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A variant in CDKAL1 influences insulin response and risk of type 2 diabetes
Open accessAbstract
We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.
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“Interestingly, several of the recently discovered risk loci for type 2 diabetes have been implicated in cell cycle control of β-cells and could theoretically influence adult β-cell mass or alter the timing of cell cycle exit of adult β-cells (36–39).”
From Adaptive β-Cell Proliferation Is Severely Restricted With Advanced Age (2009) · cites this paper as [36]
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“5) Some regions reveal surprising associations. For example, unexpected connections have emerged among T2D, inflammatory diseases (two loci), and cancer (four loci). A single intron of CDKAL1 was found to contain a SNP associated with T2D and insulin secretion defects (99–101, 116), and another with Crohn’s disease and psoriasis (117).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [116]
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Metadata
- Authors
- Steinthorsdottir, V., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Jonsdottir, T., Walters, G. B., Styrkarsdottir, U., Gretarsdottir, S., Emilsson, V., Ghosh, S., Baker, A., Snorradottir, S., Bjarnason, H., Ng, M. C. Y., Hansen, T., Bagger, Y., Wilensky, R. L., Reilly, M. P., Adeyemo, A., Chen, Y., Zhou, J., Gudnason, V., Chen, G., Huang, H., Lashley, K., Doumatey, A., So, W.-Y., Ma, R. C. Y., Andersen, G., Borch-Johnsen, K., Jorgensen, T., van Vliet-Ostaptchouk, J. V., Hofker, M. H., Wijmenga, C., Christiansen, C., Rader, D. J., Rotimi, C., Gurney, M., Chan, J. C. N., Pedersen, O., Sigurdsson, G., Gulcher, J. R., Thorsteinsdottir, U., Kong, A., & Stefansson, K.
- Affiliations
- National University Hospital of Iceland (IS)
- deCODE Genetics (Iceland) (IS)
- Chinese University of Hong Kong (HK)
- Steno Diabetes Center Copenhagen (DK)
- Center for Clinical & Basic Research (DK)
- University of Pennsylvania (US)
- Howard University (US)
- Icelandic Heart Association (IS)
- University Medical Center Groningen (NL)
- Aarhus University (DK)
- ORCID
- Benediktsson, Rafn
- Walters, G Bragi
- Emilsson, Valur
- Baker, Adam
- Ng, Maggie C Y
- Hansen, Torben
- Reilly, Muredach P
- Adeyemo, Adebowale
- Zhou, Jie
- Gudnason, Vilmundur
- Chen, Guanjie
- Huang, Hanxia
- Lashley, Kerrie
- Doumatey, Ayo
- Andersen, Gitte
- Wijmenga, Cisca
- Christiansen, Claus
- Rader, Daniel J
- Rotimi, Charles
- Gurney, Mark
- Chan, Juliana C N
- Pedersen, Oluf
- Kong, Augustine
- Venue
- Nature Genetics
- Published
- 2007-04-26
- Volume
- 39
- Issue
- 6
- Pages
- 770-775
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2171874894
- Cited by
- 1,072
- References
- 29
- Citations by year
- 2026: 9 · 2025: 24 · 2024: 19 · 2023: 25 · 2022: 27 · 2021: 45 · 2020: 19 · 2019: 21 · 2018: 28 · 2017: 32 · 2016: 48 · 2015: 51 · 2014: 58 · 2013: 54 · 2012: 89
- FWCI
- 79.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- Chinese University of Hong Kong
- National Institutes of Health (5r01dk072128-04, RR03048)
- National Human Genome Research Institute (3T37TW00041-03S2)
- Fogarty International Center (T37TW000041, 3T37TW00041-03S2)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK072128)
- National Center on Minority Health and Health Disparities (3T37TW00041-03S2)
- National Center for Research Resources (RR03048, 3T37TW00041-03S2)
- National Institute on Minority Health and Health Disparities
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, CDKAL1, TCF7L2, genetic risk variants, insulin secretion, insulin response, homozygous carriers, European ancestry, Han Chinese, Icelandic population, genome-wide association study
- MeSH terms
- Insulin Secretion, Adult, Blood Glucose, Carrier Proteins, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Gene Frequency, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Nerve Tissue Proteins, Linkage Disequilibrium, Genome, Human, Case-Control Studies, Sulfur Group Transferases, Polymorphism, Single Nucleotide, Mitochondrial Proteins, Intracellular Signaling Peptides and Proteins, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Transcription Factor 7-Like 1 Protein
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