Disparate genetic influences on polycystic ovary syndrome (PCOS) and type 2 diabetes revealed by a lack of association between common variants within the TCF7L2 gene and PCOS

Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.
Diabetologia (Impact Factor: 6.67). 12/2007; 50(11):2318-22. DOI: 10.1007/s00125-007-0804-z
Source: PubMed


Common variants of the gene encoding transcription factor 7-like 2 (TCF7L2) have a powerful effect on individual risk of type 2 diabetes (per allele odds ratio approximately 1.35). Polycystic ovary syndrome (PCOS) and type 2 diabetes are familial conditions sharing common features. Based on this, the aim of the present study was to establish whether variation in TCF7L2 also influences the development of PCOS.
We conducted a genetic association study of variants of TCF7L2 (rs7903146 and rs12255372) using both case-control and quantitative trait approaches. Case-control analyses were conducted in (1) 369 PCOS cases and 2574 controls of UK British/Irish origin, and (2) 540 women with PCOS symptoms and 1083 controls from the Northern Finland Birth Cohort of 1966. Quantitative trait analyses (androgen levels) were also performed (1249 individuals).
There was no association between rs7903146 and PCOS in the UK case-control study (Cochran-Armitage test, p = 0.51); nor with symptomatic status in the Finnish cohort (p = 0.36). In addition, there were no relationships between the TCF7L2 single nucleotide polymorphism rs7903146 and androgen levels (UK cases, p = 0.99; Finnish controls, p = 0.57; Finnish symptomatic cases, p = 0.80). Results at rs12255372 were similar, reflecting strong linkage disequilibrium with rs7903146.
Our study was powered to detect an effect on PCOS susceptibility similar to that previously reported for these variants on type 2 diabetes. Failure to detect any evident association with PCOS provides the strongest evidence yet that the genetic architecture of these related conditions is qualitatively distinct.

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Available from: Stephen Franks, Aug 27, 2015
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    • "This was in agreement with the earlier study of Barber who did not find any association between rs7903146 and rs12255372 and PCOS in two cohorts: the first (UK British/Irish) consisting of 369 PCOS cases and 2577 controls; and the second (Northern Finland) comprising 540 PCOS and 1083 control women. This study found no association between TCF7L2 polymorphisms and glucose homeostasis in PCOS women (Barber et al., 2007 "
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    ABSTRACT: Background and Aims Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women in their child-bearing age, and is often associated with insulin resistance and type 2 diabetes (T2DM). Given the overlap between PCOS and T2DM, we investigated the association of Transcription Factor 7-Like 2 (TCF7L2) variants rs4506565, rs7903146, rs12243326, and rs12255372 with the susceptibility to PCOS Subjects and Methods Study subjects comprised 119 Tunisian women with PCOS (mean age 29.8±4.7years), and 150 control women (mean age 30.6±5.9years). TCF7L2 genotyping was done by the allelic discrimination/real-time PCR method. Minor allele frequencies (MAF) of rs4506565 (P=0.61), rs7903146 (P=0.68), rs12243326 (P=0.56), and rs12255372 (P =0.60), were comparable between PCOS cases and controls subjects. As the four tested TCF7L2 variants were in linkage disequilibrium, 4-locus (rs4506565, rs7903146, rs12243326, rs12255372) haplotype analysis demonstrated that haplotype 2111 was initially negatively associated with PCOS [P=0.035; OR (95% CI)=0.13 (0.02 - 0.85)], which was later lost upon correcting for multiple comparisons [Pc=0.248]. Our data suggest that there is weak or no contribution of TCF7L2 gene polymorphism to PCOS in Tunisian women. Further studies with larger samples are necessary to confirm this observation.
    Gene 10/2013; 533(2). DOI:10.1016/j.gene.2013.09.104 · 2.14 Impact Factor
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    • "GWAS reported association of a SNP in TCF7L2 with T2DM and IR in Caucasians [21,27,28] but a negative association to body weight [21,28-30]. In PCOS patients, using a sample size and design similar to their FTO study [12], a case-control comparison did not provide evidence for an association of TCF7L2 variants with disease status [31]. A further (negative) correlation to weight status was robustly found for a non-synonymous polymorphism Val103Ile in the melanocortin-4 receptor gene (MC4R) [32-34]. "
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    ABSTRACT: The polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS. 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.
    BMC Medical Genetics 01/2010; 11(1):12. DOI:10.1186/1471-2350-11-12 · 2.08 Impact Factor
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    Indium Phosphide and Related Materials, 2004. 16th IPRM. 2004 International Conference on; 01/2004
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