Amr Sawalha, M.D.

Marvin and Betty Danto Research Professor of Connective Tissue Research
Professor of Internal Medicine, Division of Rheumatology
Accepting Students

Research Interests

Our research program focuses on elucidating genetic and epigenetic contribution to the pathogenesis of systemic autoimmune and inflammatory rheumatic diseases. We apply state-of-the-art genomic, epigenomic, and bioinformatics 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 autoimmunity. Our research program is currently funded by an NIH R01 grant, a recently awarded U19 Autoimmunity Center of Excellence grant, and a grant from the Lupus Research Institute, and funding from the University of Michigan and a Research Endowment. Recent work from our lab includes genome-wide DNA methylation studies demonstrating that naïve CD4+ T cells in lupus are epigenetically poised for pathologic levels of type-1 interferon regulated gene expression. This work provided a mechanistic explanation for type-1 interferon hyper-responsiveness in autoimmunity. We recently identified specific "epigenetic susceptibility" loci associated with the development of renal involvement in lupus. 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 in monocytes and CD4+ T cells underlie the pathogenesis and therapeutic response in this disease. Our recent work in Takayasu arteritis identified multiple 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, IL6, LILRB3, and FCGR2A. Future studies will also focus on functional characterization of these susceptibility loci to determine how they contribute to the pathogenesis of these complex immune-mediated diseases. Using "epigenetic immunophenotyping" we characterized the inflammatory response in giant cell arteritis and identified novels molecules involved in the pathogenesis of this form of large vessel vasculitis and potential new targets for therapy. The future direction of our lab will continue to focus on three main themes: novel discoveries in the genetic and epigenetic causation of complex autoimmune diseases, functional characterization of these novel findings to provide mechanistic insights into disease pathogenesis, and the development of genetic and epigenetic biomarkers of disease severity, activity, response to therapy, and phenotypic progression.

Publications