Novel Genetic Loci for Nontuberculous Mycobacterial Pulmonary Disease and Potential Protective Effect of Body Mass Index.

RATIONALE Although nontuberculous mycobacteria (NTM) are widespread, only some individuals develop NTM-pulmonary disease (NTM-PD), suggesting the involvement of host factors. OBJECTIVES To identify the genomic structure of NTM-PD and determine whether a definitive association exists between NTM-PD and nine risk factors. METHODS We performed genome-wide association studies in two independent Korean cohorts involving 1,949 NTM-PD patients and 2,955 healthy participants. Significantly associated genetic variants were validated in Japanese (1,137 cases, 1,546 controls) and European (243 cases, 570 controls) cohorts, respectively. Genes associated with lead variants were identified using several methods including quantitative trait loci analyses and their roles in NTM-PD were supported by single-cell transcriptome datasets. Genetic correlations and Mendelian randomization between NTM-PD and nine risk factors were examined. MEASUREMENTS AND MAIN RESULTS We identified two novel loci and replicated a locus associated with NTM-PD: rs60084385 (odds ratio (OR), 1.34; 95% confidence interval (CI), 1.21-1.48; P, 6.97×10-9); rs1479595 (OR, 1.40; 95% CI, 1.27-1.55; P, 7.08×10-11); and rs194792 (OR, 1.70; 95% CI, 1.50-1.93; P, 1.39×10-16). These associations were replicated in the independent cohorts. The three loci were significantly associated with expression levels of IL1Rs, PDE8B, and PRKCB, respectively, whose involvement in the pathogenesis of NTM-PD were further validated. Among the risk factors, only body mass index demonstrated both a significant genetic correlation with NTM-PD (rg, -0.57; false discovery rate [FDR], 1.33×10-5) and a potential causal relationship (OR, 0.38; 95% CI, 0.24-0.59; FDR, 8.55×10-5). CONCLUSIONS Our study identified three genetic loci associated with NTM-PD and a negative association of BMI with NTM-PD.