K121Q polymorphism in the ENPP1 gene shows association with obesity in Indian women with PCOS

Nuzhat Shaikh; Roshan Dadachanji; Anushree Patil; Srabani Mukherjee

Nuzhat Shaikh Global Gene Corp Pvt Ltd. 404, Alpha, Main Street, Hiranandani Gardens, Powai, Mumbai 400076, India https://orcid.org/0000-0001-9718-697X
Roshan Dadachanji Department of Molecular Endocrinology, National Institute for Research in Reproductive Health, Indian Council for Medical Research, Parel, Mumbai 400 012, India https://orcid.org/0000-0002-9923-3431
Anushree Patil Department of Clinical Research, National Institute for Research in Reproductive Health, Parel, Mumbai 400012, India
Srabani Mukherjee ICMR-National Institute for Research in Reproductive Health https://orcid.org/0000-0001-9243-4428

Keywords: PCOS; ENPP1; obesity; genetics; polymorphism; association study

Abstract

Abstract

Aim: To evaluate the influence of the K121Q variant of ENPP1 gene on the risk of PCOS development and its associated traits of glucose tolerance, insulin resistance, hyperandrogenemia and dyslipidemia in Indian women.

Methods: Genotyping of K121Q polymorphism of ENPP1 was performed in women with PCOS (N = 185) and controls (N =153) women, while phenotypic characterization in terms of clinical, biochemical and hormonal parameters was performed in 83 controls and 143 PCOS women. Genotype only and genotype–phenotype associations were determined by appropriate statistical tests.

Results: K121Q polymorphism showed comparable genotypic frequency distribution between controls and women with PCOS even after BMI-based classification. Intriguingly, both lean and obese controls showed significant association of polymorphic allele with total testosterone levels. Amongst women with PCOS, this polymorphism was significantly associated with lowered LH levels and LH:FSH ratios in lean women, and reduced triglyceride levels in obese women only, respectively. Importantly, the Q allele was found to be significantly associated with increased risk of obesity in women with PCOS only.

Conclusion: This is the first study to determine that even though the K121Q polymorphism of ENPP1 does not influence PCOS risk in Indian women, it beneficially impacts hyperandrogenemia, gonadotropin levels and dyslipidemia in women in accordance with their underlying obesity and physiological status. The contribution of the Q allele to elevated tendency towards obesity may aid clinicians in suggesting appropriate therapeutic interventions to avert long term cardiometabolic complications. This warrants deeper focus on the complex genetic pathomechanisms underlying PCOS.