CLINICAL STUDY The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome Susanne Hahn, Ulrich H Frey 1 , Winfried Siffert 1 , Susanne Tan 2 , Klaus Mann 2 and Onno E Janssen 2 Endokrinologikum Ruhr, Center forendocrine and metabolic diseases, Alter Markt 4, 44866 Bochum, Germany, 1 Institute of Pharmacogenetics, and 2 Division of Endocrinology, Department of Medicine, University Hospital of Essen Medical School, Essen, Germany (Correspondence should be addressed to S Hahn; Email: susanne.hahn@endokrinologikum.com) Abstract Objective: Variants in the Gs protein a subunit gene (GNAS1) are known to be involved in the pathogenesis of several endocrine and metabolic disorders. To understand genetic determinants of androgen excess, insulin resistance, and obesity in polycystic ovary syndrome (PCOS), we investigated the effect of the common GNAS1 T393C polymorphism on the phenotype of German PCOS women. Design: Two hundred and seventy-eight PCOS women and 820 Caucasian controls were genotyped for the common T393C polymorphism in GNAS1. To this end, genomic DNA was amplified by PCR with specific oligonucleotides and genotypes were determined using the restriction enzyme FokI. In addition, we evaluated whether the T393C polymorphism had an influence on the response to 6 months metformin treatment in a subgroup of 105 PCOS women. Methods: Anthropometric variables, metabolic parameters including indices of insulin resistance measured by oral glucose tolerance testing, and endocrine biochemical as well as clinical parameters were measured in all PCOS subjects. Results: GNAS1 genotype distributions were not significantly different between PCOS women and controls. In PCOS women, no significant differences in endocrine clinical and biochemical variables were found between the genotypes. However, the C-allele carrier group had significantly higher mean body weight, body mass index, leptin levels, and higher indices of insulin resistance compared with women with GNAS1 TT-genotype. Metformin treatment significantly improved hyperandrogenism, menstrual cyclicity, body weight, and insulin resistance independent of GNAS1 genotype. The major determinant of weight loss was body weight before treatment. Conclusion: The T393C polymorphism is not associated with PCOS in Caucasian women, but may represent a genetic marker for increased susceptibility for obesity in this cohort. European Journal of Endocrinology 155 763–770 Introduction Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders, affecting more than 5% of reproductive aged women. Family studies support a familial aggregation of PCOS (1), consistent with a genetic basis for this disorder. Associations of PCOS with mutations in a variety of candidate genes involved in pathways regulating steroid hormone synthesis (2, 3) or insulin metabolism have been analyzed, without evidence of a single common defect. In women with PCOS, the impairment of insulin metabolism is thought to be influenced by both environmental (4) and genetic factors (5, 6). Recently published studies from the Czech Republic (7) and Finland (8) have shown that insulin resistance and metabolic abnormalities are related to obesity rather than to PCOS per se. Obesity is a common feature of women with PCOS in different ethnic cohorts affecting about half of the entire PCOS population (9, 10). Genetic polymorphisms predisposing to obesity are of major interest. It is well known that obesity is due to environmental factors and lifestyle, but a great amount of body mass variation is likely to be inherited (11). Defects in the melanocortin pathway are related to severe obesity (12). Similar results were obtained for leptin receptor mutations (13), variations of the resistin gene (14), and the adiponectin locus (15). In Germans, Chinese, and South Africans, the 825T allele of the gene GNB3 encoding the G-protein b3 subunit is significantly associated with obesity with odds ratios (ORs) between 2 and 3 (16). In PCOS women, the microsatellite CA-repeat polymorphism in the interleukin 6R-a gene was shown to influence obesity (17). European Journal of Endocrinology (2006) 155 763–770 ISSN 0804-4643 q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02275 Online version via www.eje-online.org