My research interest is in the genetics and epigenetics of complex autoimmune and inflammatory diseases, with a particular focus on lupus and systemic vasculitis. We apply state-of-the-art genomic and epigenomic methodologies and subsequent functional studies using both in vitro and in vivo systems to identify and characterize genetic loci and pathways involved in the pathogenesis of immune-mediated diseases. Using careful clinical phenotyping and extensive national and international collaborations, we aim at discovering genomic and epigenomic markers for disease progression, specific organ involvement, and response to therapy in systemic autoimmune diseases. Recent work from our lab includes genome-wide DNA methylation studies demonstrating that naive CD4+ T cells in lupus are epigenetically poised for pathologic levels of type I interferon–regulated gene expression. This work provided the first mechanistic explanation for type I interferon hyper-responsiveness in autoimmunity. Our work in Behçet’s disease led to the identification of multiple independent genetic susceptibility loci in the HLA region, including a variant between MICA and HLA-B genes that explains the association previously attributed to HLA-B*51. Outside of the HLA, we discovered the genetic association with UBAC2 in Behçet’s disease and provided strong evidence that reversible epigenetic modifications of cytoskeletal dynamics underlie the pathogenesis and therapeutic response in this disease. Our recent work in Takayasu arteritis identified five genetic susceptibility loci, both inside and outside of the HLA, including genes encoding for immune system molecules that are potential therapeutic targets, such as IL12B and FCGR2A.
Amr H. Sawalha, MD