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

## TL;DR

This study uses genetic data to show that endocrine, nutritional, and metabolic diseases increase the risk of pulmonary tuberculosis, with some factors like high cholesterol and BMI offering protection.

## Contribution

The study provides novel genetic evidence of a causal link between endocrine, nutritional, and metabolic diseases and pulmonary tuberculosis using Mendelian randomization.

## Key findings

- Endocrine, nutritional, and metabolic disease significantly increases the risk of pulmonary tuberculosis (OR = 1.41).
- High cholesterol, BMI, and LDL-c are negatively correlated with PTB risk in European ancestry populations.
- Type 2 diabetes shows no causal association with PTB risk.

## Abstract

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.

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.

The inverse variance weighting analyses indicated that ENMD significantly increased the risk of PTB (OR = 1.41, 95% CI: 1.18–1.68, p < 0.001) after removing outliers. Interestingly, at the genetic level of European ancestry, there is no evidence of increased risk of PTB with T2DM (OR = 1.05, 95% CI: 0.99–1.12, p = 0.10), whereas high cholesterol (OR = 0.41, 95% CI: 0.22–0.79, p < 0.05), BMI (OR = 0.78, 95% CI: 0.69–0.88, p < 0.001) was negatively correlated with the risk of PTB, and LDL‐c showed a weak inverse correlation with PTB (OR = 0.90, 95% CI: 0.81–0.99, p = 0.03). Sensitivity analyses confirmed the robustness of these findings.

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.