Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population.
OBJECTIVE
Genome-wide association studies have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2, and LOC387761 loci that significantly increase the risk of type 2 diabetes. We aimed to replicate these observations in a population-based cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes.


METHODS
We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose.


RESULTS
We confirmed the associations between type 2 diabetes and variants near CDKAL1 (odds ratio 1.49 [95% CI 1.27-1.75]; P = 8.91 x 10(-7)) and CDKN2A/B (1.31 [1.12-1.54]; P = 1.0 x 10(-3)). We observed significant association of SNPs in IGF2BP2 (1.17 [1.03-1.32]; P = 0.014) and SLC30A8 (1.12 [1.01-1.25]; P = 0.033) with combined IFG/type 2 diabetes. The SNPs in CDKAL1, IGF2BP2, and SLC30A8 were also associated with impaired beta-cell function estimated by homeostasis model assessment of beta-cell function. When combined, each additional risk allele from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634 increased the risk for type 2 diabetes by 1.24-fold (P = 2.85 x 10(-7)) or for combined IFG/type 2 diabetes by 1.21-fold (P = 6.31 x 10(-11)). None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG. Significant association was observed between the HHEX/IDE SNPs and type 2 diabetes in individuals from Shanghai only (P < 0.013) but not in those from Beijing (P > 0.33).


CONCLUSIONS
Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction.
Wu
Ying
Y
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Li
Huaixing
H
Loos
Ruth J F
RJ
Yu
Zhijie
Z
Ye
Xingwang
X
Chen
Lihua
L
Pan
An
A
Hu
Frank B
FB
Lin
Xu
X
D000368:Aged; D044466:Asian People / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics*; D002681:China; D015331:Cohort Studies; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases
C493966:CDKN2B protein, human; D027682:Cation Transport Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C078492:HHEX protein, human; D018398:Homeodomain Proteins; C498779:IGF2BP2 protein, human; D016601:RNA-Binding Proteins; C492522:SLC30A8 protein, human; D014157:Transcription Factors; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human