Replication of association of a novel insulin receptor gene polymorphism with polycystic ovary syndrome

• Published in: Fertility and sterility Vol. 95; no. 5; pp. 1736 - 1741.e11
• Main Authors: Goodarzi, Mark O., M.D., Ph.D, Louwers, Yvonne V., M.D, Taylor, Kent D., Ph.D, Jones, Michelle R., B.Sc, Cui, Jinrui, M.S, Kwon, Soonil, Ph.D, Chen, Yii-Der I., Ph.D, Guo, Xiuqing, Ph.D, Stolk, Lisette, Ph.D, Uitterlinden, André G., Ph.D, Laven, Joop S.E., M.D., Ph.D, Azziz, Ricardo, M.D., M.P.H., M.B.A
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2011; Elsevier
• Subjects: Adolescent; Adult; alleles; animal ovaries; Biological and medical sciences; body mass index; Case-Control Studies; Cohort Studies; Female; Female genital diseases; Gene Frequency; Genome-Wide Association Study; glycogen synthase kinases; Gynecology. Andrology. Obstetrics; Humans; INSR; insulin; insulin receptors; Internal Medicine; Medical sciences; Middle Aged; Models, Biological; Non tumoral diseases; Obstetrics and Gynecology; patients; PCOS; polycystic ovary syndrome; Polycystic Ovary Syndrome - genetics; Polycystic Ovary Syndrome - metabolism; Polymorphism, Single Nucleotide - physiology; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; replication; Reproducibility of Results; signal transducing adaptor proteins; single nucleotide polymorphism; SNP; Young Adult; Alabama; replication; PCOS; SNP; INSR; Gynecology; Female sterility; Polycystic ovary; Obstetrics; Female genital diseases; Ovarian diseases; Cyst; Replication; Benign neoplasm; Polymorphism; Hormonal receptor
• ISSN: 0015-0282; 1556-5653
• DOI: 10.1016/j.fertnstert.2011.01.015

Objective To evaluate association with polycystic ovary syndrome (PCOS) of 295 variants in 39 genes central to metabolic insulin signaling and glycogen synthase kinase 3β (GSK-3β) regulation, followed by replication efforts. Design Case-control association study, with discovery and replication cohorts. Setting Subjects were recruited from reproductive endocrinology clinics, and controls were recruited from communities surrounding the University of Alabama at Birmingham and Erasmus Medical Center, Rotterdam. Patient(s) A total of 273 cases with PCOS and 173 control subjects in the discovery cohort; and 526 cases and 3,585 control subjects in the replication cohort. All subjects were caucasian. Intervention(s) Phenotypic and genotypic assessment. Main Outcome Measure(s) Detection of 295 single-nucleotide polymorphisms (SNPs), PCOS status. Result(s) Several SNPs were associated with PCOS in the discovery cohort. Four insulin receptor ( INSR ) SNPs and three insulin receptor substrate 2 ( IRS2 ) SNPs associated with PCOS were genotyped in the replication cohort. One INSR SNP (rs2252673) replicated association with PCOS. The minor allele conferred increased odds of PCOS in both cohorts, independent of body mass index. Conclusion(s) A pathway-based tagging SNP approach allowed us to identify novel INSR SNPs associated with PCOS, one of which confirmed association in a large replication cohort.