Relationship of insulin receptor substrate-1 and -2 genotypes to phenotypic features of polycystic ovary syndrome.
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 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp), 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 Gly(972)Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. The IRS-2 Gly(1057)Asp 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 Gly(1057)Asp 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.
Ehrmann
David A
DA
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. dehrmann@medicine.bsd.uchicago.edu
Tang
Xu
X
Yoshiuchi
Issei
I
Cox
Nancy J
NJ
Bell
Graeme I
GI
D000328:Adult; D019943:Amino Acid Substitution; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020125:Mutation, Missense; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D011110:Polymorphism, Genetic; D011972:Receptor, Insulin / Q000235:genetics
D001786:Blood Glucose; D017931:DNA Primers; D006442:Glycated Hemoglobin; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011972:Receptor, Insulin; C526292:IRS1 protein, human; C526297:IRS2 protein, human