The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn’s disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo . ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP , with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner. Author summary Research to date has identified many genetic variants that are more common in people with a particular disease. However, in conditions that reflect multiple genetic and environmental factors, it is difficult to know with certainty if and why any particular genetic variant is causative and the mechanism that may underlie this. Such variants are often outside of protein-coding exons, instead falling in regions that regulate gene expression. In these cases, the genetic variation may alter transcription factor binding and subsequent gene expression. In this study, we have examined how genetic variation affects T-bet binding to DNA, as a key transcriptional regulatory mechanism in the immune response. An inability to mount this response effectively can result in increased susceptibility to infections or cancer, while a response that is too strong, or wrongly targeted, can result in uncontrolled/chronic inflammatory and autoimmune conditions. We have found that T-bet binding sites are specifically enriched in genetic variants associated with the mucosal autoinflammatory diseases UC, Crohn’s disease and celiac disease. We also identify genetic variants that alter T-bet binding and gene expression. This discovery thus identifies a molecular mechanism through which genetic variants can be associated with increased risk of mucosal autoimmune disease.
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