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
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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. RESEARCH DESIGN AND 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.
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Despite heterogeneity across populations in risk allele frequency or effect size in type 2 diabetes genes, the combined effects of multiple genetic variants using genetic scores based on the number of risk alleles appear to be similar across different ethnic groups.
“Despite heterogeneity across populations in risk allele frequency or effect size in type 2 diabetes genes, the combined effects of multiple genetic variants using genetic scores based on the number of risk alleles appear to be similar across different ethnic groups.”
From Globalization of Diabetes (2011) · cites this paper as [42]
Typically, each risk allele increment is associated with a 10-20% increased risk of type 2 diabetes.
“Typically, each risk allele increment is associated with a 10–20% increased risk of type 2 diabetes (41,42).”
From Globalization of Diabetes (2011) · cites this paper as [42]
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- Authors
- Wu, Y., Li, H., Loos, R. J. F., Yu, Z., Ye, X., Chen, L., Pan, A., Hu, F. B., & Lin, X.
- Affiliations
- Chinese Academy of Sciences (CN)
- University of Cambridge (GB)
- Harvard University (US)
- 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
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-10-01
- Volume
- 57
- Issue
- 10
- Pages
- 2834-2842
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2551696
- OpenAlex
- W2112027875
- Cited by
- 240
- References
- 29
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 5 · 2020: 3 · 2019: 9 · 2018: 8 · 2017: 12 · 2016: 14 · 2015: 26 · 2014: 19 · 2013: 16 · 2012: 29
- FWCI
- 15.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (30571562)
- Chinese Academy of Sciences
- National Key Research and Development Program of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- type 2 diabetes, impaired fasting glucose, CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, single nucleotide polymorphisms, genetic susceptibility, beta-cell function, Han Chinese, replication of genetic associations
- MeSH terms
- Zinc Transporter 8, Aged, China, Diabetes Mellitus, Type 2, Female, Genotype, Humans, Male, Middle Aged, tRNA Methyltransferases, Transcription Factors, Cohort Studies, RNA-Binding Proteins, Glucose Intolerance, Homeodomain Proteins, Cyclin-Dependent Kinase Inhibitor p16, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Cation Transport Proteins, Asian People, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase 5
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