Calpain-10 Variants and Haplotypes are Associated with Polycystic Ovary Syndrome in Caucasians Short running title: Association of Calpain-10 and PCOS

Polycystic ovary syndrome (PCOS) is known to be associated with an increased risk of type 2 diabetes mellitus (T2DM) and has been proposed to share a common genetic background with T2DM. Recent studies suggest the Calpain 10 gene (CAPN10) being an interesting candidate gene for PCOS susceptibility. However, contradictory results were reported concerning the contribution of certain CAPN10 variants, especially of UCSNP-44, to genetic predisposition to T2DM, hirsutism and PCOS. By means of MALDI-TOF MS technique we genotyped an expanded SNP panel including the CAPN10 UCSNP-44, -43, -56, ins/del-19, -110, -58, -63, and -22 in a sample of 146 German PCOS women and 606 population-based controls. Statistical analysis revealed an association between UCSNP-56 and susceptibility to PCOS with an odds ratio (OR) of 2.91 (95% CI=1.51-5.61) for women carrying an AA genotype compared to GG. As expected, the 22-genotype of the ins/del-19 variant which is in high linkage disequilibrium (r2=0.98) with UCSNP-56, was also significantly associated (OR=2.98, 95% CI=1.55-5.73). None of the further tested variants alone showed any significant association with PCOS. A meta-analysis including our study (altogether 623 PCOS cases and 1224 controls) also showed significant association only with ins/del19. The most common haplotype TGG3AGCA was significantly associated with a lower risk for PCOS (OR=0.487, p=0.0057). In contrast the TGA2AGCA haplotype was associated with an increased risk for PCOS (OR=3.557, p=0.0011). In conclusion, by investigating a broad panel of CAPN10 variants our results pointed to an allele-dose-dependent association of UCSNP-56 and ins/del-19 with PCOS.