Abstract
Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic progressive lung disease that is increasing in incidence. Host genetic factors are associated with NTM-PD susceptibility. However, the heritability of NTM-PD is not well understood. Here, we perform a two-stage genome-wide association study (GWAS) and discover a susceptibility locus at 16p21 associated with NTM-PD, especially with pulmonary Mycobacterium avium complex (MAC) disease. As the lead variant, rs194800 C allele augments protein kinase C beta (PRKCB) gene expression and associates with severer NTM-PD. The functional studies show that PRKCB exacerbates M. avium infection and promotes intracellular survival of M. avium in macrophages by inhibiting phagosomal acidification. Mechanistically, PRKCB interacts with subunit G of the vacuolar-H+-ATPase (V-ATPase) and vacuolar protein sorting-associated protein 16 homolog (VPS16), blocking the fusion between lysosomes and mycobacterial phagosomes. PRKCB inhibitor has therapeutic potential against M. avium infection. These findings provide insights into the genetic etiology of NTM-PD and highlight PRKCB as an attractive target for host-directed therapy of MAC disease.