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Background  Previous studies identified melatonin receptor 1B ( MTNR1B ), islet-specific glucose 6 phosphatase catalytic subunit-related protein ( G6PC2 ), glucokinase ( GCK ) and glucokinase regulatory protein ( GCKR ) as candidate genes for type 2 diabetes (T2D) acting through elevated fasting plasma glucose (FPG). We examined the associations of the reported common variants of these genes with T2D and glucose homeostasis in three independent Chinese cohorts.    Methodology/Principal Findings  Five single nucleotide polymorphisms (SNPs),  MTNR1B  rs10830963,  G6PC2  rs16856187 and rs478333,  GCK  rs1799884 and  GCKR  rs780094, were genotyped in 1644 controls (583 adults and 1061 adolescents) and 1342 T2D patients. The G-allele of  MTNR1B  rs10830963 and the C-alleles of both  G6PC2  rs16856187 and rs478333 were associated with higher FPG (0.0034< P <6.6×10 −5 ) in healthy controls. In addition to our previous report for association with FPG, the A-allele of  GCK  rs1799884 was also associated with reduced homeostasis model assessment of beta-cell function (HOMA-B) ( P  = 0.0015). Together with  GCKR  rs780094, the risk alleles of these SNPs exhibited dosage effect in their associations with increased FPG ( P  = 2.9×10 −9 ) and reduced HOMA-B ( P  = 1.1×10 −3 ). Meta-analyses strongly supported additive effects of  MTNR1B  rs10830963 and  G6PC2  rs16856187 on FPG.    Conclusions/Significance  Common variants of  MTNR1B ,  G6PC2  and  GCK  are associated with elevated FPG and impaired insulin secretion, both individually and jointly, suggesting that these risk alleles may precipitate or perpetuate hyperglycemia in predisposed individuals.

Common Polymorphisms in MTNR1B, G6PC2 and GCK Are Associated with Increased Fasting Plasma Glucose and Impaired Beta-Cell Function in Chinese Subjects