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: ORHO-MELANDER, MARJU - LUND UNIVERSITY; MELANDER, OLLE - LUND UNIVERSITY; GUIDUCCI, CANDACE - BROAD INST @ MIT/HARVARD; PEREZ-MARTINEZ, PABLO - UNIVERSITY OF CORDOBA; CORELLA, DOLORES - UNIVERSITY OF VALENCIA; ROOS, CHARLOTTA - LUND UNIVERSITY; TEWHEY, RYAN - BROAD INST @ MIT/HARVARD; RIEDER, MARK - DPT OF GENOME SCIENCES; HALL, JENNIFER - UNIVERSITY OF MINNESOTA; ABECASIS, GONCALO - UNIVERSITY OF MICHIGAN; TAI, E SHYONG - SINGAPORE GEN HOSPITAL; WELCH, CULLAN - UNIVERSITY OF MINNESOTA; ARNETT, DONNA - UNIVERSITY OF ALABAMA; LYSSENKO, VALERIYA - LUND UNIVERSITY; LINDHOLM, EERO - LUND UNIVERSITY; SAXENA, RICHA - BROAD INST @ MIT/HARVARD; DE BAKKER, PAUL - BROAD INST @ MIT/HARVARD; BURTT, NOEL - BROAD INST @ MIT/HARVARD; VOIGHT, BENJAMIN - BROAD INST @ MIT/HARVARD; HIRSCHHORN, JOEL - BROAD INST @ MIT/HARVARD; Tucker, Katherine; HEDNER, THOMAS - SAHLGRENSKA ACADEMY; TUOMI, TIINAMAIJA - UNIVERSITY OF HELSINKI; ISOMAA, BO - FOLKHALSAN RESEARCH; ERIKSSON, KARL-FREDRIK - LUND UNIVERSITY; TASKINEN, MARJA-RIITTA - UNIVERSITY OF HELSINKI; WAHLSTRAND, BJORN - SAHLGRENSKA ACADEMY; HUGHES, THOMAS - NOVARTIS INSTITUTES; Parnell, Laurence; Lai, Chao Qiang; BERGLUND, GORAN - LUND UNIVERSITY; PELTONEN, LEENA - NPHI, HELSINKI; VARTIAINEN, ERKKI - NPHI, HELSINKI; JOUSILAHTI, PEKKA - NPHI, HELSINKI; HAVULINNA, AKI - NPHI, HELSINKI; SALOMAA, VEIKKO - NPHI, HELSINKI; NILSSON, PETER - LUND UNIVERSITY; GROOP, LEIF - LUND UNIVERSITY; ALTSHULER, DAVID - BROAD INST @ MIT/HARVARD; Ordovas, Jose; KATHIRESAN, SEKAR - HARVARD MED SCHOOL

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/15/2008
Publication Date: 8/4/2008
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.