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Identification of functional enhancer variants associated with type I diabetes in CD4+ T cells.
Mishra, Arpit; Jajodia, Ajay; Weston, Eryn; Jayavelu, Naresh Doni; Garcia, Mariana; Hossack, Daniel; Hawkins, R David.
Afiliación
  • Mishra A; Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
  • Jajodia A; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, United States.
  • Weston E; Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
  • Jayavelu ND; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, United States.
  • Garcia M; Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
  • Hossack D; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, United States.
  • Hawkins RD; Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
Front Immunol ; 15: 1387253, 2024.
Article en En | MEDLINE | ID: mdl-38947339
ABSTRACT
Type I diabetes is an autoimmune disease mediated by T-cell destruction of ß cells in pancreatic islets. Currently, there is no known cure, and treatment consists of daily insulin injections. Genome-wide association studies and twin studies have indicated a strong genetic heritability for type I diabetes and implicated several genes. As most strongly associated variants are noncoding, there is still a lack of identification of functional and, therefore, likely causal variants. Given that many of these genetic variants reside in enhancer elements, we have tested 121 CD4+ T-cell enhancer variants associated with T1D. We found four to be functional through massively parallel reporter assays. Three of the enhancer variants weaken activity, while the fourth strengthens activity. We link these to their cognate genes using 3D genome architecture or eQTL data and validate them using CRISPR editing. Validated target genes include CLEC16A and SOCS1. While these genes have been previously implicated in type 1 diabetes and other autoimmune diseases, we show that enhancers controlling their expression harbor functional variants. These variants, therefore, may act as causal type 1 diabetic variants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T CD4-Positivos / Elementos de Facilitación Genéticos / Predisposición Genética a la Enfermedad / Diabetes Mellitus Tipo 1 Límite: Humans Idioma: En Revista: Front Immunol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T CD4-Positivos / Elementos de Facilitación Genéticos / Predisposición Genética a la Enfermedad / Diabetes Mellitus Tipo 1 Límite: Humans Idioma: En Revista: Front Immunol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza