Association of 18 Confirmed Susceptibility Loci for Type 2 Diabetes with Indices of Insulin Release, Proinsulin Conversion, and Insulin Sensitivity in 5 327 Non-diabetic Finnish Men
- Alena Stančáková1,
- Teemu Kuulasmaa1,
- Jussi Paananen1,
- Anne U. Jackson2,
- Lori L. Bonnycastle3,
- Francis S. Collins3,
- Michael Boehnke2,
- Johanna Kuusisto1 and
- Markku Laakso (markku.laakso{at}kuh.fi)1
- 1Department of Medicine, University of Kuopio and Kuopio University Hospital, 70210 Kuopio, Finland
- 2Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, USA
- 3National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Abstract
Objective We investigated the effects of 18 confirmed type 2 diabetes risk SNPs on insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin.
Research Design and Methods A total of 5 327 non-diabetic men (age 58±7 years, BMI 27.0±3.8 kg/m2) from a large population-based cohort were included. Oral glucose tolerance test and genotyping of SNPs in/near PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, LOC387761, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B were performed. HNF1B rs757210 was excluded due to failure to achieve Hardy-Weinberg equilibrium.
Results Six SNPs (TCF7L2, SLC30A8, HHEX, CDKN2B, CDKAL1, MTNR1B) were significantly (P<6.9×10−4) and two SNPs (KCNJ11 and IGF2BP2) were nominally (P<0.05) associated with early-phase insulin release (InsAUC0-30/GluAUC0-30), adjusted for age, BMI and insulin sensitivity (Matsuda ISI). Combined effects of these 8 SNPs reached −32% reduction in InsAUC0-30/GluAUC0-30 in carriers of ≥11 vs. ≤3 weighted risk alleles. Four SNPs (SLC30A8, HHEX, CDKAL1, TCF7L2) were significantly or nominally associated with indices of proinsulin conversion. Three SNPs (KCNJ11, HHEX, TSPAN8) were nominally associated with Matsuda ISI (adjusted for age and BMI). The effect of HHEX on Matsuda ISI became significant after additional adjustment for InsAUC0-30/GluAUC0-30. Nine SNPs did not show any associations with examined traits.
Conclusions Eight type 2 diabetes-related loci were significantly or nominally associated with impaired early-phase insulin release. Effects of SLC30A8, HHEX, CDKAL1, and TCF7L2 on insulin release could be partially explained by impaired proinsulin conversion. HHEX might influence both insulin release and insulin sensitivity.
Footnotes
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- Received January 27, 2009.
- Accepted May 27, 2009.
- Copyright © American Diabetes Association
