ADDITIVE EFFECTS OF GENETIC VARIATION IN GCK AND G6PC2 ON INSULIN SECRETION AND FASTING GLUCOSE
- Xia Li1,
- Yu-Hsiang Shu1,
- Anny H. Xiang1,
- Enrique Trigo2,
- Johanna Kuusisto3,
- Jaana Hartiala1,4,
- Amy J. Swift5,
- Miwa Kawakubo1,
- Heather M. Stringham6,
- Lori L. Bonnycastle5,
- Jean M. Lawrence7,
- Markku Laakso3,
- Hooman Allayee1,4,
- Thomas A. Buchanan2,8 and
- Richard M. Watanabe (rwatanab{at}usc.edu)1,8
- 1. Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine of USC, 1540 Alcazar St., CHP-220, Los Angeles, CA 90033
- 2. Department of Medicine, Division of Endocrinology, Keck School of Medicine of USC, 1333 San Pablo St., BMT-B11, Los Angeles, CA 90033
- 3. Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
- 4. Institute for Genetic Medicine, Keck School of Medicine of USC, 2250 Alcazar St., Suite 240, Los Angeles, CA 90033
- 5. Genome Technology Branch, National Human Genome Research Institute, Bethesda, 50 South Drive, Building 50, Bethesda, MD 20892
- 6. Department of Biostatistics, School of Public Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109
- 7. Research and Evaluation, Kaiser Permanente of Southern California, 100 S. Los Robles St., Pasadena, CA 91101
- 8. Department of Physiology & Biophysics, Keck School of Medicine of USC, 1333 San Pablo St., Los Angeles, CA 90033
Abstract
Objective: GCK and G6PC2 regulate the glucose cycling step in pancreatic β-cells and may regulate insulin secretion. GCK rs1799884 and G6PC2 rs560887 have been independently associated with fasting glucose, but their interaction on glucose-insulin relationships is not well characterized.
Research Design and Methods: We tested whether these variants are associated with diabetes-related quantitative traits in Mexican Americans from the BetaGene study and attempted to replicate our findings in Finnish men from the METSIM study.
Results: rs1799884 was not associated with any quantitative trait (corrected p>0.1), whereas rs560887 was significantly associated with the OGTT 30-minute incremental insulin response (30′ ΔInsulin, corrected p=0.021). We found no association between quantitative traits and the multiplicative interaction between rs1799884 and rs560887 (p>0.26). However, the additive effect of these SNPs was associated with fasting glucose (corrected p=0.03) and 30′ ΔInsulin (corrected p=0.027). This additive association was replicated in METSIM (fasting glucose, p=3.5×10−10 30′ ΔInsulin, p=0.028). When we examined the relationship between fasting glucose and 30′ ΔInsulin stratified by GCK and G6PC2, we noted divergent changes in these quantitative traits for GCK, but parallel changes for G6PC2. A similar pattern was observed in METSIM.
Conclusions: We conclude that variation in GCK and G6PC2 have additive effects on both fasting glucose and insulin secretion.
Footnotes
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- Received February 18, 2009.
- Accepted August 27, 2009.
- Copyright © American Diabetes Association
