Genetic Susceptibility to Pulmonary Tuberculosis

Genetic susceptibility to pulmonary tuberculosis reflects the interplay between host variation and Mycobacterium tuberculosis infection. Human populations exhibit heterogeneous risk of progression from exposure to active disease, driven by multiple host loci that modulate innate and adaptive immunity. Variants in genes governing antigen presentation, cytokine signalling and phagocytic pathways influence macrophage activation, T-cell responses and granuloma formation. Genome-wide association studies have highlighted human leukocyte antigen (HLA) class II alleles as key determinants of peptide binding and T-cell stimulation, while candidate-gene analyses continue to implicate cytokine genes such as IFNG and IL6R. In addition to sequence variation, epigenetic marks including promoter methylation contribute to individual differences in transcriptional regulation of immune genes. Recent advances now integrate host and pathogen genomes to reveal co-evolutionary adaptation, underscoring the global significance of genetic insights for vaccine design, risk stratification and host-directed therapies.

Research from Nature Portfolio

Recent studies have implemented genome-to-genome analyses in diverse TB-endemic populations to map host–pathogen interaction points. By analysing paired human and M. tuberculosis whole-genome sequences, researchers identified human loci such as DAP and RIMS3 that interact with specific mycobacterial lineages and converge on interferon-γ signalling pathways. These findings reveal a complex interactome reflecting co-evolution, in which host polymorphisms and lineage-specific bacterial markers jointly influence disease outcome. The approach offers a framework for large-scale investigations across matched host–pathogen cohorts, with potential applications in precision epidemiology and targeted interventions.

Genetic Susceptibility to Pulmonary Tuberculosis publication trend

The graph below shows the total number of articles in genetic susceptibility to pulmonary tuberculosis across all publications each year (not limited to Nature Index journals).

Technical terms

Genome-wide association study (GWAS): A high-throughput approach that scans the genome for common genetic variants associated with disease susceptibility by comparing affected and unaffected individuals.

Mendelian randomisation: A method using genetic variants as instrumental variables to infer causal relationships between a biomarker and disease outcome, mitigating confounding.

Single nucleotide polymorphism (SNP): A single base-pair change in DNA sequence that may affect gene function or regulation and contribute to individual differences in disease risk.

HLA class II genes: A set of highly polymorphic loci encoding proteins that present antigenic peptides to CD4+ T cells, shaping adaptive immune responses.

CpG methylation: An epigenetic modification in which a methyl group is added to cytosine residues in CpG dinucleotides, influencing chromatin accessibility and gene expression.

References

1. Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease. Nature Communications (2023).
2. Altered IL-6 signalling and risk of tuberculosis: a multi-ancestry mendelian randomisation study. The Lancet Microbe (2024).
3. Genome‐wide association study of tuberculosis in the western Chinese Han and Tibetan population. MedComm (2023).
4. Association of IFN-γ +874 A/T SNP and hypermethylation of the -53 CpG site with tuberculosis susceptibility. Frontiers in Cellular and Infection Microbiology (2023).