Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus
Open accessAbstract
Many of the type 2 diabetes loci identified through genome-wide association studies localize to non-protein-coding intronic and intergenic regions and likely contain variants that regulate gene transcription. The CDC123/CAMK1D type 2 diabetes association signal on chromosome 10 spans an intergenic region between CDC123 and CAMK1D and also overlaps the CDC123 3'UTR. To gain insight into the molecular mechanisms underlying the association signal, we used open chromatin, histone modifications and transcription factor ChIP-seq data sets from type 2 diabetes-relevant cell types to identify SNPs overlapping predicted regulatory regions. Two regions containing type 2 diabetes-associated variants were tested for enhancer activity using luciferase reporter assays. One SNP, rs11257655, displayed allelic differences in transcriptional enhancer activity in 832/13 and MIN6 insulinoma cells as well as in human HepG2 hepatocellular carcinoma cells. The rs11257655 risk allele T showed greater transcriptional activity than the non-risk allele C in all cell types tested. Using electromobility shift and supershift assays we demonstrated that the rs11257655 risk allele showed allele-specific binding to FOXA1 and FOXA2. We validated FOXA1 and FOXA2 enrichment at the rs11257655 risk allele using allele-specific ChIP in human islets. These results suggest that rs11257655 affects transcriptional activity through altered binding of a protein complex that includes FOXA1 and FOXA2, providing a potential molecular mechanism at this GWAS locus.
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Functional investigation of a genetic variant associated with Type 2 diabetes, previously assigned to CDC123 and CAMK1D based on proximity, revealed that the variant affects the distal CAMK1D gene and not CDC123.
“Similarly, functional investigation of a genetic variant associated with Type 2 diabetes, and previously assigned to the CDC123 and CAMK1D genes based on proximity, revealed that the variant affects the distal CAMK1D gene and not CDC123 (Fogarty et al., 2014; GTEx Consortium, 2015).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Fogarty et al., 2014
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- Authors
- Fogarty, M. P., Cannon, M. E., Vadlamudi, S., Gaulton, K. J., & Mohlke, K. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Centre for Human Genetics (GB)
- Corresponding author
- Mohlke, Karen L.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-09-11
- Volume
- 10
- Issue
- 9
- Pages
- e1004633
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4161327
- OpenAlex
- W2025665777
- Cited by
- 93
- References
- 51
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 7 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 12 · 2018: 12 · 2017: 5 · 2016: 10 · 2015: 9
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- UNC Libraries
- Funders
- Broad Institute (HHSN268201000029C)
- National Institutes of Health (10XS170, #HHSN261200800001E, HHSN268201000029C, 10XS171, HHSN261200800001C, 10ST1035, U42OD011158)
- University of North Carolina at Chapel Hill
- National Heart, Lung, and Blood Institute (HHSN268201000029C, HHSN261200800001E)
- National Institute of Mental Health (HHSN261200800001E)
- National Institute on Drug Abuse (DA027040, R21DA027040)
- National Human Genome Research Institute (HHSN261200800001E)
- NIH Office of the Director (HHSN261200800001E)
- National Cancer Institute (HHSN261200800001E), HHSN268201000029C)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-072193, R01DK072193)
- National Institute of Neurological Disorders and Stroke
- Common Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- type 2 diabetes, FOXA1, FOXA2, regulatory variants, transcription factor binding, 3' untranslated region, intergenic regions, MIN6 cells, HepG2 cells, pancreatic islets, histone modifications, open chromatin
- MeSH terms
- Alleles, Animals, Cell Line, Diabetes Mellitus, Type 2, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Islets of Langerhans, Protein Binding, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Genetic Variation, Cell Cycle Proteins, Polymorphism, Single Nucleotide, Hepatocytes, Mice, Hepatocyte Nuclear Factor 3-alpha, Hepatocyte Nuclear Factor 3-beta, Calcium-Calmodulin-Dependent Protein Kinase Type 1, Genome-Wide Association Study, Genetic Loci
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