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OBJECTIVE-Recent studies in European populations have reported a reciprocal association of glucokinase regulatory protein (GCKR) gene with triglyceride versus fasting plasma glucose (FPG) 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, sex, and/or BMI. 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 triglycerides (P = 5.4 × 10^sup -7^), while the A-allele of GCK rs1799884 was associated with higher FPG (P = 3.1 × 10^sup -7^). A novel interaction effect between the two SNPs on FPG was also observed (P = 0.0025). Meta-analyses strongly supported the additive effects of the two SNPs on FPG and triglycerides, respectively.
CONCLUSIONS-In support of the intimate relationship between glucose and lipid metabolisms, GCKR and GCK genetic polymorphisms interact to increase FPG 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. Diabetes 58:765-769, 2009
The glycolytic enzyme glucokinase (GCK) is a glucose sensor that plays a key role in maintaining blood glucose homeostasis. In the pancreatic β-cells, GCK controls insulin secretion and biosynthesis (1). In the liver, GCK regulates glycogen synthesis and gluconeogenesis, and its activity is competitively inhibited by glucokinase regulatory protein (GCKR) (1,2).
In support of these functions, rare mutations in the GCK gene have been found to be associated with maturity-onset diabetes of the young (MODY), permanent neonatal diabetes, and hyperinsulinemia of infancy (3). Moreover, a common promoter variant (-30A) (rs1799884) of GCK has been found to be associated with increased fasting plasma glucose (FPG) and lowered birth weight in general Caucasian populations (4,5). Recently, a genome-wide association (GWA) study conducted by the Diabetes Genetics Initiative identified a common intronic polymorphism...