Additive Effects of Genetic Variation in GCK and G6PC2 on Insulin Secretion and Fasting Glucose

Additive Effects of Genetic Variation in GCK and G6PC2 on Insulin Secretion and Fasting Glucose Xia Li 1 , Yu-Hsiang Shu 1 , Anny H. Xiang 1 , Enrique Trigo 2 , Johanna Kuusisto 3 , Jaana Hartiala 1 , 4 , Amy J. Swift 5 , Miwa Kawakubo 1 , Heather M. Stringham 6 , Lori L. Bonnycastle 5 , Jean M. Lawrence 7 , Markku Laakso 3 , Hooman Allayee 1 , 4 , Thomas A. Buchanan 2 , 8 and Richard M. Watanabe 1 , 8 1 Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, California; 2 Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California; 3 Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland; 4 Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; 5 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland; 6 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan; 7 Research and Evaluation, Kaiser Permanente of Southern California, Pasadena, California; 8 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California. Corresponding author: Richard M. Watanabe, rwatanab{at}usc.edu . X.L. and Y.-H.S. contributed equally to this study. Abstract OBJECTIVE Glucokinase ( GCK ) and glucose-6-phosphatase catalytic subunit 2 ( 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 METabolic Syndrome in Men (METSIM) Study. RESULTS rs1799884 was not associated with any quantitative trait (corrected P > 0.1), whereas rs560887 was significantly associated with the oral glucose tolerance test 30-min 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 single nucleotide polymorp