Investigating Host Genetic Risk Factors for Tuberculosis in Highly Endemic South African Populations. Genetic ancestry in the Northern Cape TB (NCTB) cohort

Tuberculosis (TB) remains one of the deadliest infectious diseases in both the developing and developed world. Little is known about host genetic risk factors for developing active TB infection, particularly in highly endemic regions such as South Africa. To address this gap and empower a broader understanding of disease biology, we will perform large-scale recruitment and generate deep genetic and immunological data from understudied populations of South Africa most severely affected by TB, where endemicity is extremely high but known environmental risk factors are relatively low. Previous studies in the study of TB host genetics are weakened by their comparison of active TB with healthy controls and with limited knowledge of Mycobacterium tuberculosis (M.tb) exposure: our strength is that we will investigate the factors that mediate a successful immune response to prevent active TB following M.tb infection. We will recruit participants from understudied southern African populations most severely affected by TB, where endemicity is extremely high but typical environmental risk factors are relatively low. The extraordinary genetic variation in southern Africa together with enhanced susceptibility to TB provides an unparalleled opportunity to identify risk variants and immunologically characterize disease control. We also propose unique analyses integrating ancestry with genotype to boost power given our previous discoveries. Both in our primary discoveries, and in opportunities for future contributions to meta-analyses with other datasets, this will provide a greater understanding of disease pathophysiology for one of the leading causes of infectious disease mortality across both the developing and developed world. To perform these analyses, we have assembled a unique group of population geneticists, statistical geneticists, and immunologists both in the United States and in South Africa.