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Aberrations in ID3 are strongly associated with numerous human disease processes including Burkitt\u2019s lymphoma. We previously identified that a single-nucleotide polymorphism (SNP) in ID3 at rs11574 is associated with increased vascular disease burden in three independent cohorts; however, the mechanisms by which this SNP alters ID3 function and impacts vascular cells are unknown. Here, we show that the minor allele of rs11574 specifically disrupts ID3\u2019s ability to bind the E-protein E12. Computational analysis and confirmatory biochemical experiments revealed that rs11574\u2019s effects on ID3:E12 dimerization are dependent upon a key residue within E12\u2019s unique loop domain. Functionally, the disruption of ID3:E12-binding promotes E12 binding to and activation of the p21 promoter. Isogenic human cell lines harboring the rs11574 minor allele exhibited decreased cell proliferation and altered expression of genes involved in proliferation. RNAseq revealed distinct roles for E12 and E47 in transcriptional regulation of vascular smooth muscle cells (VSMCs). Primary human VSMCs from subjects with the rs11574 minor allele exhibited reduced mitogen-stimulated proliferation. Taken together, these results provide the first characterization of altered molecular and cellular functions of this disease-associated SNP in ID3 at rs11574.<\/jats:p>","DOI":"10.1093\/narmme\/ugag003","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:36:38Z","timestamp":1768566998000},"source":"Crossref","is-referenced-by-count":0,"title":["A prevalent disease-associated\u00a0SNP in the human\n                    <i>ID3<\/i>\n                    gene regulates E-protein activity and cellular proliferation"],"prefix":"10.1093","volume":"3","author":[{"given":"Christopher A","family":"Henderson","sequence":"first","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Medical Scientist Training Program, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5886-3437","authenticated-orcid":false,"given":"Brett P","family":"Ransegnola","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Medical Scientist Training Program, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Department of Pathology, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Garmey","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Robert M. Beirne Cardiovascular Research Center, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Khan","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u00e9douane","family":"Aherrahrou","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Center for Public Health Genomics, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Purdy","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shijie","family":"Wu","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Zhou","sequence":"additional","affiliation":[{"name":"Robert M. Beirne Cardiovascular Research Center, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer L","family":"Kirby","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Robert M. Beirne Cardiovascular Research Center, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J","family":"Lipinski","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Robert M. Beirne Cardiovascular Research Center, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vicki","family":"Gordon","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Yeager","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mete","family":"Civelek","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Center for Public Health Genomics, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coleen\u00a0A","family":"McNamara","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Robert M. Beirne Cardiovascular Research Center, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]},{"name":"Cardiovascular Division\/Department of Medicine, University of Virginia School of Medicine , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"2026020405220326500_B1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1159\/000362452","article-title":"Inhibitor of differentiation 3, a transcription factor, regulates hyperlipidemia-associated kidney disease","volume":"126","author":"Nackiewicz","year":"2014","journal-title":"Nephron Exp Nephrol"},{"key":"2026020405220326500_B2","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1016\/j.ymthe.2022.06.018","article-title":"Corneal fibrosis abrogation by a localized AAV-mediated inhibitor of differentiation 3 (Id3) gene therapy in rabbit eyes in 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