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FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome.

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 (?(2)?= 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.

SUBMITTER: Ewens KG

PROVIDER: S-EPMC3024473 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome.

Ewens Kathryn G KG Jones Michelle R MR Ankener Wendy W Stewart Douglas R DR Urbanek Margrit M Dunaif Andrea A Legro Richard S RS Chua Angela A Azziz Ricardo R Spielman Richard S RS Goodarzi Mark O MO Strauss Jerome F JF

PloS one 20110120 1

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 identifie ...[more]

PMID: 21283731

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Project description:BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder causing infertility in reproductive-age women. The cause of PCOS is not fully understood but it is thought to be influenced by environmental and genetic factors. Obesity is greatly related to PCOS and its reduction is one of the major aims in treating PCOS. Melanocortin 4 receptor (MC4R) gene polymorphisms were detected to be associated with different levels of obesity. Therefore, we aimed to determine the genotype and allele frequency of MC4R variants rs12970134 (A/G) and rs17782313 (C/T) in PCOS and investigate their association with PCOS and its clinical variables.MethodsA case-control study was conducted on 189 women, consisting of 95 PCOS cases and 94 controls. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan™ Genotyping assays. Quantitative data were presented as (median ± interquartile range (IQR) whereas qualitative data were presented as frequencies. The chi-squared test was used to observe the difference between SNPs within the study groups (PCOS and control subjects). Multinomial logistic regression was used to test the risk of obesity and development of PCOS considering p < 0.05 is statistically significant.ResultsRs12970134 and rs17782313 are significantly associated with body mass index (BMI, kg/m2, p < 0.0001) in PCOS women but not associated with PCOS itself. Risk alleles in our population are A in rs12970134 and C in rs17782313 that are associated with high BMI (> 30 kg/m2) in obese women with PCOS (OR = 1.348, p = 0.002 and OR = 1.364, p = 0.002 respectively) in the homozygous state. In addition, we found that the other genotypes for non-obese PCOS group, AG/GG for rs12970134 and CT/TT for rs17782313, are associated with hirsutism, loss of hair, hyperandrogenism and anti-Müllerian hormone in PCOS.ConclusionsThese findings demonstrate that MC4R single nucleotide polymorphisms, rs12970134 and rs17782313, are correlated with elevated BMI in PCOS but are not causative factors for PCOS among women in the western region of Saudi Arabia. Moreover, the reverse genotypes are associated with major clinical variants in non-obese (< 30 kg/m2) PCOS patients may demonstrate a poor prognosis for this group.

Project description:BackgroundPolycystic ovary syndrome is a multifactorial endocrine disorder impacting women of reproductive age. Variations within the FTO gene have been linked to both obesity and type 2 diabetes mellitus. Given that PCOS is frequently associated with obesity and compromised glucose tolerance, we investigated the prevalence of the rs9939609 variant within the FTO gene among women diagnosed with PCOS and a control group. Our aim is to uncover potential correlations between this genetic variant, metabolic attributes, and endocrine markers within the Gujarat province of India.MethodWe enrolled a total of 114 participants, (62 individuals diagnosed with PCOS and 52 healthy controls). DNA extraction from venous blood was conducted for all participants. The rs9939609 polymorphism was investigated through tetra-primer amplification refractory mutation system-polymerase chain reaction. Furthermore, we performed biochemical assessments to quantify levels of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), total testosterone, prolactin (PRL), and Dehydroepiandrosterone sulfate (DHEAS). Statistical analyses were carried out utilizing SPSS version 21 (IBM, USA).ResultsThe present study did not reveal any noteworthy association between cases and controls. The frequencies of genotypes and alleles within the cohorts displayed no statistically significant differences (p = 0.25, p = 0.68, and p = 0.78, respectively). The dominant model indicated a modest risk (OR:1.13, 95%CI: 0.55 to 2.38) toward PCOS development. There was a noticeable statistical difference observed in the levels of total testosterone, DHEAS, and BMI between the case and control groups (p < 0.002, p < 0.0002, p < 0.0008). However, no variations in clinical variables were observed among genotypes within the PCOS group.ConclusionThis is the first study to investigate the association of FTO gene polymorphism and PCOS in Gujarati population. Our study findings indicate that the FTO gene variant is not directly linked to the onset of PCOS. However, it appears to exert an influence on metabolic factors such as obesity and insulin resistance. Notably, our results suggest that insulin resistance is more frequently observed among PCOS patients who are obese, as compared to those with non-obese PCOS patients.

Project description:Study questionIs there a relationship between the genetic risk for polycystic ovary syndrome (PCOS) and genetic variants that influence timing of menopause?Summary answerThe genetic risk score, which sums the contribution of variants at all menopause loci, was associated with PCOS.What is already knownOvarian parameters and anti-Mullerian hormone levels suggest that women with PCOS should have a later age at menopause.Study design, size, durationThe study was a case-control examination of genetic variants associated with age at menopause in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston recruited from 2003 to 2012. Replication was performed in women from Greece (cases, n = 884 and controls, n = 311).Participants/materials, settings, methodsPCOS was defined by the National Institutes of Health criteria in Boston and Greece (n = 783), with additional subjects fulfilling the Rotterdam criteria (hyperandrogenism, polycystic ovary morphology and regular menses) in Greece (n = 101). Controls in Boston and Greece had regular menstrual cycles and no hyperandrogenism. Allele frequencies for variants previously associated with age at menopause were examined in PCOS cases and controls, along with the relationship to quantitative traits.Main results and role of chanceThe variant rs11668344-G was associated with decreased risk of PCOS (odds ratio: 0.77 [0.59-0.93]; P = 0.004). There was a strong relationship between the late menopause allele rs12294104-T and increased LH levels (β ± SE; 0.26 ± 0.06; P = 5.2 × 10(-5)) and the LH:FSH ratio (0.28 ± 0.06; P = 2.7 × 10(-6)). The minor allele at rs10852344-T was associated with smaller ovarian volume (-0.16 ± 0.05; P = 0.0012). A genetic risk score calculated from 16 independent variants associated with age at menopause was also associated with PCOS (P < 0.02), LH and the LH:FSH ratio (both P < 0.05).Limitations, reasons for cautionThe variant rs11668344 was not associated with PCOS in the Greek cohort, but results exhibited the same direction of effect as the Boston cohort. However, it is possible that the individual association was a false positive in the Boston cohort.Wider implications of the findingsThe study demonstrates that gene variants known to influence age at menopause are also associated with risk for PCOS. Further, our data suggest that the relationship between age at menopause and PCOS may be explained, at least in part, by effects on LH levels and follicle number. The data point to opposing influences of the genetic variants on both menopausal age and PCOS.Study funding/competing interestsThe project was supported by award number R01HD065029 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, award number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources and award 1-10-CT-57 from the American Diabetes Association. C.K.W. is a consultant for Takeda Pharmaceuticals.Trial registration numberNCT00166569.

Dataset Information

FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome.

Publications

FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome.

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