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

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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

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dc.contributor.author Orho-Melander, Marju
dc.contributor.author Melander, Olle
dc.contributor.author Guiducci, Candace
dc.contributor.author Perez-Martinez, Pablo
dc.contributor.author Corella, Dolores
dc.contributor.author Roos, Charlotta
dc.contributor.author Tewhey, Ryan
dc.contributor.author Rieder, Mark J.
dc.contributor.author Hall, Jennifer
dc.contributor.author Abecasis, Goncalo
dc.contributor.author Tai, E. Shyong
dc.contributor.author Welch, Cullan
dc.contributor.author Arnett, Donna K.
dc.contributor.author Lyssenko, Valeriya
dc.contributor.author Lindholm, Eero
dc.contributor.author Burtt, Noel
dc.contributor.author Voight, Benjamin F.
dc.contributor.author Tucker, Katherine L.
dc.contributor.author Hedner, Thomas
dc.contributor.author Tuomi, Tiinamaija
dc.contributor.author Isomaa, Bo
dc.contributor.author Eriksson, Karl-Fredrik
dc.contributor.author Taskinen, Marja-Riitta
dc.contributor.author Wahlstrand, Björn
dc.contributor.author Hughes, Thomas E.
dc.contributor.author Parnell, Laurence D.
dc.contributor.author Lai, Chao-Qiang
dc.contributor.author Berglund, Göran
dc.contributor.author Peltonen, Leena
dc.contributor.author Vartiainen, Erkki
dc.contributor.author Jousilahti, Pekka
dc.contributor.author Havulinna, Aki S.
dc.contributor.author Salomaa, Veikko
dc.contributor.author Nilsson, Peter
dc.contributor.author Groop, Leif
dc.contributor.author Ordovas, Jose M.
dc.contributor.author Kathiresan, Sekar
dc.contributor.author Saxena, Richa
dc.contributor.author de Bakker, Paul I Wen
dc.contributor.author Hirschhorn, Joel Naom
dc.contributor.author Altshuler, David Matthew
dc.date.accessioned 2011-09-24T21:43:05Z
dc.date.issued 2008
dc.identifier.citation Orho-Melander, Marju, Olle Melander, Candace Guiducci, Pablo Perez-Martinez, Dolores Corella, Charlotta Roos, Ryan Tewhey, and et al. 2008. Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57(11): 3112-3121. en_US
dc.identifier.issn 0012-1797 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5141362
dc.description.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. en_US
dc.language.iso en_US en_US
dc.publisher American Diabetes Association en_US
dc.relation.isversionof doi://10.2337/db08-0516 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570409/pdf/ en_US
dash.license LAA
dc.title Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Diabetes en_US
dash.depositing.author Saxena, Richa
dc.date.available 2011-09-24T21:43:05Z
dash.affiliation.other HMS^Anaesthesia-Massachusetts General Hospital en_US
dash.affiliation.other HMS^Medicine-Brigham and Women's Hospital en_US
dash.affiliation.other HMS^Genetics en_US
dash.affiliation.other HMS^Medicine-Massachusetts General Hospital en_US
dash.affiliation.other HMS^Genetics en_US

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