PROJECT SUMMARY/ABSTRACT Background: Approximately 13% of African Americans (AA), who suffer disproportionately from kidney and cardiovascular disease, carry two copies of the Apolipoprotein L1 (APOL1) gene risk variants (RV). These RVs contribute to renal and cardiovascular mortality, yet no therapies address gene mechanism. In cell culture and animal models, inflammatory cytokines increase APOL1 expression and worsen APOL1 high-risk genotype (HRG) related injury. The degree to which immune activation and resultant increased APOL1 expression synergizes with APOL1 genotype to precipitate human disease, such as lupus nephritis, is not understood. We will test the overarching hypothesis that APOL1 HRG SLE patients experience worsened disease features both due to SLE inflammatory mediators which induce gene expression and to protein coding changes carried on the variant allele. Importantly, an unprecedented number of biologic therapies are available to pharmacologically modulate immune pathways. Therefore understanding the relative contribution of specific immune pathways to APOL1 HRG associated disease may offer new treatment opportunities in this sensitive population. Preliminary Data: In our unique, AA SLE cohort and Ghanaian replication cohort, our group reproducibly identified APOL1 HRG associated traits including hypertension, renal dysfunction, and early atherosclerosis. Both in SLE monocytes and primary monocyte cell cultures, we identified SLE-relevant immune stimuli that induce APOL1 expression. We showed that HRG monocytes in response to high APOL1 expression exhibit mitochondrial dysfunction. These findings have clinical implications as they support a strategy aimed at reducing immune activation to mitigate APOL1 expression and resultant HRG associated disease features. Methods: To understand APOL1 immune regulation, we will analyze SLE patient monocyte transcriptional profiles by RNA-seq to assess immune pathway activation. APOL1 genotype, APOL1 transcriptional expression, and immune pathway scores will be tested for association with clinical outcomes, independently and in interaction models. We will determine whether increased APOL1 expression synergizes with risk genotype, and which immune system pathways reflected in the RNA-seq data are associated with APOL1 expression. We will validate the human transcriptional analysis using in-vitro monocyte cell culture models. Objectives and Career Development: This proposal leverages unique clinical and laboratory resources, and highly collaborative environment between experts in statistical genetics, functional genomics, immunology, cardiology, and rheumatology. It will lay the groundwork to propose future larger-scale studies designed to target specific immune pathways in APOL1 HRG patients. Furthermore, it will allow the PI to become an expert in the functional genomics of autoimmune disease and related kidney and vascular comorbidities, genetic modeling in complex clinical traits, and inno...