Unraveling genetic causality between type 2 diabetes and pulmonary tuberculosis on the basis of Mendelian randomization

Abstract

Abstract Background The comorbidity rate between type 2 diabetes mellitus (T2DM) and pulmonary tuberculosis (PTB) is high and imposes enormous strains on healthcare systems. However, whether T2DM is causally associated with PTB is unknown owing to limited evidence from prospective studies. Consequently, the present study aimed to clarify the genetic causality between T2DM and PTB on the basis of Mendelian randomization (MR) analysis. Methods Genetic variants for T2DM and PTB were obtained from the IEU OpenGWAS project. The inverse variance weighted method was used as the main statistical analysis method and was supplemented with MR-Egger, weighted median, simple mode, and weighted mode methods. Heterogeneity was analyzed using Cochran’s Q statistic. Horizontal pleiotropy was assessed using the MR-PRESSO global test and MR-Egger regression. Robustness of the results was verified using the leave-one-out method. Results A total of 152 independent single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to assess the genetic causality between T2DM and PTB. Patients with T2DM had a higher risk of PTB at the genetic level (odds ratio (OR) for MR-Egger was 1.550, OR for weighted median was 1.540, OR for inverse variance weighted was 1.191, OR for simple mode was 1.629, OR for weighted mode was 1.529). There was no horizontal pleiotropy or heterogeneity among IVs. The results were stable when removing the SNPs one by one. Conclusions This is the first comprehensive MR analysis that revealed the genetic causality between T2DM and PTB in the East Asian population. The study provides convincing evidence that individuals with T2DM have a higher risk of developing PTB at the genetic level. This offers a significant basis for joint management of concurrent T2DM and PTB in clinical practice.