American Indians (AIs) have some of the shortest life-expectancies with geographic inequalities even more pronounced in rural counties like those in the Cherokee Nation catchment area. The causes for these findings are multi-factorial and are impacted by poorer outcomes in many chronic health conditions, such as the rheumatic diseases. Unfortunately, US tribal members have some of the highest rates of rheumatic disease in the nation, including diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis. To help address these health inequalities, this project seeks to understand the molecular immunologic phenotypes and potential mechanisms of accelerated aging in Oklahoma tribal patients to better inform diagnosis and treatments. Together, OMRF, OUHSC and the Cherokee Nation have assembled rheumatic disease research and infrastructure which are critical for the success of this proposed project, such as collections of samples and associated clinical data from 454 AI SLE patients, 190 AI RA patients and 300 AI controls, as well as thousands of additional patients and controls of other racial/ethnic backgrounds. Tribal NARCH rheumatology clinics have enrolled 273 additional tribal rheumatic disease patients. Joint findings to date include: it is common for tribal populations to have overlapping features of rheumatic disease (without meeting standard classification criteria), disease-specific autoantibody markers are not present in American Indian patients, and up to 41% of AI SLE patients have high concentrations of previously unidentified autoantibodies. Some unknown SLE specificities are directed against mitochondrial or myositis-specific antigens. Based upon these results, this application brings together three cutting-edge scientific approaches, precision medicine/deep molecular phenotyping, big data analytics/visualization and molecular mechanisms of accelerated aging, to identify dysregulated pathways in AI rheumatic disease patients. We will address the associated hypotheses through the following aims: (1) Perform a comprehensive molecular phenotypic evaluation of serologic, gene expression and cellular evidence of autoimmune disease- associated changes in American Indian patients with SLE or RA compared to matched controls to identify unique and important disease pathways which are enriched in AI autoimmunity. (2) Evaluate American Indian rheumatic autoimmune disease patients for molecular evidence of accelerated aging. Our key personnel have mentored over 20 American Indian students to advanced degrees and academic, medical and tribal service careers as physicians, physician assistants, and scientists. This project provides additional training to tribal students, with the initial three already identified. Training in clinical research, data management, data analytics, clinical immunology and precision medicine will be provided to the tribal students and investigators, which focuses on identifying molecular information to select and refine rational, directed therapies to improve AI rheumatic disease patient outcomes.