Among ethnic groups in the US, African Americans continue to display the lowest life expectancy and highest overall rates of cancer deaths (including colorectal, breast and prostate cancers), infant mortality, asthma, and cardiometabolic diseases (including heart disease, hypertension and obesity). Complex diseases and environmental insults all invoke and/or subvert host inflammation, with individual immune and variable responses to therapeutic agents being dictated in part by genetic variants. Precision diagnoses and prognoses of individual patient responses rely on assessing known disease and immune markers before, during and/or after treatment. This proposal will interrogate the functional effects and druggablity of under- studied gene variants related to immune and drug response within the genome of individuals of African ancestry (AAs). Immune gene variants most common among AAs and predicted to be druggable will be engineered into cells lines of different geographical ancestry and evaluated for functional effects in vitro and/or in vivo and modeled in silico to predict structural changes to the wild type proteins and possible variant-drug interactions. Novel assays to screen for compounds with therapeutic potential will be developed and used for screening. Lead compound candidates will then be validated, optimized and tested in vitro and/or in vivo. This project has the potential to 1) establish ancestry-related host immunity as a contributing biological parameter of complex disease disparities; 2) fill in critical knowledge gaps by identifying novel players and mechanisms of inflammation and their role in complex disease; and, 3) possibly lead to the development of effective therapies to address health disparities.