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Common Variants in Maturity-Onset Diabetes of the Young Genes Contribute to Risk of Type 2 Diabetes in Finns

¹ Genome Technology Branch, National Genome Research Institute, Bethesda, Maryland
² Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
⁴ Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California
⁵ Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
⁶ Department of Public Health, University of Helsinki, Helsinki, Finland
⁷ South Ostrobothnia Central Hospital, Seinäjoki, Finland
⁸ Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
⁹ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina

Address correspondence and reprint requests to Francis S. Collins, MD, PhD, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-2152. E-mail: francisc{at}mail.nih.gov

Abbreviations: FUSION, Finland-U.S. Investigation of NIDDM Genetics Study; LD, linkage disequilibrium; MODY, maturity-onset diabetes of the young; SNP, single nucleotide polymorphism

Prior reports have suggested that variants in the genes for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but results have been conflicting and coverage of the MODY genes has been incomplete. To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals. For each of the five genes, we selected 1) nonredundant single nucleotide polymorphisms (SNPs) (r²< 0.8 with other SNPs) from the HapMap database or another linkage disequilibrium map, 2) SNPs with previously reported type 2 diabetes association, and 3) nonsynonymous coding SNPs. We tested 128 SNPs for association with type 2 diabetes in 786 index cases from type 2 diabetic families and 619 normal glucose-tolerant control subjects. We followed up 35 of the most significant SNPs by genotyping them on another 384 case subjects and 366 control subjects from Finland. We also supplemented our previous HNF4A results by genotyping 12 SNPs on additional Finnish samples. After correcting for testing multiple correlated SNPs within a gene, we find evidence of type 2 diabetes association with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A. Our data suggest that common variants in several MODY genes play a modest role in type 2 diabetes susceptibility.

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