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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Several 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.
“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]
Some regions reveal surprising associations; unexpected connections have emerged among T2D, inflammatory diseases (two loci), and cancer (four loci), including CDKAL1, GCKR, TCF2, JAZF1, and TCF7L2.
“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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- 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 › Surgery › 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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