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Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low
Carolina Ortega-Azorín, Jose V Sorlí, Eva M Asensio, Oscar Coltell, Miguel Martínez-González, Jordi Salas-Salvadó, Maria-Isabel Covas, Fernando Arós, José Lapetra, Lluís Serra-Majem, Enrique Gómez-Gracia, Miquel Fiol, Guillermo Sáez-Tormo, Xavier Pintó, Miguel Mu?oz, Emilio Ros, Jose M Ordovás, Ramon Estruch, Dolores Corella
Cardiovascular Diabetology , 2012, DOI: 10.1186/1475-2840-11-137
Abstract: Case-control study in 7,052 high cardiovascular risk subjects (3,430 type 2 diabetes cases and 3,622 non-diabetic subjects) with no differences in BMI. Diet was assessed by validated questionnaires. FTO-rs9939609 and MC4R-rs17782313 were determined. An aggregate genetic score was calculated to test additive effects. Gene-diet interactions were analyzed.Neither of the polymorphisms was associated with type 2 diabetes in the whole population. However, we found consistent gene-diet interactions with adherence to the MedDiet both for the FTO-rs9939609 (P-interaction=0.039), the MC4R-rs17782313 (P-interaction=0.009) and for their aggregate score (P-interaction=0.006). When adherence to the MedDiet was low, carriers of the variant alleles had higher type 2 diabetes risk (OR=1.21, 95%CI: 1.03-1.40; P=0.019 for FTO-rs9939609 and OR=1.17, 95%CI:1.01-1.36; P=0.035 for MC4R-rs17782313) than wild-type subjects. However, when adherence to the MedDiet was high, these associations disappeared (OR=0.97, 95%CI: 0.85-1.16; P=0.673 for FTO-rs9939609 and OR=0.89, 95%CI:0.78-1.02; P=0.097 for MC4R-rs17782313). These gene-diet interactions remained significant even after adjustment for BMI. As MedDiet is rich in folate, we also specifically examined folate intake and detected statistically significant interaction effects on fasting plasma glucose concentrations in non-diabetic subjects. However these findings should be interpreted with caution because folate intake may simply reflect a healthy dietary pattern.These novel results suggest that the association of the FTO-rs9939609 and the MC4R-rs17782313 polymorphisms with type 2 diabetes depends on diet and that a high adherence to the MedDiet counteracts the genetic predisposition.The Fat Mass and Obesity (FTO) and Melanocortin-4 Receptor (MC4R) genes are considered leading obesity-associated loci [1-6]. Both genes have been found to be highly expressed in the hypothalamus in rats [7] suggesting a role in a role in the central regulation
The Obesity-Associated Polymorphisms FTO rs9939609 and MC4R rs17782313 and Endometrial Cancer Risk in Non-Hispanic White Women  [PDF]
Galina Lurie,Mia M. Gaudet,Amanda B. Spurdle,Michael E. Carney,Lynne R. Wilkens,Hannah P. Yang,Noel S. Weiss,Penelope M. Webb,Pamela J. Thompson,Keith Terada,Veronica Wendy Setiawan,Timothy R. Rebbeck,Jennifer Prescott,Irene Orlow,Tracy O'Mara,Sara H. Olson,Steven A. Narod,Rayna K. Matsuno,Jolanta Lissowska,Xiaolin Liang,Douglas A. Levine,Loic Le Marchand,Laurence N. Kolonel,Brian E. Henderson,Montserrat Garcia-Closas,Jennifer Anne Doherty,Immaculata De Vivo,Chu Chen,Louise A. Brinton,Mohammad R. Akbari,Marc T. Goodman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016756
Abstract: Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.03–1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91–1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.
