Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis

Abstract

POLYCYSTIC OvarY SYndrOme (PCOS)is one of the most common heterogeneous endocrine disorders, which affect 5%-10% of women in reproductive age and is a leading causes of female infertility [1]. It is characterized by menstrual irregularity, hyperandrogenism, insulin resistance, and increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) [2,3]. Candidate genes for etiology of PCOS involve in ovarian and adrenal steroidogenesis, steroid hormone actions, gonadotropin action and regulation, insulin action and secretion, energy homeostasis, chronic inflammation and others [4]. Yet the "PCOS genes" remain elusive. Insulin resistance is a key component in the pathogenesis of PCOS and the predisposition to type 2 diabetes [5,6], however, the mechanisms for defects in insulin signaling in the disorder are comAssociation of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis Yuan Ruan, Jianhua Ma and Xiaojing Xie Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China abstract. Insulin resistance (IR) plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS) which is a common disorder in premenopausal women. The association between the single nucleotide polymorphisms (SNPs) of insulin receptor substrate (IRS) gene and PCOS in several populations has been studied, but the results are conflicting. The aim of this study was undertaken to investigate association of IRS-1 and IRS-2 genes polymorphisms with PCOS by conducting a meta-analysis. Literature search was conducted through PubMed and EMBASE databases (up to July 31, 2011). Fifteen articles with 1,358 cases and 1,561 controls were enrolled in the meta-analysis of the association between Gly972Arg variant and PCOS, and five articles with 519 cases and 883 controls were enrolled in the meta-analysis of Gly1057Asp variant. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed and random-effects models. The Q-statistic test was used to assess heterogeneity, and Begg's test and Egger's test were used to evaluate publication bias. Sensitivity analysis was also performed. Our results indicated that A allele of Gly972Arg conferred a significantly increased risk of PCOS compared with G allele (OR = 1.91, 95% CI: 1.36-2.68). However, in Gly1057Asp polymorphism the OR of allele A vs. G is 0.92 (95% CI: 0.72, 1.18). Our meta-analysis suggested that IRS-1 Gly972Arg polymorphism might be considered a significant risk for PCOS. Otherwise, no significant associations were observed in IRS-2 Gly1057Asp polymorphism which needs to be further confirmed by further studies.Key words: Insulin receptor substrate, Polymorphisms, Polycystic ovary syndrome, Meta-analysis plex and have not been fully elucidated [7,8].Insulin receptor substrates proteins (IRS) are critical for insulin mediated signal transduction in insulin target tissues. Several studies have shown that two common polymorphisms in IRS particularly Gly972Arg (rs1801278) in ...

Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

“…One case-control study replicated the insulin receptor (414), and several independent studies have reported evidence for an association with IRS-1 (417). Studies have not significantly associated the diabetes susceptibility region of the TCF7L2 gene with the PCOS reproductive phenotype, although studies have associated a novel region of the gene with PCOS-affected status (418).…”

Past, Present and Future of Insulin Gene and Its Related Genes In Relation To Polycystic Ovary Syndrome

“…Recent four researches in the association between IRS-1 Gly972Arg polymorphism and PCOS still had different conclusions [38][39][40][41]. Very recent meta-analysis by Ruan Y in 2012 concluded that IRS-1 Gly972Arg polymorphism is associated with PCOS, and this variation might be considered as a risk factor for PCOS further this study also concluded that no significant association was detected between IRS-2 Gly1057Asp polymorphism and PCOS [12].…”

“…In the reproductive system, it stimulates ovaries to produce and secrete androgens, enhances ovarian growth, and inhibits apoptosis in the ovarian follicles, which may cause cyst formation [9,11]. Because insulin resistance, hyperinsulinaemia, and β-cell dysfunction are common features of PCOS, insulin, and the other members of insulinsignaling pathway have been considered to be candidates for PCOS [12]. A Variable Number of Tandem Repeats (VNTR) polymorphism located in the 5' regulatory element of the insulin gene INS, affects its transcriptional regulation, and is associated with hyperinsulinemia, fasting insulin levels, susceptibility to T2DM, birth weight, and childhood obesity and juvenile obesity [10].…”

“…Although a considerable progress has been made in identifying PCOS susceptibility genes in the last decade, this progress has been much slower in comparison to mapping studies of some of the other complex human traits, such as T2DM and obesity [12]. Still a number of strong PCOS susceptibility candidate genes are under scrutiny and with just started genome wide association studies, we are still far from fully understanding all the genetic contributions to this disorder.…”

Genetic Markers of Polycystic Ovary Syndrome: Emphasis on Insulin Resistance

“…A Mendelian meta-analysis has confirmed significant association of IRS-1 (Gly972Arg) polymorphism with the risk of developing PCOS and impaired insulin signaling [36]. A recent meta-analysis also revealed significant association of IRS-1 Gly972Arg polymorphism with PCOS but not with IRS-2 Gly1057Asp polymorphism [55].…”