In summary, based on our results, we propose a model in which an autoimmune disease pleiotropic variant, i.e., rs4728142, directs a short-range chromatin loop between its upstream enhancer and the IRF5-short promoter by affecting the chromatin binding of a putative structural regulator, ZBTB3, which causes aberrant IRF5 activation and autoimmune disease risk (Fig. 7e). Here, IRF5 is linked to autoimmune disease.