Statistical and Biological Gene-Lifestyle Interactions of MC4R and FTO with Diet and Physical Activity on Obesity: New Effects on Alcohol Consumption  [PDF]
Dolores Corella, Carolina Ortega-Azorín, Jose V. Sorlí, M. Isabel Covas, Paula Carrasco, Jordi Salas-Salvadó, Miguel ángel Martínez-González, Fernando Arós, José Lapetra, Lluís Serra-Majem, Rosa Lamuela-Raventos, Enrique Gómez-Gracia, Miquel Fiol, Xavier Pintó, Emilio Ros, Amelia Martí, Oscar Coltell, Jose M. Ordovás, Ramon Estruch
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052344
Abstract: Background Fat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) and are relevant genes associated with obesity. This could be through food intake, but results are contradictory. Modulation by diet or other lifestyle factors is also not well understood. Objective To investigate whether MC4R and FTO associations with body-weight are modulated by diet and physical activity (PA), and to study their association with alcohol and food intake. Methods Adherence to Mediterranean diet (AdMedDiet) and physical activity (PA) were assessed by validated questionnaires in 7,052 high cardiovascular risk subjects. MC4R rs17782313 and FTO rs9939609 were determined. Independent and joint associations (aggregate genetic score) as well as statistical and biological gene-lifestyle interactions were analyzed. Results FTO rs9939609 was associated with higher body mass index (BMI), waist circumference (WC) and obesity (P<0.05 for all). A similar, but not significant trend was found for MC4R rs17782313. Their additive effects (aggregate score) were significant and we observed a 7% per-allele increase of being obese (OR = 1.07; 95%CI 1.01–1.13). We found relevant statistical interactions (P<0.05) with PA. So, in active individuals, the associations with higher BMI, WC or obesity were not detected. A biological (non-statistical) interaction between AdMedDiet and rs9939609 and the aggregate score was found. Greater AdMedDiet in individuals carrying 4 or 3-risk alleles counterbalanced their genetic predisposition, exhibiting similar BMI (P = 0.502) than individuals with no risk alleles and lower AdMedDiet. They also had lower BMI (P = 0.021) than their counterparts with low AdMedDiet. We did not find any consistent association with energy or macronutrients, but found a novel association between these polymorphisms and lower alcohol consumption in variant-allele carriers (B+/?SE: ?0.57+/?0.16 g/d per-score-allele; P = 0.001). Conclusion Statistical and biological interactions with PA and diet modulate the effects of FTO and MC4R polymorphisms on obesity. The novel association with alcohol consumption seems independent of their effects on BMI.
Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women  [PDF]
Gaurav Garg, Jitender Kumar, Fiona E. McGuigan, Martin Ridderstr?le, Paul Gerdhem, Holger Luthman, Kristina ?kesson
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088565
Abstract: Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r2 = 0.2–0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs. CC: BUA: 100 vs. 103 vs. 103; p = 0.002); (SOS: 1521 vs. 1526 vs. 1524; p = 0.008); (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03) and vitamin D (93 vs. 91 vs. 90; p = 0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067). Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p≤0.001). Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.
Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier  [PDF]
A. E. Taylor,M. N. Sandeep,C. S. Janipalli,C. Giambartolomei,D. M. Evans,M. V. Kranthi Kumar,D. G. Vinay,P. Smitha,V. Gupta,M. Aruna,S. Kinra,R. M. Sullivan,L. Bowen,N. J. Timpson,G. Davey Smith,F. Dudbridge,D. Prabhakaran,Y. Ben-Shlomo,K. S. Reddy,S. Ebrahim,G. R. Chandak
Journal of Obesity , 2011, DOI: 10.1155/2011/307542
Abstract: Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (<.05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers ( for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.
Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS)
Susanne Tan, André Scherag, Onno Janssen, Susanne Hahn, Harald Lahner, Tiina Dietz, Susann Scherag, Harald Grallert, Carla Vogel, Rainer Kimmig, Thomas Illig, Klaus Mann, Johannes Hebebrand, Anke Hinney
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-12
Abstract: We conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4).The FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously.The stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease.The polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting about 6% of women of child-bearing age [1]. It is classically characterised by chronic anovulation, hyperandrogenism and polycystic ovarian morphology on ultrasonography [2]. In addition, a close relationship exists between obesity, insulin resistance (IR) and PCOS [3,4]. Despite a growing body of evidence demonstrating a substantial heritability of PCOS and the intrinsic impact of IR on the development of PCOS, its etiology and underlying pathophysiology still remains elusive.To date, multiple genetic studies in PCOS have been performed examining genes coding for enzymes of steroid biosynthesis like CYP11, CYP17, CYP19, androgen receptor, insulin, insulin receptor and enzymes in the post-receptor signal cascade of insulin. H
Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier  [PDF]
A. E. Taylor,M. N. Sandeep,C. S. Janipalli,C. Giambartolomei,D. M. Evans,M. V. Kranthi Kumar,D. G. Vinay,P. Smitha,V. Gupta,M. Aruna,S. Kinra,R. M. Sullivan,L. Bowen,N. J. Timpson,G. Davey Smith,F. Dudbridge,D. Prabhakaran,Y. Ben-Shlomo,K. S. Reddy,S. Ebrahim,G. R. Chandak
Journal of Obesity , 2011, DOI: 10.1155/2011/307542
