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Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

¹ Department of Clinical Sciences, University Hospital Malmö, Clinical Research Center, Lund University, Malmö, Sweden
² Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
³ Lipids and Atherosclerosis Research Unit, Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain
⁴ Nutrition and Genomics Laboratory, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
⁵ Genetic and Molecular Epidemiology Unit and CIBER Fisiopatología de la Obesidad y Nutrición, School of Medicine University of Valencia, Valencia, Spain
⁶ Department of Genome Sciences, University of Washington, Seattle, Washington
⁷ Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
⁸ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
⁹ Department of Endocrinology, Singapore General Hospital, Singapore
¹⁰ Dietary Assessment and Epidemiology Research Program, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts
¹¹ Department of Epidemiology, University of Alabama, Birmingham, Alabama
¹² Department of Clinical Pharmacology, Sahlgrenska Academy, Göteborg, Sweden
¹³ Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
¹⁴ Folkhälsan Research Center, Helsinki, Finland
¹⁵ Novartis Institutes for BioMedical Research, Cambridge, Massachusetts
¹⁶ Department of Clinical Sciences, Medicine, Lund University, Malmö, Sweden
¹⁷ Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland
¹⁸ Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
¹⁹ Center for Human Genetic Research and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
²⁰ Department of Genetics, Harvard Medical School, Boston, Massachusetts
²¹ Cardiovascular 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

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 (P_meta = 3 x 10^–56) and glucose (P_meta = 1 x 10^–13) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 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.

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