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United States Department of Agriculture

Agricultural Research Service

Research Project: NUTRITION, CARDIOVASCULAR HEALTH, AND GENOMICS Title: A Common Missense Variant in the Glucokinase Regulatory Protein Gene (GCKR) Is Associated with Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

Authors
item Orho-Melander, Marju - LUND UNIVERSITY
item Melander, Olle - LUND UNIVERSITY
item Guiducci, Candace - BROAD INST @ MIT/HARVARD
item Perez-Martinez, Pablo - UNIVERSITY OF CORDOBA
item Corella, Dolores - UNIVERSITY OF VALENCIA
item Roos, Charlotta - LUND UNIVERSITY
item Tewhey, Ryan - BROAD INST @ MIT/HARVARD
item Rieder, Mark - DPT OF GENOME SCIENCES
item Hall, Jennifer - UNIVERSITY OF MINNESOTA
item Abecasis, Goncalo - UNIVERSITY OF MICHIGAN
item Tai, E Shyong - SINGAPORE GEN HOSPITAL
item Welch, Cullan - UNIVERSITY OF MINNESOTA
item Arnett, Donna - UNIVERSITY OF ALABAMA
item Lyssenko, Valeriya - LUND UNIVERSITY
item Lindholm, Eero - LUND UNIVERSITY
item Saxena, Richa - BROAD INST @ MIT/HARVARD
item DE Bakker, Paul - BROAD INST @ MIT/HARVARD
item Burtt, Noel - BROAD INST @ MIT/HARVARD
item Voight, Benjamin - BROAD INST @ MIT/HARVARD
item Hirschhorn, Joel - BROAD INST @ MIT/HARVARD
item Tucker, Katherine
item Hedner, Thomas - SAHLGRENSKA ACADEMY
item Tuomi, Tiinamaija - UNIVERSITY OF HELSINKI
item Isomaa, Bo - FOLKHALSAN RESEARCH
item Eriksson, Karl-Fredrik - LUND UNIVERSITY
item Taskinen, Marja-Riitta - UNIVERSITY OF HELSINKI
item Wahlstrand, Bjorn - SAHLGRENSKA ACADEMY
item Hughes, Thomas - NOVARTIS INSTITUTES
item Parnell, Laurence
item Lai, Chao Qiang
item Berglund, Goran - LUND UNIVERSITY
item Peltonen, Leena - NPHI, HELSINKI
item Vartiainen, Erkki - NPHI, HELSINKI
item Jousilahti, Pekka - NPHI, HELSINKI
item Havulinna, Aki - NPHI, HELSINKI
item Salomaa, Veikko - NPHI, HELSINKI
item Nilsson, Peter - LUND UNIVERSITY
item Groop, Leif - LUND UNIVERSITY
item Altshuler, David - BROAD INST @ MIT/HARVARD
item Ordovas, Jose
item Kathiresan, Sekar - HARVARD MED SCHOOL

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 15, 2008
Publication Date: August 4, 2008
Citation: Orho-Melander, M., Melander, O., Guiducci, C., Perez-Martinez, P., Corella, D., Roos, C., Tewhey, R., Rieder, M.J., Hall, J., Abecasis, G., Tai, E., Welch, C., Arnett, D.K., Lyssenko, V., Lindholm, E., Saxena, R., De Bakker, P., Burtt, N., Voight, B.F., Hirschhorn, J.N., Tucker, K., Hedner, T., Tuomi, T., Isomaa, B., Eriksson, K., Taskinen, M., Wahlstrand, B., Hughes, T.E., Parnell, L.D., Lai, C., Berglund, G., Peltonen, L., Vartiainen, E., Jousilahti, P., Havulinna, A.S., Salomaa, V., Nilsson, P., Groop, L., Altshuler, D., Ordovas, J.M., Kathiresan, S. 2008. A Common Missense Variant in the Glucokinase Regulatory Protein Gene (GCKR) Is Associated with Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations. Diabetes. 57:3112-3121.

Interpretive Summary: Most common health problems affecting the US population are the result of multiple genetic and environmental factors. Unhealthy environmental factors are relatively well known and include, among others, poor nutrition, sedentary life, and tobacco smoking. On the other hand, the genetic drivers of disease are poorly known in the general population due to the technical limitations surrounding genetic research in previous decades and the complexity of the problem. New technologies and very large populations are needed to reliably identify genetic variants that modulate an individual’s disease risk. Using genetic technology that examines the entire genome for mutations, we have identified a polymorphism in a gene called glucokinase regulatory protein (GCKR) which is a marker for plasma triglyceride (TG) concentrations, a cardiovascular disease risk factor. Here, we sought to further solidify this finding in larger population and to study the association of GCKR variants with other risk factors. For this purpose, we investigated 12 independent cohorts comprising a total of >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the United States, African Americans from the United States, Hispanics of Caribbean origin, and Chinese, Malays and Asian Indians from Singapore). We provide definitive evidence that GCKR gene is associated with opposite effects on fasting plasma TG and glucose concentrations. Our findings point to a new molecular mechanism in humans related to risk of diabetes and cardiovascular disease. Moreover, this information could be used to predict disease risk in populations from most ethnic groups and geographical locations.

Technical 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 a total of >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the United States, African Americans from the United States, Hispanics of Caribbean origin, and Chinese, Malays and Asian Indians from Singapore). We conducted genetic fine-mapping across the approx. 417 kilobase region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap 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=3x10^-56) and glucose (pmeta=1x10^-13) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reative protein level (p=5x10^-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 C-reactive protein can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.

Last Modified: 10/22/2014
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