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Departments of Biochemistry and Molecular Biology (S.Y.A., G.I.B.), Medicine (M.H., G.I.B., D.A.E.), and Human Genetics (G.I.B.), The 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, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. E-mail: dehrmann{at}medicine.bsd.uchicago.edu.
Insulin resistance, a key factor in the pathogenesis of polycystic ovary syndrome (PCOS), is associated with a reduction in activation of muscle glycogen synthase. A 5-bp insertion-deletion polymorphism in the (AU)AT-rich element (ARE) within the 3'-untranslated region of the gene encoding the muscle-specific glycogen-targeting subunit of protein phosphatase 1 (PPP1R3) has been associated with insulin resistance and type 2 diabetes. The present study was undertaken to examine the relationship of the ARE polymorphism with clinical and hormonal characteristics of women with PCOS. We studied 186 women with PCOS who had undergone a standard 75-g oral glucose tolerance test and measurement of serum androgen and SHBG levels. Among the largest cohort of nondiabetic subjects (Caucasian, n = 112), the presence of the deletion allele (ARE-2) was associated with insulin resistance and hyperandrogenemia. There was no association of the ARE polymorphism with body mass index or blood glucose concentration during the oral glucose tolerance test. Subjects who were homozygous for the insertion allele (ARE-1/1) had a mean insulin area under the curve (99,116 ± 6,625 pmol/liter·min) that was significantly lower than that in either the heterozygous (ARE-1/2) (132,195 ± 12,340 pmol/liter·min) or homozygous (ARE-2/2) (164,661 ± 24,219 pmol/liter·min) deletion groups. In addition, ARE-1/1 subjects had significantly lower serum concentrations of dehydroepiandrosterone sulfate compared with ARE-2/2 subjects (4.2 ± 0.3 vs. 6.6 ± 0.7 µmol/liter) and a trend toward lower levels of free testosterone (78.8 ± 6.5 vs. 114.1 ± 30.8 pmol/liter). Studies of diabetic and nondiabetic PCOS women of other racial and ethnic backgrounds will be necessary to assess the impact of this and other variants in PPP1R3 upon the phenotype and natural history of women with PCOS.
This work was supported by the U.S. Public Health Service (Grants DK-20595, DK-44840, DK-47486, and RR-00055), a Clinical Research Award (to D.A.E.) from the American Diabetes Association, and a gift from the Blum-Kovler Foundation.
G.I.B. is an Investigator of the Howard Hughes Medical Institute.
Abbreviations: BMI, Body mass index; DHAS, dehydroepiandrosterone sulfate; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; PP1, protein phosphatase-1; PP1G, glycogen-bound PP1; UTR, untranslated region.
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