly different between individuals expressing different FTO rs9939609 risk variants (all P ≥ 0.66). The cohort was physically active (4516 (3043) total MET min·week−1), although homozygous risk allele carriers (AA) displayed higher TFEQ cognitive restraint compared with nonrisk allele carriers (TT) (ES = 0.33 and P=0.03). In conclusion, obesity-related parameters were not different in physically active individuals expressing different risk variants of FTO rs9939609, although homozygous risk allele carriers exhibited higher cognitive restraint.

Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus.

A chromosomal locus at 4q32.1 has been genome-wide significantly associated with coronary artery disease risk. The locus encompasses GUCY1A3, which encodes the α1 subunit of the soluble guanylyl cyclase (sGC), a key enzyme in the nitric oxide/cGMP signaling pathway. The mechanism linking common variants in this region with coronary risk is not known. Gene expression and protein expression were analyzed with quantitative polymerase chain reaction and immunoblotting, respectively. Putative allele-specific transcription factors were identified with in silico analyses and validated via allele-specific quantification of antibody-precipitated chromatin fractions. Regulatory properties of the lead risk variant region were analyzed with reporter gene assays. To assess the effect of zinc finger E box-binding homeobox 1 transcription factor (ZEB1), siRNA-mediated knockdown and overexpression experiments were performed. Association of GUCY1A3 genotype and cellular phenotypes was analyzed with vascular smooth muscle cell migration assays and platelet aggregation analyses. Whole-blood GUCY1A3 mRNA levels were significantly lower in individuals homozygous for the lead (rs7692387) risk variant. Likewise, reporter gene assays demonstrated significantly lower GUCY1A3 promoter activity for constructs carrying this allele. In silico analyses located a DNase I hypersensitivity site to rs7692387 and predicted binding of the transcription factor ZEB1 rather to the nonrisk allele, which was confirmed experimentally. Knockdown of ZEB1 resulted in more profound reduction of nonrisk allele promoter activity and a significant reduction of endogenous GUCY1A3 expression. Ex vivo-studied platelets from homozygous nonrisk allele carriers displayed enhanced inhibition of ADP-induced platelet aggregation by the nitric oxide donor sodium nitroprusside and the phosphodiesterase 5 inhibitor sildenafil compared with homozygous risk allele carriers. Moreover, pharmacological stimulation of sGC led to reduced migration only in vascular smooth muscle cells homozygous for the nonrisk allele. In the Hybrid Mouse Diversity Panel, higher levels of GUCY1A3 expression correlated with less atherosclerosis in the aorta. Rs7692387 is located in an intronic site that modulates GUCY1A3 promoter activity. The transcription factor ZEB1 binds preferentially to the nonrisk allele, leading to an increase in GUCY1A3 expression, higher sGC levels, and higher sGC activity after stimulation. Finally, human and mouse data link augmented sGC expression to lower risk of atherosclerosis.

CDH13 gene-by-PM10 interaction effect on lung function decline in Korean men

Lung function can be influenced by genetic factors, which may explain individual differences in susceptibility to the effects of air pollution. This study investigated whether the effect of particulate matter with an aerodynamic diameter ≤10 μm (PM10) on lung function is modified by Cadherin 13 (CDH13) genetic variants in Korean men. This study included a total of 1827 men who were recruited from two health check-up centers, and the annual average PM10 concentrations were used. A total of 200 single-nucleotide polymorphisms (SNPs) of the CDH13 gene were selected for this study.We found that a SNP in CHD13 intron, rs1862830, had the strongest associations with both forced expiratory volume in 1 s (FEV1) (pint = 1.90 × 10−4) and forced vital capacity (FVC) (pint = 1.88 × 10−3) by interacting with PM10 in a recessive model. A stratified association analysis according to this SNP showed that PM10 in the AG or GG genotype group was not significantly associated with either FEV1 or FVC, whereas in homozygous risk-allele carriers (AA), FEV1 and FVC decreased significantly (by 3.8% and 3.1%, respectively) per 10 μg/m3 of increase in PM10 concentration. This pattern was also reproducible in the independent subgroups that were classified according to recruitment site. The present study replicated the CDH13 gene-by-PM10 interaction effect on lung function at the gene level, revealing that a genetic variant of CDH13 modified the relationship between PM10 and lung function decline in Korean men.

Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively.

