Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations
- Marju Orho-Melander1,
- Olle Melander1,
- Candace Guiducci2,
- Pablo Perez-Martinez345,
- Dolores Corella5,
- Charlotta Roos1,
- Ryan Tewhey2,
- Mark J. Rieder6,
- Jennifer Hall7,
- Goncalo Abecasis8,
- E. Shyong Tai9,
- Cullan Welch7,
- Donna K. Arnett10,
- Valeriya Lyssenko1,
- Eero Lindholm1,
- Richa Saxena2,
- Paul I.W. de Bakker2,
- Noel Burtt2,
- Benjamin F. Voight2,
- Joel N. Hirschhorn2,
- Katherine L. Tucker11,
- Thomas Hedner12,
- Tiinamaija Tuomi1314,
- Bo Isomaa14,
- Karl-Fredrik Eriksson1,
- Marja-Riitta Taskinen13,
- Björn Wahlstrand12,
- Thomas E. Hughes15,
- Laurence D. Parnell4,
- Chao-Qiang Lai4,
- Göran Berglund16,
- Leena Peltonen17,
- Erkki Vartiainen18,
- Pekka Jousilahti18,
- Aki S. Havulinna18,
- Veikko Salomaa18,
- Peter Nilsson1,
- Leif Groop113,
- David Altshuler21920,
- Jose M. Ordovas4 and
- Sekar Kathiresan221
- 1Department of Clinical Sciences, University Hospital Malmö, Clinical Research Center, Lund University, Malmö, Sweden
- 2Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
- 3Lipids and Atherosclerosis Research Unit, Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain
- 4Nutrition and Genomics Laboratory, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
- 5Genetic and Molecular Epidemiology Unit and CIBER Fisiopatología de la Obesidad y Nutrición, School of Medicine University of Valencia, Valencia, Spain
- 6Department of Genome Sciences, University of Washington, Seattle, Washington
- 7Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
- 8Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
- 9Department of Endocrinology, Singapore General Hospital, Singapore
- 10Dietary Assessment and Epidemiology Research Program, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts
- 11Department of Epidemiology, University of Alabama, Birmingham, Alabama
- 12Department of Clinical Pharmacology, Sahlgrenska Academy, Göteborg, Sweden
- 13Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- 14Folkhälsan Research Center, Helsinki, Finland
- 15Novartis Institutes for BioMedical Research, Cambridge, Massachusetts
- 16Department of Clinical Sciences, Medicine, Lund University, Malmö, Sweden
- 17Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland
- 18Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
- 19Center for Human Genetic Research and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- 20Department of Genetics, Harvard Medical School, Boston, Massachusetts
- 21Cardiovascular Disease Prevention Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Corresponding author: Marju Orho-Melander, marju.orho-melander{at}med.lu.se
Abstract
OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval.
RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval.
RESULTS—We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (Pmeta = 3 × 10−56) and glucose (Pmeta = 1 × 10−13) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 × 10−5). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r2 = 0.93 with rs780094) as the strongest association signal in the region.
CONCLUSIONS—These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008.
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- Accepted July 29, 2008.
- Received April 17, 2008.
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