A variant in FTO shows association with melanoma risk not due to BMI.
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ABSTRACT:
SUBMITTER: Iles MM
PROVIDER: S-EPMC3640814 | biostudies-literature | 2013 Apr
REPOSITORIES: biostudies-literature
Publications
A variant in FTO shows association with melanoma risk not due to BMI.
Iles Mark M MM Law Matthew H MH Stacey Simon N SN Han Jiali J Fang Shenying S Pfeiffer Ruth R Harland Mark M Macgregor Stuart S Taylor John C JC Aben Katja K KK Akslen Lars A LA Avril Marie-Françoise MF Azizi Esther E Bakker Bert B Benediktsdottir Kristrun R KR Bergman Wilma W Scarrà Giovanna Bianchi GB Brown Kevin M KM Calista Donato D Chaudru Valérie V Fargnoli Maria Concetta MC Cust Anne E AE Demenais Florence F de Waal Anne C AC Dębniak Tadeusz T Elder David E DE Friedman Eitan E Galan Pilar P Ghiorzo Paola P Gillanders Elizabeth M EM Goldstein Alisa M AM Gruis Nelleke A NA Hansson Johan J Helsing Per P Hočevar Marko M Höiom Veronica V Hopper John L JL Ingvar Christian C Janssen Marjolein M Jenkins Mark A MA Kanetsky Peter A PA Kiemeney Lambertus A LA Lang Julie J Lathrop G Mark GM Leachman Sancy S Lee Jeffrey E JE Lubiński Jan J Mackie Rona M RM Mann Graham J GJ Martin Nicholas G NG Mayordomo Jose I JI Molven Anders A Mulder Suzanne S Nagore Eduardo E Novaković Srdjan S Okamoto Ichiro I Olafsson Jon H JH Olsson Håkan H Pehamberger Hubert H Peris Ketty K Grasa Maria Pilar MP Planelles Dolores D Puig Susana S Puig-Butille Joan Anton JA Randerson-Moor Juliette J Requena Celia C Rivoltini Licia L Rodolfo Monica M Santinami Mario M Sigurgeirsson Bardur B Snowden Helen H Song Fengju F Sulem Patrick P Thorisdottir Kristin K Tuominen Rainer R Van Belle Patricia P van der Stoep Nienke N van Rossum Michelle M MM Wei Qingyi Q Wendt Judith J Zelenika Diana D Zhang Mingfeng M Landi Maria Teresa MT Thorleifsson Gudmar G Bishop D Timothy DT Amos Christopher I CI Hayward Nicholas K NK Stefansson Kari K Bishop Julia A Newton JA Barrett Jennifer H JH
Nature genetics 20130303 4
We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10(-12), per-allele odds ratio for allele A = 1.16). In ad ...[more]
Similar Datasets
Project description:OBJECTIVE:This study aimed to explore whether a common variant in the FTO gene moderates the relationship between parental restriction and child BMI. METHODS:This study reports on baseline data from 178 parent-child (ages 9-10 years) dyads. Parents completed the Child Feeding Questionnaire and reported on socio-demographic characteristics. Each child's height, weight and FTO rs9939609 genotype was assessed. Ordinary least squares regression was used to fit the child's BMI-percentile on parental restriction and the child's FTO genotype, adjusted for covariates. A likelihood ratio test was used to compare a model with and without a multiplicative interaction term between restriction and genotype. RESULTS:Most participants (93.3%) were white, non-Hispanic. Twenty-three percent of children were overweight/obese and FTO genotype was associated with weight status. Mean parental restriction was statistically higher among overweight/obese vs. normal weight children: 3.3 (SD 0.8) vs. 2.8 (SD 1.0); t-test p-value = 0.002. Parental restriction was positively associated with child BMI-percentile and BMI-z only among children with two copies of the high-risk FTO allele (p for interaction = 0.02), where each one-point increase in parental restriction was associated with a 14.7 increase in the child's BMI-percentile or a 0.56-point increase in the child's BMI z-score. CONCLUSION:For only the children with two high-risk alleles, parental restriction was positively associated with child BMI-percentile.
| S-EPMC4873182 | biostudies-literature
Project description: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.
| S-EPMC4476623 | biostudies-literature
Project description:A substantial body of research has explored the relative roles of genetic and environmental factors on phenotype expression in humans. Recent research has also sought to identify gene-environment (or g-by-e) interactions, with mixed success. One potential reason for these mixed results may relate to the fact that genetic effects might be modified by changes in the environment over time. For example, the noted rise of obesity in the United States in the latter part of the 20th century might reflect an interaction between genetic variation and changing environmental conditions that together affect the penetrance of genetic influences. To evaluate this hypothesis, we use longitudinal data from the Framingham Heart Study collected over 30 y from a geographically relatively localized sample to test whether the well-documented association between the rs993609 variant of the FTO (fat mass and obesity associated) gene and body mass index (BMI) varies across birth cohorts, time period, and the lifecycle. Such cohort and period effects integrate many potential environmental factors, and this gene-by-environment analysis examines interactions with both time-varying contemporaneous and historical environmental influences. Using constrained linear age-period-cohort models that include family controls, we find that there is a robust relationship between birth cohort and the genotype-phenotype correlation between the FTO risk allele and BMI, with an observed inflection point for those born after 1942. These results suggest genetic influences on complex traits like obesity can vary over time, presumably because of global environmental changes that modify allelic penetrance.