Aims/hypothesisGenome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases.MethodsWe performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity.ResultsKnown obesity-associated variants in FTO showed strong evidence of deviation from additivity (pDOMDEV = 3 × 10−5) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m2, 27.54 (95% CI 27.50, 27.58) kg/m2 and 28.07 (95% CI 28.00, 28.14) kg/m2, respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (pDOMDEV = 0.003; meta-analysis pDOMDEV = 1 × 10−7). For type 2 diabetes, we detected a recessive effect (pDOMDEV = 5 × 10−4) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance.Conclusions/interpretationAlthough we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci.Access to research materialsSummary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3908-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Neuropeptide Y gene-by-psychosocial stress interaction effect is associated with obesity in a Korean population

BackgroundChronic psychosocial stress is a crucial risk factor in the development of many diseases including obesity. Neuropeptide Y (NPY), distributed throughout the peripheral and central nervous system, is believed to pay a role in the pathophysiologic relationship between stress and obesity. Although several animal studies have investigated the impact on obesity of interactions between NPY single nucleotide polymorphisms (SNPs) and stress, the same remains to be analyzed in humans. MethodsTo identify NPY gene-by-stress interaction effects on human obesity, we analyzed the interaction between four NPY SNPs and stress with obesity-related traits, including visceral adipose tissue (VAT). A total of 1468 adult subjects were included for this analysis. ResultsIn a SNP-only model without interaction with stress, no significant SNPs were found (pSNP>0.05). However, NPY SNPs-by-stress interaction effects were significantly linked to body mass index (BMI), waist circumference, and VAT (pint<0.05), even though a significant interaction effect for rs16135 on BMI was not identified. These significant interaction effects were also detected in interaction results for the binary traits of obesity. Among the obesity traits, mean changes of VAT by increased stress levels in homozygous risk allele carriers were the greatest (range of mean increases for four SNPs (min-max)=12.57cm2−29.86cm2). ConclusionsThis study suggests that common polymorphisms for NPY were associated with human obesity by interacting with psychosocial stress, emphasizing the need for stress management in obesity prevention.

Pharmacological inhibition of FTO.

In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO’s demethylase activity could be therapeutically useful for the treatment of obesity.

PNPLA3-Associated Steatohepatitis: Toward a Gene-Based Classification of Fatty Liver Disease

Nonalcoholic fatty liver disease is one of the most common hepatic disorders worldwide. Given the high-calorie nutrition of children and adults, nonalcoholic fatty liver disease (NAFLD) is expected to become a major cause of cirrhosis and eventually liver transplantation. Familial clustering and ethnic differences indicate that genetic factors contribute to NAFLD. Recently, the common variant p.I148M of the enzyme adiponutrin (PNPLA3) has emerged as a major genetic determinant of hepatic steatosis and nonalcoholic steatohepatitis as well as its pathobiological sequelae fibrosis, cirrhosis, and hepatocellular cancer. PNPLA3 encodes a lipid droplet-associated, carbohydrate-regulated lipogenic and/or lipolytic enzyme. Homozygous carriers of the PNPLA3 variant are prone to develop cirrhosis in the absence of other risk factors such as alcohol or viral hepatitis. Here we review the plethora of studies that unraveled the association between PNPLA3 and NAFLD in children and adults, discuss its distinct effects on liver and metabolic traits, and introduce the term PNPLA3-associated steatohepatitis (PASH) as a novel gene-based liver disease. Given the prevalence of the risk allele in 40 to 50% of Europeans, the authors conclude that PNPLA3 should be considered in the diagnostic workup of fatty liver disease and that homozygous risk allele carriers might benefit from careful cancer surveillance.

ZNF804A and cortical structure in schizophrenia: in vivo and postmortem studies.

Recent evidence indicated that the ZNF804A (rs1344706) risk allele A is associated with better cognitive performance in patients with schizophrenia. Moreover, it has been demonstrated that ZNF804A may also be related to relatively intact gray matter volume in patients. To further explore these putatively protective effects, the impact of ZNF804A on cortical thickness and folding was examined in this study. To elucidate potential molecular mechanisms, an allelic-specific gene expression study was also carried out. Magnetic resonance imaging cortical thickness and folding were computed in 55 genotyped patients with schizophrenia and 40 healthy controls. Homozygous risk allele carriers (AA) were compared with AC/CC carriers. ZNF804A gene expression was analyzed in a prefrontal region using postmortem tissue from another cohort of 35 patients. In patients, AA carriers exhibited significantly thicker cortex in prefrontal and temporal regions and less disturbed superior temporal cortical folding, whereas the opposite effect was observed in controls, ie, AA carrier status was associated with thinner cortex and more severe altered cortical folding. Along with this, our expression analysis revealed that the risk allele is associated with lower prefrontal ZNF804A expression in patients, whereas the opposite effect in controls has been observed by prior analyses. In conclusion, our analyses provide convergent support for the hypothesis that the schizophrenia-associated ZNF804A variant mediates protective effects on cortex structure in patients. In particular, the allele-specific expression profile in patients might constitute a molecular mechanism for the observed protective influence of ZNF804A on cortical thickness and folding and potentially other intermediate phenotypes.

Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation

Common single nucleotide polymorphisms at chromosome 4q25 (rs2200733, rs10033464) are associated with both lone and typical atrial fibrillation (AF). Risk alleles at 4q25 have recently been shown to predict recurrence of AF after ablation in a population of predominately lone AF, but lone AF represents only 5%-30% of AF cases. To test the hypothesis that 4q25 AF risk alleles can predict response to AF ablation in the majority of AF cases. Patients enrolled in the Vanderbilt AF Registry underwent 378 catheter-based AF ablations (median age 60 years; 71% men; 89% typical AF) between 2004 and 2011. The primary end point was time to recurrence of any nonsinus atrial tachyarrhythmia (atrial tachycardia, atrial flutter, or AF). Two-hundred atrial tachycardia, atrial flutter, or AF recurrences (53%) were observed. In multivariable analysis, the rs2200733 risk allele predicted a 24% shorter recurrence-free time (survival time ratio 0.76; 95% confidence interval [CI] 0.6-0.95; P = .016) compared with wild type. The heterozygous haplotype demonstrated a 21% shorter recurrence-free time (survival time ratio 0.79; 95% CI 0.62-0.99) and the homozygous risk allele carriers a 39% shorter recurrence-free time (survival time ratio 0.61; 95% CI 0.37-1.0; P = .037). Risk alleles at the 4q25 loci predict impaired clinical response to AF ablation in a population of patients with predominately typical AF. Our findings suggest that the rs2200733 polymorphism may hold promise as an objectively measured patient characteristic that can be used as a clinical tool for selecting patients for AF ablation.

Variation in IL7R predisposes to sarcoid inflammation

Sarcoidosis is a chronic granulomatous disorder characterized by a massive influx of Th1 lymphocytes. Both naive and memory T cells express high levels of interleukin 7 receptor-alpha (IL7R alpha), encoded by the IL7R gene. The purpose of this study was to investigate the role of the IL7R gene region in susceptibility to sarcoidosis. Six common single-nucleotide polymorphisms (SNPs) spanning IL7R were genotyped and analyzed in 475 sarcoidosis patients and 465 healthy controls. Replication of one significant associated SNP was carried out in 206 independent sarcoidosis patients, 127 controls and 126 patients with Löfgren's disease. The rs10213865 SNP was associated with sarcoidosis (P=0.008), and in silico analysis showed a complete linkage (r(2)=1, D'=1) with a functional nonsynonymous coding SNP in exon 6 (rs6897932, T244I). Combined analysis of 663 individuals with sarcoidosis and 586 controls (homozygous carriers of risk allele, P=5 x 10(-4), odds ratio=1.49 (1.19-1.86)) provided strong statistical support for a genuine association of IL7R with the risk of sarcoidosis. In addition, we report the same trend between variation in the IL7R gene and patients with Löfgren's disease, suggesting that variation in IL7R may confer general risk for developing granulomatous lung disease.

The growth hormone – IGF1 axis as a mediator for association between FTO variants and obesity

Evidence from numerous epidemiological studies in more than 50,000 individuals indicate that risk alleles of the fat mass- and obesity-associated gene (FTO) are distinctly associated with increased BMI values and an enhanced risk for obesity and type 2 diabetes. The molecular mechanisms that link variants in FTO to increased fat mass remain obscure. We re-analyzed the association of rs9926289, one of the tightly linked FTO risk variants, with BMI in the Study of Health in Pomerania (SHIP), a population-based cross-sectional health survey in the north-eastern part of Germany. SHIP comprised 4310 individuals recruited in each five years age strata from 20 to 79 years of age. FTO genotypes of 4068 individuals were obtained, the distribution of which mirrored that of other studies in Caucasian populations. The entire SHIP population was invited to participate in a five years follow-up survey, termed SHIP1, and 3300 individuals (76.6% of the SHIP cohort) were successfully re-examined. FTO genotypes were available for 3267 subjects of SHIP1, which allowed for a longitudinal analysis how FTO risk alleles affected BMI and weight changes within a five years period. For the entire SHIP population we observed a significant association of the risk allele with obesity as indicated by an odds ratio (OR) of 1.27 (95% confidence intervals (CI) 1.06–1.53; p=0.0096; recessive model, logistic regression). We observed a distinct age dependency for the association of FTO risk alleles with BMI. For individuals younger than 56 years of age mean (n=2340) BMI for homozygous carriers of the risk allele amounted to 30.0±0.2kg/m2 compared to 26.2±0.2 and 26.2±0.1kg/m2 for homozygous carriers of the low-risk allele and heterozygotes, respectively (p=0.018; linear model, adjusted for age and gender). OR for obesity in homozygous carriers of the risk allele amounted to 1.64 (CI 1.27–2.10; recessive model; logistic regression adjusted for age, gender). For the SHIP population older than 56 years of age an association of the FTO risk allele with BMI or obesity was no longer observable. The levels of plasma insulin-like growth factor 1 (IGF1) also follow a strong age dependency. Homozygous carriers of the FTO risk allele exhibited significantly lower plasma IGF1 levels (crude models and after adjustment for age, gender, BMI and IGF1 binding protein 3 levels). We propose that FTO, which is predominantly expressed in the hypothalamus, affects the growth hormone – IGF1 axis which may in turn affect the body composition and fat mass.