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

• Published in: PloS one Vol. 5; no. 7; p. e11428
• Main Authors: Tam, Claudia Ha Ting, Ho, Janice Sin Ka, Wang, Ying, Lee, Heung Man, Lam, Vincent Kwok Lim, Germer, Soren, Martin, Mitchell, So, Wing Yee, Ma, Ronald Ching Wan, Chan, Juliana Chung Ngor, Ng, Maggie Chor Yin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.07.2010; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adenosine; Adolescents; Adult; Adults; Alleles; Analysis; Asian Continental Ancestry Group - genetics; Beta cells; Binding sites; Blood Glucose - metabolism; Blood proteins; Catalysis; Chromosomes; Circadian rhythm; Diabetes; Diabetes and Endocrinology/Type 2 Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Fasting; Fasting - blood; Female; Gene expression; Gene loci; Genes; Genetic aspects; Genetics and Genomics/Complex Traits; Genetics and Genomics/Genetics of Disease; Genetics and Genomics/Medical Genetics; Genetics and Genomics/Population Genetics; Genomics; Genotype; Glucokinase; Glucokinase - genetics; Glucose; Glucose-6-Phosphatase - genetics; Homeostasis; Hospitals; Humans; Hyperglycemia; Insulin; Insulin secretion; Insulin-Secreting Cells - pathology; Insulin-Secreting Cells - physiology; Isoenzymes; Laboratory testing; Male; Medicine; Melatonin; Meta-analysis; Middle Aged; Pancreatic beta cells; Phosphatases; Plasma; Polymorphism, Single Nucleotide - genetics; Receptors, Melatonin - genetics; Rodents; Secretion; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Type 2 diabetes; Hong Kong China; United States > US; China; New Jersey
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0011428

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. 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<6.6x10(-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=2.9x10(-9)) and reduced HOMA-B (P=1.1x10(-3)). Meta-analyses strongly supported additive effects of MTNR1B rs10830963 and G6PC2 rs16856187 on FPG. 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.