Association of TLR2, TLR4, and IFN-γ gene polymorphisms with pulmonary tuberculosis susceptibility among Yemeni patients

Tuberculosis (TB), caused by Mycobacterium tuberculosis , remains a major global public health challenge. Host genetic variation in immune-related genes may influence susceptibility to pulmonary tuberculosis (PTB). This study investigated the association of Toll-like receptor 2( TLR2 ) rs3804099 (T/C), Toll-like receptor 4 ( TLR4 ) rs11536889 (G/C), and interferon-gamma ( IFN-γ ) rs2069718 (A/G) polymorphisms with PTB susceptibility in the Yemeni population. A case–control study was conducted between 2022 and 2025 and included 400 Yemeni participants (200 newly diagnosed PTB patients and 200 healthy controls selected for comparability with respect to age, sex, and geographic region. PTB diagnosis was confirmed using sputum smear microscopy, GeneXpert MTB/RIF assay, and mycobacterial culture. Genotyping was performed using TaqMan ® real-time PCR assays. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) under different genetic models. Bonferroni correction was applied to the three primary allelic comparisons. Smoking and lack of Bacillus Calmette–Guérin (BCG) vaccination were identified as significant PTB risk factors. The TLR2 rs3804099 C allele was significantly associated with increased PTB susceptibility (OR = 1.40, 95% CI: 1.10–1.90, p = 0.013), while the CC genotype was associated with increased PTB susceptibility under the recessive model. Similarly, the TLR4 rs11536889 C allele and CC genotype were significantly associated with elevated PTB risk. In addition, the IFN-γ rs2069718 G allele and AG/GG genotypes were associated with increased susceptibility to PTB. The primary allelic associations for the three investigated SNPs remained significant after Bonferroni correction. These findings suggest that TLR2 , TLR4 , and IFN-γ polymorphisms may contribute to PTB susceptibility in the Yemeni population. However, given the modest sample size and lack of an independent replication cohort, the findings should be considered preliminary. Further large-scale and functional studies are needed to validate these associations.