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The Methionine 196 Arginine Polymorphism in Exon 6 of the TNF Receptor 2 Gene (TNFRSF1B) Is Associated with the Polycystic Ovary Syndrome and Hyperandrogenism

Instituto de Investigaciones Biomédicas (B.P.), Consejo Superior de Investigaciones Científicas, 28029 Madrid, Spain; Departments of Molecular Genetics (J.L.S.M.) and Endocrinology (H.F.E.-M.), Hospital Ramón y Cajal, 28034 Madrid, Spain; and Division of Endocrinology and Metabolic Diseases (R.C., P.M.), University of Verona, I-37126 Verona, Italy

Address all correspondence and requests for reprints to: Héctor F. Escobar-Morreale, M.D., Ph.D., Department of Endocrinology, Hospital Ramón y Cajal, Carretera de Colmenar km. 9, 100, 28034 Madrid, Spain. E-mail: . hector.escobar{at}uam.es

Abstract

Inflammatory cytokines such as TNF may play a role in the pathogenesis of common metabolic disorders, including hyperandrogenism and the polycystic ovary syndrome (PCOS). The TNF receptor 2 mediates most of the metabolic effects of TNF. In the present study, we have evaluated serum soluble TNF receptor 2 levels, and several common polymorphisms in the TNF receptor 2 gene (TNFRSF1B), in women presenting with PCOS or hyperandrogenic disorders. Initial studies included 103 hyperandrogenic patients (42 presenting with PCOS) and 36 controls from Spain. The 196R alleles of the M196R (676 TG) variant in exon 6 of TNFRSF1B, which is in linkage disequilibrium with a CA-repeat microsatellite polymorphism in intron 4 of TNFRSF1B, tended to be more frequent in hyperandrogenic patients than in controls (P = 0.056), reaching statistical significance when the analysis was restricted to include only PCOS patients (P < 0.03). Extended analysis including another 11 hyperandrogenic patients from Spain and 64 patients and 29 controls from Italy confirmed the association between 196R alleles of the M196R variant and hyperandrogenic disorders (P < 0.05), which was maintained when restricting the analysis to PCOS patients (P < 0.02). On the contrary, the 3'-untranslated region (exon 10) variants 1663 GA, 1668 TG, and 1690 TC were not associated with hyperandrogenism. The soluble TNF receptor 2 levels were not different between patients and controls but were increased in obese subjects, compared with lean individuals, and were affected by the interaction between the 1663 GA and 1668 TG variants in the 3'-untranslated region of TNFRSF1B. The TNFRSF1B genotype did not influence any clinical or biochemical variable related to hyperandrogenism or insulin sensitivity and was not associated with obesity, both in hyperandrogenic patients and healthy controls considered separately. In conclusion, the M196R (676 TG) variant in exon 6 of TNFRSF1B is associated with hyperandrogenism and PCOS, further suggesting a role for inflammatory cytokines in the pathogenesis of these disorders.

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