Causal association between adiposity and susceptibility to nontuberculous mycobacterial pulmonary disease: a Mendelian randomization study

Abstract Background Nontuberculous mycobacterial pulmonary disease (NTM-PD) is frequently observed in lean individuals. Although low body mass index (BMI) and reduced adiposity have been linked to NTM-PD, the causal relationship remains uncertain due to confounding and reverse causation. Mendelian randomization (MR) can address these limitations by using genetic variants as instrumental variables. Methods A two-sample MR analysis was performed to assess the causal effects of anthropometric and body composition traits—including height, BMI, waist–hip ratio (WHR), body fat percentage, and appendicular lean mass—on NTM-PD risk. Summary-level genome-wide association study (GWAS) data were obtained from large European ancestry cohorts including UK Biobank, GIANT, and FinnGen. Causal estimates were generated using inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode approaches. Heterogeneity and pleiotropy were assessed using MR-Egger intercepts, Cochran’s Q, and MR-PRESSO tests, and robustness was evaluated using leave-one-out analyses. Results Genetically predicted body fat percentage was inversely associated with NTM-PD (IVW odds ratio 0.240, 95% CI 0.084–0.692, p = 0.008), an association that survived correction for multiple testing (adjusted p = 0.04). BMI showed a similar but nonsignificant inverse trend ( p = 0.180), and no associations were observed for height, waist-hip ratio, or appendicular lean mass. Sensitivity analyses revealed no evidence of heterogeneity or horizontal pleiotropy, and leave-one-out analyses confirmed the robustness of the findings. Conclusions These findings suggest that reduced adiposity — reflected most clearly in body fat percentage estimates — may increase susceptibility to NTM-PD, warranting further clinical investigation.