Genotype effects of glucokinase regulator on lipid profiles and glycemic status are modified by circulating calcium levels: results from the Korean Genome and Epidemiology Study

Single nucleotide polymorphisms (SNPs) in the glucokinase regulator (GCKR) are associated with major cardiovascular risk factors (ie, lipid profile and glycemic status). Recently, GCKR was shown to be related to circulating calcium levels involved in lipid and glycemic controls. Therefore, we hypothesized that GCKR SNPs are associated with major cardiovascular risk factors in the Korean population, and the association is modified by circulating calcium levels. Epidemiological data and GCKR SNPs (rs780093T>C, rs780094 T>C, and rs1260326 T>C) were collected from a subset of Ansung-Ansan cohort in the Korean Genome and Epidemiology Study (n = 7815). Consistent with the results of previous studies, GCKR SNPs were significantly associated with decreased total cholesterol and triglyceride levels and increased glucose levels and insulin resistance. Minor C allele carriers, particularly CC homozygotes, had lower serum calcium levels than TT homozygotes for all 3 SNPs. Particularly, the effect of GCKR SNPs on total cholesterol, triglyceride, fasting glucose, and insulin resistance was apparent when serum calcium levels were in normal range (8.8-10.1 mg/dL). When serum calcium levels were high (≥10.2 mg/dL), CC homozygotes also had significantly lower triglyceride and higher fasting glucose than TT homozygotes. However, the associations were not observed when serum calcium levels were low (<8.8 mg/dL). In conclusion, GCKR SNPs are associated with lipid profiles and glycemic status in the Korean population, and the genetic effect is modified by basal circulating calcium levels, particularly in normal or high ranges. It provides important information for individualized prevention and management of cardiovascular risk associated with GCKR SNPs.