PROJECT SUMMARY The principle genetic and environmental risk factors underlying the pathogenesis of autoimmune hepatitis (AIH) are not well investigated. Better understanding the explainable risks in AIH is essential to elucidate disease heterogeneity, predict outcomes, and transition to a model of individualized clinical care. In this career development application, the candidate is proposing a hypothesis-driven research strategy to address important knowledge gaps in the field of genetic and environmental risks in AIH. This builds on a recently completed prospective study of patients with AIH and matched controls funded by an institutional KL2 award. The specific aims of the research strategy are to (1) develop a large cohort of patients with AIH and matched controls with detailed assessment of environmental risk factors and linked biologic samples utilizing traditional and novel recruitment strategies; (2) interrogate selected environmental triggers associated with new onset AIH; and (3) identify novel disease specific HLA associations and assess for genetic and environmental interactions. To achieve these aims, the candidate will (1) develop a large cohort of patients with well phenotyped AIH and matched controls who undergo carefully assessment of environmental risk factors and provide their genomic DNA; (2) systematically interrogate viral and medication-related environmental triggers of newly diagnosed AIH patients and two control groups; (3) conduct HLA deep sequencing utilizing the Illumina MiSeq platform to identify putative HLA-specific associations and perform gene-environment interaction studies. The proposed career development plan integrates in-depth mentoring from a multidisciplinary team of senior scientists, advanced coursework in genomics, genetic and molecular epidemiology, and immunology; experiential learning through the conduct of the proposed research plan, and a highly supportive research environment. The mentorship team, which includes independent investigators with expertise in clinical and translational research in hepatology (Chalasani), immunologic-mediated drug-hypersensitivity and HLA genetics (Phillips), clinical virology and mentoring (Gupta); epidemiologic data analysis and biostatistics (Gao), will guide the candidate's research and career development. The superb institutional infrastructure for facilitating junior investigators and substantial institutional commitment to the candidate greatly strengthen this application. At the conclusion of this program, the candidate will be well positioned to become an independent physician-investigator in autoimmune liver diseases and hepatogenomics.!