Assessing Causality Between Endocrine, Nutritional, and Metabolic Disease and Pulmonary Tuberculosis: A Mendelian Randomization Study.

Background and Aims: Observational studies frequently report co-occurrence between endocrine, nutritional, and metabolic disease (ENMD) and pulmonary tuberculosis (PTB). However, the causal properties between them remain poorly defined. Our aim in this study was to investigate the causal effect of ENMD on PTB using Mendelian randomization analysis. Methods: We obtained single nucleotide polymorphisms linked to ENMD, ENMD-related diseases, and clinical features, as well as PTB, from the IEU OpenGWAS project. Inverse variance weighting was used as the primary analytical method, complemented by Weighted median and MR-Egger regression to assess their causal relationship. Heterogeneity and horizontal pleiotropy were assessed using Cochran's Q test and MR regression intercepts. The robustness of the results is evaluated by sensitivity analysis leave-one-out and MR-PRESSO. Results: The inverse variance weighting analyses indicated that ENMD significantly increased the risk of PTB (OR = 1.41, 95% CI: 1.18-1.68, Conclusion: This MR study provides novel genetic evidence that ENMD significantly elevates PTB risk. Notably, high cholesterol, BMI, and LDL-c exhibit protective effects against PTB at the genetic level in European ancestry, while T2DM shows no causal association. These findings highlight the complex role of metabolic factors in tuberculosis susceptibility and suggest potential biological mechanisms linking metabolic dysregulation to PTB pathogenesis.