Identification of functional enhancer variants associated with type I diabetes in CD4+ T cells

TL;DR

The paper identifies functional enhancer variants in CD4+ T cells that may contribute to type I diabetes by affecting gene expression.

Contribution

The study identifies and validates functional enhancer variants associated with type I diabetes in CD4+ T cells.

Findings

Four CD4+ T-cell enhancer variants associated with type I diabetes were found to be functional.

Three enhancer variants weaken activity while one strengthens activity.

Functional variants are linked to genes CLEC16A and SOCS1, which are implicated in type I diabetes.

Abstract

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 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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