Association of HLA class I allele and tuberculosis susceptibility: a systematic review and meta-analysis

Mycobacterium tuberculosis (M.tuberculosis) continues to cause one of the most pressing health burdens in the world, especially in developing nations, in the form of tuberculosis (TB). In addition to socio-environmental factors, it is widely believed that host genetic factors, particularly polymorphisms within the human leukocyte antigen (HLA) system, may play an extensive role in the likelihood of a host's TB infection. Studies on the influence of HLA class I alleles (HLA-A, -B, -C) in human susceptibility to TB reported contradictory results. Therefore, this systematic review and meta-analysis aim to see the association of HLA class I alleles with susceptibility to TB in humans. In this meta-analysis, the literature was searched using PubMed, ScienceDirect, and Google Scholar, until 23rd May 2025. A total of 13 eligible case-control studies were included, comprising 1951 TB cases and 2109 matched healthy controls. Together with a 95% Confidence interval, pooled odds ratio was calculated for each allele. To evaluate heterogeneity I² statistic was used. Sensitivity and subgroup analyses were also performed. Publication bias was investigated using Egger's and Begg's tests. The analysis results demonstrated 40 HLA class I alleles (12-A, 22-B, 6-C). HLA-A32 (OR = 1.67, 95% CI= 1.09-2.56, p = 0.0191) and B58 (OR = 1.45, 95% CI= 1.02-2.07, p = 0.0404) found to be associated with increased TB risk, while HLA-A1 (OR = 0.70, 95% CI= 0.57-0.85; p = 0.0007) showed a protective trend after analysis. Sensitivity analysis strengthened the significance of all different alleles. Regional variations emerged: B58 was a risk allele in Africa, and A32 was a risk allele in Asia. HLA-B15 and B35 were reported to have a statistically significantly increased risk in North America. Post-sensitivity analysis revealed possible publication bias, as HLA-B17 shifted from susceptibility to a protective effect. This is the first meta-analysis that systematically evaluates the associations between HLA class I alleles and TB susceptibility. Our findings determine selective associations at both the allele and regional levels. The findings of this study can inform future studies in immunogenetics and aid in formulating solutions for the prevention and treatment of TB that are tailored to individual alleles.