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: 6.88). 12/2007; 50(11):2318-22. DOI: 10.1007/s00125-007-0804-z
Source: PubMed

ABSTRACT 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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    ABSTRACT: The present systematic review and meta-analysis of case-control studies examines the associations between rs7903146 and rs12255372 polymorphisms of the TCF7L2 gene and PCOS. A search of the literature published until August 2014 was carried out in PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and LILACS. There were no other limits except for the end date. We included observational studies with women of any age diagnosed with PCOS and healthy controls that analyzed polymorphisms rs7903146 and rs12255372. We included case-control or cross-sectional studies analyzing polymorphism rs7903146 or rs12255372 in women with PCOS and healthy controls. Eighteen studies were identified after the primary literature search and seven articles were included in the meta-analysis. All employed Rotterdam criteria for the diagnosis of PCOS. The genotypic distributions in the control groups were in agreement with Hardy-Weinberg equilibrium in all studies. The pooled population included Asian descendents (Chinese, Korean), Caucasians from southern Brazil, Tunisian, and European populations (British/Irish, Northern Finns, Greeks, Czechs), including 1,892 women with PCOS and 2,695 controls. There were no significant associations between PCOS and TCF7L2 rs7903146 or rs12255372 polymorphisms, irrespective of whether allele contrast, additive, dominant, or recessive models of inheritance were used. Furthermore, no significant associations were found after stratification for ethnicity (Asian or non-Asian). There was no significant heterogeneity between studies and no publication bias. The present results suggest that rs7903146 T allele or rs12255372 is not associated with risk for PCOS in non-Asian or Asian women. This systematic review and meta-analysis are registered in PROSPERO under number CRD42013005930.
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    ABSTRACT: Abstract Objective: This meta-analysis was performed to evaluate the relationships between genetic polymorphisms in the TCF7L2 gene and polycystic ovary syndrome (PCOS) risk. Methods: The PubMed, Centralised Information Service for Complementary Medicine (CISCOM), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Google Scholar, EBSCO, Cochrane Library, and Common Biorepository Model (CBM) databases were searched for relevant articles published before November 1st, 2013, without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. The relationships were evaluated by calculating the pooled odds ratios (ORs) and their 95% confidence intervals (CIs). Seven case-control studies with a total 2458 PCOS patients and 5109 healthy subjects' met our inclusion criteria for qualitative data analysis. Two common polymorphisms (rs7903146 C→T and rs12255372 G→T) in the TCF7L2 gene were assessed. Results: The results of our meta-analysis suggested that TCF7L2 genetic polymorphisms might be strongly correlated with an increased risk of PCOS (allele model, OR=1.33, 95% CI=1.15-1.54, P<0.001; dominant model, OR=1.40, 95% CI=1.12-1.75, P=0.003), especially for the rs7903146 C→T polymorphism. A subgroup analysis was done to investigate the effect of ethnicity on an individual's risk of PCOS. Our results revealed positive significant correlations between TCF7L2 genetic polymorphisms and an increased risk of PCOS among Caucasians (allele model, OR=1.26, 95% CI=1.08-1.47, P=0.004; dominant model, OR=1.33, 95% CI=1.00-1.76, P=0.046) and Asians (allele model, OR=2.02, 95% CI=1.42-2.89, P<0.001; dominant model, OR=2.02, 95% CI=1.40-2.92, P<0.001), but not among Africans (all P<0.05). Conclusions: Our findings provide convincing evidence that TCF7L2 genetic polymorphisms may contribute to susceptibility to PCOS, especially for the rs7903146 C→T polymorphism among Caucasians and Asians.
    Metabolic syndrome and related disorders 03/2014; DOI:10.1089/met.2014.0004 · 1.92 Impact Factor
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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 · 2.08 Impact Factor


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