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Screening of 134 Single Nucleotide Polymorphisms (SNPs) Previously Associated With Type 2 Diabetes Replicates Association With 12 SNPs in Nine Genes

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

Address correspondence and reprint requests to Michael Boehnke, PhD, Department of Biostatistics, School of Public Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029. E-mail: boehnke{at}umich.edu

Abbreviations: FUSION, Finland-United States Investigation of NIDDM Genetics; LD, linkage disequilibrium; MAF, minor allele frequency; MODY, maturity-onset diabetes of the young; NGT, normal glucose tolerance; SNP, single nucleotide polymorphism; WHR, waist-to-hip ratio

More than 120 published reports have described associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. However, multiple studies of the same variant have often been discordant. From a literature search, we identified previously reported type 2 diabetes–associated SNPs. We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium (r² > 0.8) with another typed SNP. Of the 114 SNPs examined, we followed up the 20 most significant SNPs (P < 0.10) on an additional 384 case subjects and 366 control subjects from a population-based study in Finland. In the combined data, we replicated association (P < 0.05) for 12 SNPs: PPARG Pro12Ala and His447, KCNJ11 Glu23Lys and rs5210, TNF –857, SLC2A2 Ile110Thr, HNF1A/TCF1 rs2701175 and GE117881_360, PCK1 –232, NEUROD1 Thr45Ala, IL6 –598, and ENPP1 Lys121Gln. The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association (P = 0.012). We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample (P = 0.03), although we also replicated 4 of 58 SNPs from genes that had only one previous report of association.

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