Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles

Variation at the variable number tandem repeat (VNTR) minisatellite 5' of t he insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control stud ies have suggested that class III VNTR alleles are also associated with typ e 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diab etes susceptibility, me used family-based association methods in 155 parent -offspring trios from the British Diabetic Association-Warren Trios reposit ory, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR geno type, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions f ollowed Mendelian expectation, there was a marked excess of class III trans mission hom the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm t hat variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itse lf, influences type 2 diabetes susceptibility. By demonstrating that this e ffect is mediated exclusively by the paternally derived allele, these findi ngs implicate imprinted genes in the pathogenesis of type 2 diabetes.