Interaction Effect Of Genetic Polymorphisms In Glucokinase (GCK) And Glucokinase Regulatory Protein (GCKR) On Metabolic Traits In Healthy Chinese Adults And Adolescents

Abstract

Objective- Recent studies in European populations have reported a reciprocal association of glucokinase regulatory protein (GCKR) gene with triglyceride versus fasting plasma glucose levels and type 2 diabetes risk. GCKR is a rate-limiting factor of glucokinase (GCK) which functions as a key glycolytic enzyme for maintaining glucose homeostasis. We examined the associations of two common genetic polymorphisms of GCKR and GCK with metabolic traits in healthy Chinese adults and adolescents.

Research Design and Methods- Two single nucleotide polymorphisms (SNPs), rs780094 at GCKR and rs1799884 at GCK, were genotyped in 600 healthy adults and 986 healthy adolescents. The associations of these SNPs with metabolic traits were assessed by linear regression adjusted for age, gender, and/or body mass index. We also tested for the epistasis between these two SNPs and performed a meta-analysis among European and Asian populations.

Results- The T-allele of GCKR rs780094 was associated with increased triglyceride levels (P = 5.4×10⁻⁷) while the A-allele of GCK rs1799884 was associated with higher fasting plasma glucose (P = 3.1×10⁻⁷). A novel interaction effect between the two SNPs on fasting plasma glucose was also observed (P = 0.0025). Meta-analyses strongly supported the additive effects of the two SNPs on fasting plasma glucose and triglyceride, respectively.

Conclusions- In support of the intimate relationship between glucose and lipid metabolisms, GCKR and GCK genetic polymorphisms interact to increase fasting plasma glucose in healthy adults and adolescents. These risk alleles may contribute to increased diabetes risk in subjects who harbor other genetic or environmental/lifestyle risk factors.