Evidence for association between polycystic ovary syndrome (PCOS) and TCF7L2 and glucose intolerance in women with PCOS and TCF7L2.
ABSTRACT Of the recently identified type 2 diabetes mellitus (T2D) susceptibility loci, transcription factor 7-like 2 (TCF7L2) confers the greatest relative risk for T2D and significantly predicts conversion to T2D in persons with impaired glucose tolerance. TCF7L2 is, therefore, also a strong candidate gene for polycystic ovary syndrome (PCOS), a common endocrine disorder characterized by androgen excess and menstrual irregularities and associated with insulin resistance and a 7-fold increased risk for T2D.
We tested for association between 58 single nucleotide polymorphisms mapping to TCF7L2 and PCOS in 624 index (PCOS) cases and 553 control women of European ancestry. Furthermore, in the women with PCOS, we tested for association with seven reproductive and metabolic quantitative traits.
Although we did not detect evidence for association between the previously described TCF7L2 T2D locus, the proinsulin:insulin molar ratio, a marker of pancreatic beta-cell dysfunction, was strongly associated with this locus (P = 2.1 x 10(-4)). We also observed evidence for association between PCOS and two single nucleotide polymorphisms, rs11196236 (P = 9.0 x 10(-4)) and rs11196229 (P = 0.0027) mapping more than 100 kb centromeric to the previously published T2D susceptibility loci.
We have observed evidence of association with two independent TCF7L2 loci in a PCOS cohort: 1) association between the proinsulin:insulin molar ratio and the T2D locus; and 2) association with reproductive PCOS phenotype and a novel locus. This study suggests that variation in different regions of a susceptibility gene contributes to distinct phenotypes.
Article: Glucose intolerance, insulin resistance and cardiovascular risk factors in first degree relatives of women with polycystic ovary syndrome.[show abstract] [hide abstract]
ABSTRACT: The aim of the present study was to evaluate insulin resistance (IR), glucose tolerance status and cardiovascular risk factors in first degree relatives of patients with polycystic ovary syndrome (PCOS). A total of 120 family members [Mothers(PCOS) (n = 40), Fathers(PCOS) (n = 38), Sisters(PCOS) (n = 25) and Brothers(PCOS) (n = 17)] of 55 patients with PCOS and 75 unrelated healthy control subjects without a family history of diabetes or PCOS (four age- and weight-matched subgroups, i.e. Control(Mothers), Control(Fathers), Control(Sisters) and Control(Brothers)) were studied. IR was assessed by homeostatic model assessment (HOMA IR), log HOMA, insulin sensivity index (ISI), the quantitative insulin sensitivity check index (QUICKI) and area under the curve for insulin during the oral glucose tolerance test (AUCI, AUCG) in with normal glucose tolerance (NGT) subjects and controls. Serum adiponectin, resistin, homocysteine and lipid levels were measured. The prevalence of any degree of glucose intolerance was 40% in Mothers(PCOS) and 52% in Fathers(PCOS). In total, six (15%) glucose tolerance disorders were identified in the Control(Mothers) and Control(Fathers) in first degree relatives of control subjects. The first degree relatives of PCOS patients had significantly higher serum fasting insulin, HOMA-IR, Log HOMA and AUCI levels in all subgroups than the control subjects. The control subjects had significantly elevated QUCKI, ISI levels and serum adiponectin levels compared to the first degree relatives of PCOS subjects in all subgroups. The serum Hcy and resistin levels increased significantly in both Fathers(PCOS) and Mothers(PCOS) groups but not Brothers(PCOS) and Sister(PCOS). The results of the present study support the finding that the first degree relatives of PCOS patients carry an increased risk of cardiovascular disease, as do PCOS patients.Human Reproduction 10/2005; 20(9):2414-20. · 4.47 Impact Factor