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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

Orho-Melander, Marju LU ; Melander, Olle LU ; Guiducci, Candace; Perez-Martinez, Pablo; Corella, Dolores; Roos, Charlotta LU ; Tewhey, Ryan; Rieder, Mark J.; Hall, Jennifer and Abecasis, Goncalo, et al. (2008) In Diabetes 57(11). p.3112-3121
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 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... (More)
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 (Less)
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Contribution to journal
publication status
published
subject
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Diabetes
volume
57
issue
11
pages
3112 - 3121
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000260564800032
  • scopus:54249088172
ISSN
1939-327X
DOI
10.2337/db08-0516
language
English
LU publication?
yes
id
fca3c87c-cae7-4801-a8bf-ac681f2c2cf1 (old id 1284715)
date added to LUP
2009-02-09 09:27:02
date last changed
2017-10-22 04:04:48
@article{fca3c87c-cae7-4801-a8bf-ac681f2c2cf1,
  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 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},
  author       = {Orho-Melander, Marju and Melander, Olle and Guiducci, Candace and Perez-Martinez, Pablo and Corella, Dolores and Roos, Charlotta and Tewhey, Ryan and Rieder, Mark J. and Hall, Jennifer and Abecasis, Goncalo and Tai, E. Shyong and Welch, Cullan and Arnett, Donna K. and Lyssenko, Valeriya and Lindholm, Eero and Saxena, Richa and de Bakker, Paul I. W. and Burtt, Noel and Voight, Benjamin F. and Hirschhorn, Joel N. and Tucker, Katherine L. and Hedner, Thomas and Tuomi, Tiinaimaija and Isomaa, Bo and Eriksson, Karl-Fredrik and Taskinen, Marja-Riitta and Wahlstrand, Bjoern and Hughes, Thomas E. and Parnell, Laurence D. and Lai, Chao-Qiang and Berglund, Göran and Peltonen, Leena and Vartiainen, Erkki and Jousilahti, Pekka and Havulinna, Aki S. and Salomaa, Veikko and Nilsson, Peter and Groop, Leif and Altshuler, David and Ordovas, Jose M. and Kathiresan, Sekar},
  issn         = {1939-327X},
  language     = {eng},
  number       = {11},
  pages        = {3112--3121},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  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},
  url          = {http://dx.doi.org/10.2337/db08-0516},
  volume       = {57},
  year         = {2008},
}