| S-EPMC4299180 | biostudies-literature
Project description:In 2016, a large meta-analysis brought the number of susceptibility loci for migraine to 38. While sub-type analysis for migraine without aura (MO) and migraine with aura (MA) found some loci showed specificity to MO, the study did not test the loci with respect to other subtypes of migraine. This study aimed to test the hypothesis that single nucleotide polymorphisms (SNPs) robustly associated with migraine are individually or collectively associated with menstrual migraine (MM).Genotyping of migraine susceptibility SNPs was conducted using the Agena MassARRAY platform on DNA samples from 235 women diagnosed with menstrual migraine as per International Classification for Headache Disorders II (ICHD-II) criteria and 140 controls. Alternative genotyping methods including restriction fragment length polymorphism, pyrosequencing and Sanger sequencing were used for validation. Statistical analysis was performed using PLINK and SPSS.Genotypes of 34 SNPs were obtained and investigated for their potential association with menstrual migraine. Of these SNPs, rs2506142 located near the neuropilin 1 gene (NRP1), was found to be significantly associated with menstrual migraine (p?=?0.003). Genomic risk scores were calculated for all 34 SNPs as well as a subset of 7 SNPs that were nearing individual significance. Overall, this analysis suggested these SNPs to be weakly predictive of MM, but of no prognostic or diagnostic value.Our results suggest that NRP1 may be important in the etiology of MM. It also suggests some genetic commonality between common migraine subtypes (MA and MO) and MM. The identification of associated SNPs may be the starting point to a better understanding of how genetic factors may contribute to the menstrual migraine sub-type.
| S-EPMC5906416 | biostudies-literature
Project description:BACKGROUND:Variations in the fat mass and obesity-associated (FTO) gene (16q12.2) are associated with obesity in some populations. This study aimed to determine the relationship between FTO gene polymorphism and adiposity&related markers in Turkish adults was aimed. METHODS:The present study included 200 participants aged 18-65?years, who were genotyped for variants of the FTO gene (rs9939609). Anthropometric measurements were performed. Body compositions were analyzed with Tanita BC 545?N Inner ScanTM. Infrared analyzer (VISCANTM) was also used to determinate the degree of abdominal fat. Body mass index (BMI), body adiposity index (BAI) and lipid accumulation products (LAP) index which are used in body fat estimation were calculated. Body fat amounts were classified using gender-based cut-offs. Odds ratio (OR) and 95% confidence interval (CI) were calculated to determine the risk of having a high body fat amount associated with the risk allele. RESULTS:The frequency of the rs9939609 AA genotype was 19.0%, which was 42.5% for the AT genotype and 38.5% for the TT genotype (wild type). AA genotype was found to be higher in females than in males (26.0 and 12.0%, respectively). The total body fat amount of the individuals with AA genotype was high (28.5?±?9.25%) compared to AT (27.0?±?10.31%) and TT (23.7?±?10.62%) genotype (p?<?0.05). However, there was no difference in abdominal fat amounts (%) (AA:38.6%, AT:36.2%, TT:33.7%), internal fat levels and waist/hip ratios (p?>?0.05). Significance of association between FTO genotypes and total body fat (%) was retained after adjustment for BMI and gender as well. BMI, LAP, and BAI index values were not different between different genotypes in all individuals and different genders (p?>?0.05). CONCLUSION:Our study supports that the FTO rs9939609 polymorphism is associated with fat accumulation in the whole body without being associated with abdominal fat accumulation in Turkish adults.
| S-EPMC6896279 | biostudies-literature
Project description:BACKGROUND:Genetic and environmental factors play a crucial role in the development of type 2 diabetes mellitus (T2DM) and obesity. This study aimed to investigate the association of the fat-mass and obesity-associated gene (FTO) rs9939609 variant with T2DM and body mass index (BMI) among Palestinian population. METHODS:A total of 399 subjects were recruited, of whom 281 were type 2 diabetic patients and 118 normoglycemic subjects. All of them were unrelated, aged >?40 years and recruited within the period 2016-2017. The A allele of FTO rs9939609 was identified by PCR-RFLP. RESULTS:Significant association of the minor allele A of FTO rs9939609 and T2DM risk was observed with an allelic odd ratio of 1.92 (95% CI [1.09-3.29], p?=?0.02) adjusted for age and gender, this association partly attenuated when adjusted for BMI with OR of 1.84, (95%CI [1.04-3.05], p?=?0.03). Stratified data by glycemic status across FTO genotypes showed that A allele was marginally associated with increased BMI among diabetic group (p?=?0.057) but not in control group (p?=?0.7). Moreover, no significant association was observed between FTO genotypes and covariates of age, gender, T2DM complications or any tested metabolic trait in both diabetic and nondiabetic individuals (p?>?0.05). CONCLUSIONS:The variant rs9939609 of the FTO gene was associated with T2DM in Palestine. This is the first study conducted on this gene in the Palestinian population and provides valuable information for comparison with other ethnic groups. Further analysis with larger sample size is required to elucidate the role of this variant on the predisposition to increased BMI in Palestinians.
| S-EPMC6119238 | biostudies-literature
Project description:BackgroundFat mass and obesity-associated gene (FTO) has been associated with obesity, especially the common variant rs9939609. Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder and over 50% of patients are overweight/obese. Thus FTO is a potential candidate gene for PCOS but their relationship is confusing and remains to be clarified in different population with a large sample size.MethodThis study was performed adopting a two-stage design by genotyping SNP rs9939609. The first set comprise of 741 PCOS and 704 control subjects, with data from our previous GWAS. The second phase of replication study was performed among another independent group of 2858 PCOS and 2358 control subjects using TaqMan-MGB probe assay. All subjects are from Han Chinese.ResultsThe less meaningful association of FTO rs9939609 and PCOS discovered in GWAS (P?=?2.47E-03), was further confirmed in the replication study (P?=?1.86E-09). Using meta-analysis, the P-meta value has reached 6.89E-12, over-exceeding the genome-wide association level of 5.00E-8. By combination, the P value was 1.26E-11 and after BMI adjustment it remained significant(P?=?1.82E-06). To further elucidate whether this association is resulted from obesity or PCOS per se, the samples were divided into two groups-obese and non-obese PCOS, and the results were still positive in obese group (P obese?=?5.81E-05, OR?=?1.55), as well as in non-obese PCOS group (P non-obese?=?7.06E-04, OR?=?1.28).ConclusionVariant rs9939609 in FTO is associated with PCOS in Chinese women, not only in obese PCOS subjects, but also in non-obese cases.
| S-EPMC3698074 | biostudies-literature
Project description:Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation.We addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children.Expression of IRX3 was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of IRX3 and IRX5 with the presence of the FTO risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that IRX3 expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in UCP1-negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI, IRX3 expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children.One interpretation of our observation of FTO risk variants linked to IRX3 expression and adipocyte size restricted to lean children, along with the decreased IRX3 expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children.
| S-EPMC4999231 | biostudies-literature
Project description:The association between common variants in the FTO gene with weight, adiposity and body mass index (BMI) has now been widely replicated. Although the causal variant has yet to be identified, it most likely maps within a 47 kb region of intron 1 of FTO. We performed a genome-wide association study in the Sorbian population and evaluated the relationships between FTO variants and BMI and fat mass in this isolate of Slavonic origin resident in Germany. In a sample of 948 Sorbs, we could replicate the earlier reported associations of intron 1 SNPs with BMI (eg, P-value=0.003, beta=0.02 for rs8050136). However, using genome-wide association data, we also detected a second independent signal mapping to a region in intron 2/3 about 40-60 kb away from the originally reported SNPs (eg, for rs17818902 association with BMI P-value=0.0006, beta=-0.03 and with fat mass P-value=0.0018, beta=-0.079). Both signals remain independently associated in the conditioned analyses. In conclusion, we extend the evidence that FTO variants are associated with BMI by putatively identifying a second susceptibility allele independent of that described earlier. Although further statistical analysis of these findings is hampered by the finite size of the Sorbian isolate, these findings should encourage other groups to seek alternative susceptibility variants within FTO (and other established susceptibility loci) using the opportunities afforded by analyses in populations with divergent mutational and/or demographic histories.
| S-EPMC2987177 | biostudies-literature
Project description:BACKGROUND:Body constitutional types described in the traditional Korean medicine system, Sasang constitutional medicine, are heritable, as has been revealed by twin and family studies. Thus, individuals with the same constitution type usually have similar pathophysiological and psychological traits. In several recent genome-wide association (GWA) analyses performed to identify constitution-associated variants, the association signals were not replicated due to small sample size and dissimilar, non-objective methods for classification of the constitutional types. METHODS:We conducted GWA analysis and followed replication analysis in two large populations (5,490 subjects: 3,810 subjects at discovery stage and 1,680 subjects at replication stage) to identify the replicable constitution-associated variants, wherein subjects with the highest tertile of constitution probability values versus the reference with the lowest tertile of the values obtained from a recently developed constitution analysis tool were compared. RESULTS:We found that the obesity-risk variant in intron 1 of the fat mass and obesity-associated (FTO) gene was replicably inversely associated with the So-Eum (SE) type, characterized by reduced appetite, slim body, and cautious personality (rs7193144 in combined samples: odds ratio = 0.729, p = 1.47 × 10(-7)), and substantial association signal remained after controlling for body mass index (BMI). In contrast, the association of the variant with the Tae-Eum type, characterized by high body mass, disappeared after controlling BMI. CONCLUSIONS:In summary, the obesity-risk variant in FTO intron 1 was inversely associated with the SE type, independent of BMI, which corresponded well with the characteristics of the SE type, such as the lowest body mass and lowest susceptibility to metabolic disorders among the constitutional types. Therefore, the obesity-risk variant of FTO associated with body mass increase might be involved in the determination of body constitution type.
| S-EPMC4432511 | biostudies-literature