The 312N variant of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR) confers up to 2•7-fold increased risk of polycystic ovary syndrome in a Sardinian population

Objective Polycystic ovary syndrome (PCOS) is a frequent condition, affecting about 15% of women of reproductive age. Because of its familial occurrence, a multifactorial model of susceptibility, including both genetic and environmental factors, has been proposed. However, the identification of genetic factors has been elusive. Design Casecontrol study aimed at evaluating possible associations between functionally relevant variants of the luteinizing hormone/choriogonadotrophin receptor gene (LHCGR) and PCOS phenotype. Patients A total of 198 PCOS and 187 non-PCOS women, aged 1435 years, of Sardinian origin, were referred to the outpatient clinic of the Department of Obstetrics and Gynaecology of the University of Cagliari (Sardinia). PCOS diagnosis was based on the Rotterdam criteria. Measurements We determined the genotype of ins18LQ, S291N and S312N variants at the LHCGR locus. Genotype was related to the presence or absence of PCOS and to several clinical and biochemical characteristics. Results The presence of at least one 312N allele was strongly associated with PCOS risk (OR, 2.04; 95% CI, 1.323.14; ?2, 10.47; P = 0.001). 312N homozygosity was associated with a further risk increase (OR, 2.73; 95% CI, 1.255.95; ?2, 6.65; P = 0.01). The number of ins18LQ alleles was associated with LH serum levels in controls (?2, 8.04, P = 0.017). Conclusions For the first time, we have identified a genetic variant that is strongly associated with PCOS in an isolated population. These results, if confirmed in other cohorts, may provide the opportunity to test the S312N genotype at the LHCGR locus in fertile women to assess the risk of PCOS. The avoidance of triggering factors like weight increase may improve the reproductive outcome of potentially at-risk subjects.