GENETIC PREDICTORS AND BIOMARKERS IN TUBERCULOSIS INFECTION: A SYSTEMATIC REVIEW OF VARIANTS ACROSS POPULATIONS

Toll-like receptor (TLR) polymorphisms may influence susceptibility to extrapulmonary tuberculosis (EPTB). This systematic review examines the association between TLR polymorphisms and EPTB risk and summarizes pulmonary TB (PTB) data from the same studies for phenotype comparison across populations. A comprehensive search of PubMed, Web of Science, and Scopus was conducted using relevant keywords. The study followed PRISMA guidelines, and Mendeley was used for reference management. Studies assessing the association between TLRs polymorphisms and EPTB susceptibility, progression, or treatment outcomes in human subjects were included, while non-human studies and unrelated research were excluded. The Joanna Briggs Institute (JBI) checklist was used to assess study validity. The extracted data included study details, population, control group, and outcomes. Of 620 records, 212 were screened, and 11 met the inclusion criteria. Evidence largely from Asians implicates TLR2 variants in disease risk: Arg753Gln was associated with pulmonary TB and TB peritonitis; the Del/Del genotype conferred strong EPTB risk; and 597CC/T597C showed phenotype-and population-specific effects, including meningeal TB. A TIRAP (TLR adaptor) C558T variant was linked to higher TB susceptibility, with stronger effects in TB meningitis than pulmonary disease. Functional data in intraocular TB demonstrated augmented pro-inflammatory CD4⁺ T-cell responses after TLR2/TLR9 stimulation. The findings of this systematic review concluded that TLR2-axis genetics appear to modulate TB risk, particularly for EPTB. These findings support phenotype-specific risk stratification and highlight the need for multi-ancestry studies with standardized endpoints and mechanistic validation.