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

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 finemap across the associated genomic interval.RESEARCH DESIGN AND METHODS-We performed association studies in 12 independent cohorts comprising Ͼ45,000 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 ϳ417-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 (P meta ϭ 3 ϫ 10 Ϫ56) and glucose (P meta ϭ 1 ϫ 10 Ϫ13 ) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P ϭ 5 ϫ 10 Ϫ5). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r 2 ϭ 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

Discrete associations of the GCKR variant with metabolic risk in a Chinese population: longitudinal change analysis

“…The present study was the first to investigate the associations of rs780092 with risk of incident dyslipidaemia and type 2 diabetes. Our findings are in line with results from previous studies in whites and Asians, in which the GCKR variant reversely associated with TG levels and type 2 diabetes risk [4,6,9,13]. Notably, one prospective cohort study has shown that the T-allele of rs1260326 was strongly associated with lower fasting glucose and, conversely, higher TG during a 9 year study [9].…”

“…Notably, one prospective cohort study has shown that the T-allele of rs1260326 was strongly associated with lower fasting glucose and, conversely, higher TG during a 9 year study [9]. Another prospective study also demonstrated that the rs1260326 variant was associated with longitudinal changes in TG but not fasting plasma glucose levels [4]. Similarly, a significant association between rs780092 and 5 year change in log 10 TG was also observed in our study, although rs780092 was not significantly associated with increasing levels of fasting plasma glucose.…”

“…Intriguingly, several recent genome-wide association studies (GWASs) have shown that variants in glucokinase regulatory protein (GRP) gene (GCKR) were related to elevated blood TG, total cholesterol (TC) and lipoprotein levels, but showed significant associations with lower glucose levels and a reduced risk of type 2 diabetes [1][2][3]. This discrete association with lipid and glucose metabolism has been replicated in several studies [4][5][6][7][8][9]; notably, these previous studies were performed in cross-sectional settings, mainly in white populations. Studies assessing the association of GCKR variants with incident type 2 diabetes and dyslipidaemia in prospective cohorts are sparse [8], especially those focusing on the longitudinal changes in metabolic traits, or in other ethnic groups [9].…”

Uric acid transport and disease

“…The role of GCKR in urate transport is, however, unclear. This protein is known for its role in the control of glucokinase activity and glucose utilization by liver, and other genetic association studies have found the GCKR locus to influence triglyceride levels (79,80).…”

Genetic Associations with Metabolic Syndrome and Its Quantitative Traits by Race/Ethnicity in the United States

“…Even though large consortia meta-analyses have not reported variants near ENPP1, we included it in our analysis because of strong prior associations of rs1044498 with IR. [27][28][29] The C allele at rs1260326 near GCKR is associated with higher IR and lower TG levels 30 ; we therefore used the T alleles at this locus as the risk alleles in analyses of TG levels. Two of the seven SNPs associated with IR are also associated with increased BMI (rs9939609 near FTO and rs11152213 near MCR4).…”