Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits

Context: Variation at the insulin gene VNTR ( variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome ( PCOS), but findings have been inconsistent and all studies have featured small sample sizes. Objective: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility. Design: Case-control, family-based association and quantitative trait analyses. Setting and Participants: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects ( cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the - 23HphI variant. Intervention(s): None. Main Outcome Measure(s): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype. Results: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS( UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis chi(2)). Transmission analysis in trios showed no excess transmission of either allele ( P = 0.62), regardless of parent of origin ( maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample ( UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58). Conclusions: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.