Further evidence for the GCKR rs780094 as a susceptible polymorphism for type 2 diabetes

Abstract

Results: Glucokinase activity is regulated by glucokinase regulatory protein (GCKR), which binds to GCK and inhibits its activity. Recently, it was reported that GCKR (rs780094) was associated with fasting plasma glucose (FPG) and triglyceride (TG) in various ethnic populations (A allele for low FPG and high TG). Further studies showed the association between rs780094 and T2DM (A allele for low risk). In this study, we examined the association between rs780094 and T2DM in Japanese subjects by analyzing 488 cases and 398 controls, and carried out meta-analysis with two previous reports comprising 13,096 individuals (6224 controls and 6872 cases). We also analyzed the association between the SNP and clinical parameters in the general Japanese population (n=1854). In the case control study, the A allele of rs780094 was associated with the reduced risk of T2DM [odds ratio=0.711 (95% C.I=0.589-0.859), p=4.2∗ 10-4]. Meta-analysis showed the association between rs780094 and the reduced risk of T2DM [odds ratio=0.898 (95% C.I=0.854-0.945), p=3.2∗ 10-5]. In the general Japanese population, subjects with A/A genotype of rs780094 had lower plasma levels of FPG (GG 98±20, AA 95±14 mg/dl, p=0.008), fasting insulin (GG 7.2±5.7, AA 6.2±4.7 uU/ml, p=0.008), and HOMA-IR (GG 1.8±1.7, AA 1.5±1.3, p=0.002) than those with G/G genotype. Conversely, subjects with A/A genotype had higher level of TG than those with G/G genotype (GG 107±69, AA 114±78 mg/dl, p=0.028). In additive model, the A allele was also associated with lower FPG (GG 98±20, GA 97±20, AA 95±14 mg/dl, p=0.006), fasting insulin(GG 7.2±5.7, GA 6.4±4.2, AA 6.2±4.7 uU/ml, p=0.007), and HOMA-IR(GG 1.8±1.7, GA 1.6±1.2 AA 1.5±1.3, p=0.003) levels, but not with TG level. Therefore, we replicated rs780094 as a marker of susceptibility to T2DM in Japanese subjects and meta-analysis. The A/A genotype of rs780094 was associated with reduced FPG, fasting insulin, and HOMA-IR, and increased TG in the Japanese general population. Additive effects of the A allele were found only in FPG, fasting insulin, and HOMA-IR.