LINKAGE AND ASSOCIATION OF INSULIN GENE VNTR REGULATORY POLYMORPHISM WITH POLYCYSTIC-OVARY-SYNDROME

Background Polycystic ovary syndrome (PCOS) is a common endocrine diso rder affecting up to 10% of women of reproductive age. Women with anov ulatory PCOS have hyperinsulinaemia, insulin resistance, and dyslipida emia, and the syndrome is associated with greatly increased risks of n on-insulin-dependent diabetes mellitus and cardiovascular disease and it often clusters in families. The VNTR (variable number of tandem rep eats) locus upstream of the insulin gene (INS) regulates insulin expre ssion. We have studied INS VNTR as a candidate genetic locus for susce ptibility to PCOS. Methods We evaluated linkage of PCOS to the INS VNT R locus on chromosome 11p15.5 in 17 families with several cases, and l ooked for an association between VNTR and PCOS in two additional clini c populations. VNTR genotypes were designated I/I, I/III, and III/III and linkage disequilibrium mapping was used to test the primary role o f the VNTR. Findings In a group of PCOS/male pattern baldness families , we obtained positive evidence for linkage to 11p15.5 (p = 0.002). Th e INS VNTR III/III genotype was associated with an increased risk of P COS in two independent case-control studies (odds ratios 8.20 [p = 0.0 05] and 5.70 [p = 0.043]). Multilocus linkage disequilibrium mapping s uggests that VNTR itself is the predisposing locus. Interpretation Map ping of susceptibility to PCOS to the INS VNTR implies that PCOS is du e, in part, to an inherited alteration in insulin production, The data suggest a mechanistic link between type 2 diabetes and PCOS, which is a risk factor for diabetes later in life.