Common polymorphisms in MTNR1B, G6PC2 and GCK are associated with increased fasting plasma glucose and impaired beta-cell function in Chinese subjects.
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.


RESULTS
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.


CONCLUSIONS
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.
Tam
Claudia Ha Ting
CH
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong, Special Administrative Region, People's Republic of China.
Ho
Janice Sin Ka
JS
Wang
Ying
Y
Lee
Heung Man
HM
Lam
Vincent Kwok Lim
VK
Germer
Soren
S
Martin
Mitchell
M
So
Wing Yee
WY
Ma
Ronald Ching Wan
RC
Chan
Juliana Chung Ngor
JC
Ng
Maggie Chor Yin
MC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D044466:Asian People / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics; D005215:Fasting / Q000097:blood*; D005260:Female; D005838:Genotype; D005941:Glucokinase / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044094:Receptors, Melatonin / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C485100:GCKR protein, human; D044094:Receptors, Melatonin; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human