Prevalence of variants in candidate genes for type 2 diabetes mellitus in the Netherlands: The Rotterdam study and the Hoorn study

We have analyzed the association of variants in the genes for amylin, insul in receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. Random samples of subjects with type 2 diab etes and controls were taken from two population-based studies, the Hoorn a nd Rotterdam studies, to reduce the risk of artifactual associations. No association was found for variants in the genes for amylin, IRS-1, and c oagulation factor V, nor was there any evidence for epistatic interactions between these gene variants. A significant difference in the frequency of t he Arg(972) allele of the IRS-1 gene was observed between control subjects from Hoorn and Rotterdam (9.4% vs. 18.6%; P < 0.05). The insulin receptor M et(985) variant was found at frequencies of 4.4% and 1.8%, respectively, in type 2 diabetic (n = 433) and normoglycemic patients (n = 799; P < 0.02). Inclusion of data from two other studies yielded a summarized odds ratio of 1.87 (95% confidence interval, 1.06-3.29; P = 0.03). We conclude that the association between the Met(985) variant in the insuli n receptor gene and type 2 diabetes, which we previously reported in the Ro tterdam study, is support;ed by the joint analysis with a second population -based study and other studies. The large regional differences in allele fr equency of the Arg(972) allele of IRS-1 gene makes genetic association stud ies of this gene less reliable.