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 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 approximately 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 GCKR 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.

FIG. 1.

In silico and genotype fine-mapping of the GCKR locus. To define the strongest signal for the association on chromosome 2p23 for triglycerides, a region spanning ∼417 kb and containing 17 annotated genes was fine-mapped by two different approaches, imputation of untyped SNPs (29) (or so-called in silico fine-mapping) (A) and genotyping tagging SNPs across the region (B). Both in silico and genotype fine-mapping methods indicated the Pro446Leu as the variant with the strongest association with triglyceride levels. The genotype consensus rate between the imputed genotypes and genotyped genotypes was ∼95.7%.

FIG. 2.

Fasting triglycerides and blood glucose levels in MPP participants before and after a mean follow-up time of 23.4 years according to GCKR Pro446Leu. In a large prospective study, the Pro446Leu was strongly associated with higher triglycerides and lower fasting blood glucose both at baseline and after the follow-up. In addition, among 12,528 individuals not on lipid-lowering medication, fasting triglyceride levels increased more during the follow-up time among Leu446 allele carriers compared with homozygous Pro446 carriers (P = 8 × 10⁻⁵), whereas the change in fasting blood glucose during the follow-up time was not significant among 12,964 individuals without diabetes either at baseline or at follow-up.