Systemic lupus erythematosus (SLE or lupus) is a complex, multi-organ, clinically heterogeneous, potentially fatal autoimmune disease with substantial genetic and environmental components. In U.S., SLE affects ~2 million people, mostly women (~90%), and prevalence is >3-5 times higher in individuals of African, Asian and Hispanic ancestries compared to European ancestry. Despite its public health importance, SLE pathogenesis is not well understood. Infection is a leading cause of morbidity and mortality, accounting for >25% of deaths in SLE patients. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide are key for defense against invading microbial pathogens, and are produced by the multi-protein NADPH- oxidase (NADPHO) system during phagocytosis. This multi-protein complex is encoded by 7 essential genes: NCF1, NCF2, NCF4, CYBA,CYBB, Rac1 or Rac2. Although NADPHO is likely to be important in SLE pathophysiology, thus far, none of the 7 genome-wide association studies detected SLE association. Using large multi-ethnic cohorts (N >17,000 from European-Americans (EA), African-Americans (AA), Hispanics (HS), and Koreans (KR)), we have identified at least 7 independent and potentially functional SLE-susceptibility variants (10-44 Lupus is a significant global health problem. In the United States alone, more than 2,000,000 individuals suffer from this devastating disease, especially people of African, Asian, or Hispanic ancestry where prevalence is 3 to 5 times higher than in those of Caucasian ancestry. Our study will identify potentially functional variants within genes of the NADPH oxidase system and their relative contributions to the development of lupus, as well as their contributions in a clinical subset of patients of each ethnicity.Public Health Relevance
