Investigating the association of previously identified genome-wide significant loci (rs10739076 and rs1784692) with PCOS susceptibility and its related traits in Indian women

Abstract

Objective(s)Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy with an enigmatic etiology. Hallmark features include irregular menstrual cycles, insulin resistance and hyperandrogenemia and affected women are prone to development of adverse reproductive and cardiometabolic outcomes like anovulatory infertility, impaired glucose tolerance, type 2 diabetes, dyslipidemia, metabolic syndrome and cardiovascular disease. Genetic underpinnings of PCOS have been investigated extensively using genome-wide association studies, which have led to the identification of several novel susceptibility loci. However, as ethnic diversity contributes to phenotypic and genetic heterogeneity, we undertook the first genetic association study to determine the association of rs10739076 of PLGRKT and rs1784692 of ZBTB16 with PCOS susceptibility and its related traits in Indian women. Study DesignThe present case-control study comprised 497 women with PCOS diagnosed according to the Rotterdam criteria and 233 age matched healthy women as controls. All participants were characterized in terms of anthropometric, hormonal and metabolic parameters and the variants were investigated by direct sequencing. Genotypic and genotype-phenotype association of these variants with PCOS susceptibility and its related biochemical and hormonal traits was analyzed with appropriate statistical tests. ResultsThe genotypic and allelic frequencies of rs1784692 of ZBTB16 were significantly decreased in lean women with PCOS only, and this variant was associated with lowered insulin levels, HOMA-IR, LH:FSH ratio along with increased ApoA1 levels and QUICKI in them. Although, the PLGRKT variant, rs10739076, showed similar frequency distribution in both lean and obese groups, it was found to be associated with reduced fasting glucose in all women with PCOS. Conclusion(s)To the best of our knowledge, this is the first study to demonstrate that ZBTB16 variant showed significant association with reduced PCOS susceptibility in lean rather than obese Indian women, highlighting the impact of obesity on determining genetic predisposition to PCOS in Indian women. In contrast, PLGRKT variant did not influence PCOS risk in lean or obese women. Importantly, both variants exerted a protective effect on glucose metabolism, insulin resistance, gonadotropin and lipid levels in women with PCOS. Determination of susceptibility variants for PCOS demand population specific replication studies to ascertain best candidate loci for PCOS.