Tuberculosis (TB) ranked as the second leading cause of mortality from infectious disease after COVID-19 in 2022, resulting in the loss of 1.3 million lives worldwide. Type 2 diabetes (T2D) is one of five risk factors of TB and an estimated 370,000 new cases were attributable to T2D in 2020. However, whether T2D is causally associated with TB is largely unknown. We aimed to infer causal relationship between T2D and pulmonary TB using a two-sample Mendelian randomization (MR) framework.

We conducted a MR analysis in the East Asian population, where pulmonary TB is endemic. Eighteen independent genome-wide significant variants of T2D from the meta-analysis of the Korean Genome and Epidemiology Study and the Taiwan Biobank (N=135,387, F-statistics=70.2) were used as instrumental variables for T2D. Outcome data for genome-wide association analysis of pulmonary TB was obtained from the Biobank Japan (N=212,453).

Summary-level MR analysis showed that higher genetic risk for T2D was significantly associated with higher risk for pulmonary TB (beta=0.324, P=3.4×10-5). This association was also significant in multiple sensitivity analyses (MR-Egger P=0.046; weighted median P=8.9×10-4; weighted mode P=0.023; MR-PRESSO P=6.7×10-4; MR-RAPS; P=9.9×10-4). Absence of horizontal pleiotropy was supported via the MR-Egger intercept test (P=0.36). Multivariable MR analysis showed that T2D’s causal effect on pulmonary TB was independent of smoking, alcohol intake, body mass index and other cardiometabolic traits. Higher genetic risk for HbA1c was also significantly associated with increased risk for pulmonary TB (43 non-erythrocytic variants, beta=0.604, P=0.029). However, genetic risk for fasting glucose showed concordant directionality but did not reach statistical significance (beta=0.266, P=0.114).

Genetically predicted T2D is significantly associated with higher risk of pulmonary TB. This MR analysis supports the causal predisposition of T2D to pulmonary TB.

Disclosure

H. Lee: None. S. Park: None. J. Choi: None. J. Park: None. J. Lee: None. J. Kim: None. K. Park: None. S. Kwak: Employee; SNUH Venture.

© 2024 by the American Diabetes Association
2024
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.