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Prevalence of Variants in Candidate Genes for Type 2 Diabetes Mellitus in The Netherlands: The Rotterdam Study and the Hoorn Study¹

Department of Molecular Cell Biology, Leiden University Medical Center (L.M.’t H., J.A.M.), 2333 AL Leiden; the Department of Epidemiology and Biostatistics, Erasmus University (R.P.S., D.E.G.), 3000 DR Rotterdam; the Julius Center for Patient Orientated Research, Utrecht University (R.P.S., D.E.G.), 3508 GA Utrecht; and the Institute for Research in Extramural Medicine, Vrije Universiteit Amsterdam (J.M.D., G.N., R.J.H.), 1081 BT Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. J. Antonie Maassen, Department of Molecular Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands. E-mail: maassen{at}rullf2.medfac.leidenuniv.nl

We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. Random samples of subjects with type 2 diabetes and controls were taken from two population-based studies, the Hoorn and Rotterdam studies, to reduce the risk of artifactual associations.

No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epi-static interactions between these gene variants. A significant difference in the frequency of the Arg⁹⁷² 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 Met⁹⁸⁵ 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 Met⁹⁸⁵ variant in the insulin receptor gene and type 2 diabetes, which we previously reported in the Rotterdam study, is supported by the joint analysis with a second population-based study and other studies. The large regional differences in allele frequency of the Arg⁹⁷² allele of IRS-1 gene makes genetic association studies of this gene less reliable.

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