GENE ENVIRONMENT TRIGGERS AND PROTEOMIC PATHWAYS MEDIATING ANTI-NUCLEAR AUTOIMMUNITY AND SYSTEMIC RHEUMATIC DISEASE - Systemic Autoimmune Rheumatic Diseases (SARDs), including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), Sjogren’s Syndrome (SS) and Systemic Sclerosis (SSc). are chronic, debilitating systemic autoimmune diseases without cure, affecting ~400/100,000 Americans and >30 million people worldwide. SARDs result in significant physical, mental and social impairment, and economic burden, costing $20,000->$60,000 USD per patient per annum. Individual SARDs have been examined in silos without an attempt to discern shared underlying features at the molecular level. Current understanding of the initial (and likely shared) origins SARDs is only rudimentary, but urgently needed to develop means for prevention and treatment. Loss of tolerance to nuclear antigens leading to the development of anti-nuclear autoantibodies (ANAs) is an early phase of SARD, present in >50% of these subjects. However, the Gene X Environmental risk factors and molecular pathways underlying this early phase of autoimmunity, and subsequent development of rheumatic disease remain unclear. Here, we dissect out these triggers, leveraging the NHS and NHSII cohorts. Whereas Aim 1 focuses on the initial development of autoantibodies, Aim 2 focuses on the subsequent development of disease. In both Aims, plasma samples from the prospective cohort will be screened for ANAs, comprehensive proteomics and environmental exposures using an immunoexposome array at baseline and at 10-yr follow-up. Genetic loci, exposome triggers. Gene X Environment interactions, and functional protein modules associated with ANAs, SARDs, or future ANA development or SARD onset will be identified. Collectively, these studies will help identify the genetic, environmental and GXE factors that are operative at the 2 steps of SARD development, namely ANA emergence and disease onset. More importantly, these studies will highlight functional molecular pathways (and mechanisms) that may be operative at each step. There is an increasing focus on the pre-disease phase in SARDs, but the inciting events and specific molecular triggers are unknown. The proposed studies address this gap by providing a higher resolution molecular map of the earliest functional pathways that precede and initiate ANAs/SARDs. This may also offer opportunities for intercepting the disease at its incipience.
