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A Common Missense Variant in the Glucokinase Regulatory Protein Gene (GCKR) Is Associated with Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

From the 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 Univeristy, Cambridge, USA
³Lipids and Atherosclerosis Research Unit, Reina Sofia University Hospital, University of Cordoba, Spain
⁴Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
⁵Genetic and Molecular Epidemiology Unit and CIBER Fisiopatología de la Obesidad y Nutrición, School of Medicine University of Valencia, Valencia, Spain
⁶University of Washington, Department of Genome Sciences, Seattle, WA, USA
⁷Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, USA
⁸Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
⁹Department of Endocrinology, Singapore General Hospital, Singapore
¹⁰Dietary Assessment and Epidemiology Research Program, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA
¹¹Department of Epidemiology, University of Alabama, Birmingham, AL, USA
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, USA
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; Department of Genetics, Harvard Medical School, Boston
²⁰Cardiovascular Disease Prevention Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston

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 a total of >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the United States, African Americans from the United States, Hispanics of Caribbean origin, and Chinese, Malays and Asian Indians from Singapore). We conducted genetic fine-mapping across the 417 kilobase region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap 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=3x10^-56) and glucose (p_meta=1x10^-13) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reative protein level (p=5x10^-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 C-reactive protein can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.

Correspondence: skathiresan{at}partners.org

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