TY - JOUR
T1 - Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations
AU - Orho-Melander, Marju
AU - Melander, Olle
AU - Guiducci, Candace
AU - Perez-Martinez, Pablo
AU - Corella, Dolores
AU - Roos, Charlotta
AU - Tewhey, Ryan
AU - Rieder, Mark J.
AU - Hall, Jennifer
AU - Abecasis, Goncalo
AU - Tai, E. Shyong
AU - Welch, Cullan
AU - Arnett, Donna K.
AU - Lyssenko, Valeriya
AU - Lindholm, Eero
AU - Saxena, Richa
AU - De Bakker, Paul I W
AU - Burtt, Noel
AU - Voight, Benjamin F.
AU - Hirschhorn, Joel N.
AU - Tucker, Katherine L.
AU - Hedner, Thomas
AU - Tuomi, Tiinamaija
AU - Isomaa, Bo
AU - Eriksson, Karl Fredrik
AU - Taskinen, Marja Riitta
AU - Wahlstrand, Björn
AU - Hughes, Thomas E.
AU - Parnell, Laurence D.
AU - Lai, Chao Qiang
AU - Berglund, Göran
AU - Peltonen, Leena
AU - Vartiainen, Erkki
AU - Jousilahti, Pekka
AU - Havulinna, Aki S.
AU - Salomaa, Veikko
AU - Nilsson, Peter
AU - Groop, Leif
AU - Altshuler, David
AU - Ordovas, Jose M.
AU - Kathiresan, Sekar
PY - 2008/11
Y1 - 2008/11
N2 - 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 phe-notypes, 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 nucleo- tide 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.
AB - 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 phe-notypes, 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 nucleo- tide 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.
UR - http://www.scopus.com/inward/record.url?scp=54249088172&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=54249088172&partnerID=8YFLogxK
U2 - 10.2337/db08-0516
DO - 10.2337/db08-0516
M3 - Article
C2 - 18678614
AN - SCOPUS:54249088172
SN - 0012-1797
VL - 57
SP - 3112
EP - 3121
JO - Diabetes
JF - Diabetes
IS - 11
ER -