Arpit Mishra, Ajay Jajodia, Eryn Weston, Naresh Doni Jayavelu, Mariana Garcia et al.
Type I diabetes is an autoimmune disease mediated by T-cell destruction of β 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 T1D 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.
Arpit Mishra, Ajay Jajodia, Eryn Weston, Naresh Doni Jayavelu, Mariana Garcia, Daniel Hossack, R. David Hawkins. Identification of functional enhancer variants associated with type I diabetes in CD4+ T cells. 2024-06-14. https://doi.org/10.3389/fimmu.2024.1387253
A synthetic oligonucleotide library tested reference and alternate alleles for 121 T1D-associated enhancer variants in activated primary human CD4+ T cells. The STARR-seq-style episomal reporter was quantified using matched plasmid-DNA and reporter-RNA counts, producing allele-specific enhancer activity estimates.
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