Abstract: Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09?Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08?Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference ( ). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers ( for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity. 1. Introduction A large number of common genetic variants have been found to be associated with obesity phenotypes in Europeans [1–3]. Variants in the FTO (fat mass and obesity-associated) gene have demonstrated the strongest associations with obesity in Europeans [1, 4, 5]. However, results from a recent study in Indians from Pune (western India) suggest that FTO may be less strongly associated with obesity in South Asians [6]. Recently, association of genetic variants near the melanocortin 4 receptor (MC4R) gene with obesity traits has been reported in several European populations [2, 7, 8]. These associations have been replicated in a UK Indian population and a Sikh population in north India [9, 10]. In both studies, risk allele frequencies were higher than in Europeans. The pathways by which these genetic variants contribute to obesity are not yet understood but there is some evidence that the effects of variants in FTO are modified by energy imbalance [11–14]. Several studies have shown that increases in body mass index (BMI) per risk allele are lower in people who engage in high levels of physical activity compared to less active people [11, 12, 15]. FTO has also been shown to be associated with dietary fat intake and overall energy consumption [13, 16–18]. However, the modifying effects of these environmental factors have not been consistently replicated [19–21]. This may reflect true population differences, study sample size, or interstudy heterogeneity of measurement of these lifestyle factors. In
Association of FTO Polymorphisms with Obesity and Metabolic Parameters in Han Chinese Adolescents  [PDF]
Junqing Wu, Jianhua Xu, Zhaofeng Zhang, Jingcao Ren, Yuyan Li, Jian Wang, Yunlei Cao, Fen Rong, Rui Zhao, Xianliang Huang, Jing Du
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098984
Abstract: Background Previous studies have suggested that fat mass-and obesity-associated (FTO) gene is associated with body mass index (BMI) and the risk of obesity. This study aims to assess the association of five FTO polymorphisms (rs9939609, rs8050136, rs1558902, rs3751812 and rs6499640) with obesity and relative parameters in Han Chinese adolescents. Methods We examined a total of 401 adolescents, 223 normal weights (58.7% boys, 41.3% girls), 178 overweight (60.1% boys, 39.9% girls), aging from 14 to 18-years-old, recruited randomly from public schools in the central region of Wuxi, a southern city of China. DNA samples were genotyped for the five polymorphisms by Sequenom Plex MassARRAY. Association of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC) were investigated. Results 1) Serum FPG, FIns, TG and TC were statistically significant higher than that in normal control group. 2) We found that BMI was higher in the rs9939609 TA+AA, rs8050136 AC+AA, rs1558902 TA+AA and rs3751812 GT+TT genotypes than in wild TT genotypes (rs9939609: P = 0.038; rs1558902: P = 0.038;), CC genotypes(rs8050136: P = 0.024) and GG genotypes (rs3751812: P = 0.024), which were not significant on adjusting for multiple testing. 3) In case-control studies, five polymorphisms were not significantly associated with overweight (p>0.05), haplotype analyses showed non-haplotype is significantly associated with a higher risk of being overweight (p>0.05). 4) There existed no significant statistical difference about FPG, FIns, TG and TC in genotype model for any SNP. Conclusions Our study has conducted a genetic association study of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC). Our study found BMI of subjects with A allele of FTO rs9939609 is higher than that with T allele. Further studies on other polymorphisms from FTO and increasing the sample size are needed.
FTO and MC4R Gene Variants Are Associated with Obesity in Polycystic Ovary Syndrome  [PDF]
Kathryn G. Ewens,Michelle R. Jones,Wendy Ankener,Douglas R. Stewart,Margrit Urbanek,Andrea Dunaif,Richard S. Legro,Angela Chua,Ricardo Azziz,Richard S. Spielman,Mark O. Goodarzi,Jerome F. Strauss III
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016390
Abstract: Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ2 = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism.
Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes to obesity in Mexican children  [cached]
Mejía-Benítez Aurora,Klünder-Klünder Miguel,Yengo Loic,Meyre David
BMC Medical Genetics , 2013, DOI: 10.1186/1471-2350-14-21
Abstract: Background Recent genome wide association studies (GWAS) and previous positional linkage studies have identified more than 50 single nucleotide polymorphisms (SNPs) associated with obesity, mostly in Europeans. We aimed to assess the contribution of some of these SNPs to obesity risk and to the variation of related metabolic traits, in Mexican children. Methods The association of six European obesity-related SNPs in or near FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes with risk of obesity was tested in 1,463 school-aged Mexican children (Ncases = 514; Ncontrols = 949). We also assessed effects of these SNPs on the variation of body mass index (BMI), fasting serum insulin levels, fasting plasma glucose levels, total cholesterol and triglyceride levels, in a subset of 1,171 nonobese Mexican children. Results We found a significant effect of GNPDA2 rs10938397 on risk of obesity (odds ratio [OR] = 1.30; P = 1.34 × 10-3). Furthermore, we found nominal associations between obesity risk or BMI variation and the following SNPs: ENPP1 rs7754561, MC4R rs17782313 and NEGR1 rs2815752. Importantly, the at-risk alleles of both MC4R rs17782313 and NPC1 rs1805081 showed significant effect on increased fasting glucose levels (β = 0.36 mmol/L; P = 1.47 × 10-3) and decreased fasting serum insulin levels (β = 0.10 μU/mL; P = 1.21 × 10-3), respectively. Conclusion Our present results suggest that some obesity-associated SNPs previously reported in Europeans also associate with risk of obesity, or metabolic quantitative traits, in Mexican children. Importantly, we found new associations between MC4R and fasting glucose levels, and between NPC1 and fasting insulin levels.
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