Journal
DIABETES
Volume 57, Issue 11, Pages 3112-3121Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db08-0516
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Funding
- Lund University
- Novo Nordic Foundations
- Swedish Medical Research Council
- Swedish Heart and Lung Foundation
- Region Skane
- Medical Faculty of Lund University
- Malmo University Hospital
- Albert Pahlsson Research Foundation
- Crafoord Foundation
- Swedish Medical Society
- Ernhold Lundstroms Research Foundation
- Mossfelt Foundation
- King Gustav V and Queen Victoria Foundation
- NIH [R01-NS-053646, P01-AG-023394-03, 53-K06-5-10, K23-HL-083102, PO1-GM-32165]
- Sigrid Juselius Foundation
- U.S. Department of Agriculture [58-1950-9-001]
- NIH-NHLBI [U01-HL-72524, HL-54776]
- Finnish Heart Foundation
- Clinical Research Institute, Helsinki University Central Hospital
- Finnish Diabetes Research Foundation
- Folkhalsan Research Foundation
- Knut and Alice Wallenberg Stiftelse
- Clinical Research Institute HUCH
- Swedish Research Council
- Doris Duke Charitable Foundation
- University of Washington School of Pharmacy
- Abbott
- Allergan
- Amgen
- Bend Research
- Bristol-Myers Squibb
- Eli Lilly
- Johnson Johnson
- Merck
- Roche
- Pfizer
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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 GCYR 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 similar to 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 GCYR 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, 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. Diabetes 57:3112-3121, 2008
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