Association of the IFNG rs2430561 (+874T/A) Variant with Pleural Tuberculosis in a Venezuelan Mestizo Population

Background: Tuberculosis (TB) has various clinical presentations. Pulmonary TB (PTB) affects only the lungs. In contrast, miliary TB (MTB) is a disseminated form of the disease, while pleural TB (PLTB) is a localized disease that affects the pleura. Immunological studies of patients with extra-pulmonary TB mainly focus on the cellular Th1 response, which produces key cytokines like IFN-γ (IFNG), TNF-α (TNFA), IL-12, and IL-6. Findings suggest that IFNG plays a functional role in host resistance to Mycobacterium tuberculosis (Mtb) infection because it facilitates macrophage containment of Mtb, prevents bacterial replication within cells, increases macrophage phagocytic activity, and allows macrophages to eliminate (or contain) the bacteria. Studies of the human genome have identified single-nucleotide polymorphisms (SNPs) in genes encoding cytokines associated with TB susceptibility. This study aimed to investigate the potential of the IFNG (rs2430561) polymorphism as a biomarker for susceptibility or non-susceptibility to PLTB in the Venezuelan mestizo population. Methods: A total of 199 individuals were included: 69 patients with PLTB and 130 asymptomatic individuals or controls. We detected the IFNG+874T/A polymorphism by sequence-specific primer polymerase chain reaction (SSP-PCR). Results: The homozygous genotype for the more common T allele (T/T) associated with high IFNG production was overrepresented in patients, whereas the analysis showed a significant association between the homozygous A/A genotype and protection against PLTB under the codominant model across both genders (OR: 0.19; 95% CI: 0.09–0.406, p = 0.000002), as well as under the recessive model (p = 0.000002) and the dominant model for allele A (OR: 0.10; 95% CI: 0.04–0.22, p < 0.0001). Conclusion: These findings highlight the potential of the IFNG +874 variant as a valuable genetic biomarker conferring a lower likelihood of developing PLTB in both genders. Final clinical utility, however, will require validation in independent cohorts and functional analyses linking genotypes to local cytokine dynamics.