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-Melander 1 ,
Olle Melander 1 ,
Candace Guiducci 2 ,
Pablo Perez-Martinez 3 4 5 ,
Dolores Corella 5 ,
Charlotta Roos 1 ,
Ryan Tewhey 2 ,
Mark J. Rieder 6 ,
Jennifer Hall 7 ,
Goncalo Abecasis 8 ,
E. Shyong Tai 9 ,
Cullan Welch 7 ,
Donna K. Arnett 10 ,
Valeriya Lyssenko 1 ,
Eero Lindholm 1 ,
Richa Saxena 2 ,
Paul I.W. de Bakker 2 ,
Noel Burtt 2 ,
Benjamin F. Voight 2 ,
Joel N. Hirschhorn 2 ,
Katherine L. Tucker 11 ,
Thomas Hedner 12 ,
Tiinamaija Tuomi 13 14 ,
Bo Isomaa 14 ,
Karl-Fredrik Eriksson 1 ,
Marja-Riitta Taskinen 13 ,
Björn Wahlstrand 12 ,
Thomas E. Hughes 15 ,
Laurence D. Parnell 4 ,
Chao-Qiang Lai 4 ,
Göran Berglund 16 ,
Leena Peltonen 17 ,
Erkki Vartiainen 18 ,
Pekka Jousilahti 18 ,
Aki S. Havulinna 18 ,
Veikko Salomaa 18 ,
Peter Nilsson 1 ,
Leif Groop 1 13 ,
David Altshuler 2 19 20 ,
Jose M. Ordovas 4 and
Sekar Kathiresan 2 21
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
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 ( P meta = 3 × 10 −56 ) and glucose ( P meta = 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, r 2 = 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
Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
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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

10.2337/db08-0516