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Relationship of Insulin Receptor Substrate-1 and -2 Genotypes to Phenotypic Features of Polycystic Ovary Syndrome

Departments of Medicine (D.A.E., X.T., N.J.C., G.I.B.), Human Genetics (N.J.C., G.I.B.), and Biochemistry and Molecular Biology (I.Y., G.I.B.), and Howard Hughes Medical Institute (G.I.B.), University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: David A. Ehrmann, M.D., Department of Medicine, Section of Endocrinology, University of Chicago, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. E-mail: . dehrmann{at}medicine.bsd.uchicago.edu

Abstract

Insulin resistance is a key component in the pathogenesis of polycystic ovary syndrome (PCOS) and type 2 diabetes. Polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, IRS-1 (Gly⁹⁷²Arg) and IRS-2 (Gly¹⁰⁵⁷Asp), influence susceptibility to type 2 diabetes. This study was undertaken to assess the influence of these polymorphisms on insulin resistance, glucose tolerance, and androgen levels in nondiabetic PCOS women.

We studied 227 PCOS subjects including 126 and 48 nondiabetic white and African-American subjects, respectively. The IRS-1 Gly⁹⁷²Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. The IRS-2 Gly¹⁰⁵⁷Asp allele frequencies were 0.85 (Gly) and 0.15 (Asp) in African-Americans and 0.59 (Gly) and 0.41 (Asp) in whites. There was no association of IRS-1 genotype with any clinical or hormonal measure in nondiabetic white or African-American PCOS subjects. However, nondiabetic subjects with the IRS-2 Gly/Gly genotype had significantly higher 2-h oral glucose tolerance test glucose levels compared with those with Gly/Asp and Asp/Asp genotypes in whites or Gly/Asp genotype in African-Americans (there were no Asp/Asp subjects in our modest size African-American sample). These results suggest that the IRS-2 Gly¹⁰⁵⁷Asp polymorphism influences blood glucose levels in nondiabetic white and African-American women with PCOS. Thus, individuals with the common IRS-2 Gly/Gly genotype may be at increased risk of developing type 2 diabetes.

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