Integration of transcriptome and mendelian randomization elucidates the protective role of aspirin in pulmonary tuberculosis development.

BACKGROUND

Pulmonary tuberculosis (PTB) is a chronic respiratory infectious disease with suboptimal treatment outcomes in some patients. The potential protective effect of aspirin against PTB and its underlying mechanisms remain unclear.

METHODS

Two-sample Mendelian randomization (MR) was used to evaluate the association between aspirin use and PTB risk. Aspirin target genes from DrugBank were further assessed by summary-data-based Mendelian randomization (SMR) using eQTLGen and the Iceland dataset. Transcriptomic analysis compared gene expression between TB progressors and nonprogressors, and Kaplan-Meier analysis examined associations between gene expression and TB progression among household contacts. In vitro experiments were performed in BCG-stimulated monocytes.

RESULTS

MR analysis showed that aspirin use was associated with reduced PTB risk (IVW: OR = 0.06, 95% CI: 0.01-0.51, p = 0.01). pQTL-based SMR identified significant associations of TNFAIP6 and NEU1 with PTB (p = 0.02, p-FDR = 0.03; p = 9.6 × 10⁻3, p-FDR = 0.03, respectively), whereas eQTL-based SMR showed no significant associations. Transcriptomic analysis revealed higher TNFAIP6 and NEU1 expression in progressors than in nonprogressors (p = 6.1 × 10⁻⁶ and p = 0.02). Kaplan-Meier analysis indicated that elevated TNFAIP6 and NEU1 expression was associated with increased TB progression risk among household contacts (p = 2.2 × 10⁻4 and p = 0.03). In vitro, aspirin reduced TNFAIP6 expression in BCG-stimulated monocytes.

CONCLUSION

These findings suggest that aspirin may reduce PTB risk and implicate TNFAIP6 and NEU1 as potential mediators, supporting aspirin as a candidate adjunctive therapeutic strategy for PTB.