Polymorphisms of the insulin receptor and the insulin receptor substrates genes in polycystic ovary syndrome: A Mendelian randomization meta-analysis

Polycystic ovary syndrome (PCOS) is a heterogeneous condition with unknown aetiology which is considered to be the most common endocrine disorder in women of reproductive age. In this work we investigated the association of insulin receptor (INSR) and insulin receptor substrates (IRSs) polymorphisms with the risk of developing PCOS. The meta-analysis of eleven studies (889 cases, 1303 controls) yielded a significant association for IRS-1 Gly972Arg (G972R) polymorphism concerning the GR vs. GG genotype (OR: 1.77, 95% Cl: 1.28, 2.45), with no between-studies heterogeneity. Concerning INSR His1058 C/T, the meta-analysis of eight studies (795 cases, 576 controls) found no significant evidence for association with PCOS (OR for the TT + CT vs. CC comparison equal to 1.28 with 95% Cl: 0.88, 1.85) and a moderate between studies variability (I-2 = 44.6%). No evidence for publication bias was found in these meta-analyses. Following a multivariate Mendelian randomization approach, the overall OR was unaffected but the overall mean difference of fasting insulin levels between carriers of GR and RR genotypes in controls was significant (2.18, 95% Cl: 0.36, 4.01). These results suggest that IRS-1 Gly972Arg polymorphism is significantly associated with the risk of developing PCOS and that this association is primarily mediated by increasing the levels of fasting insulin. The particular polymorphism is located in a region nearby two phosphorylation sites that interact physically with INSR and PI 3-kinase and there is enough evidence from the literature suggesting that the Arg972 variant is associated with decreased PI 3-kinase activity and impaired insulin-stimulated signaling.