Human genetics of tuberculosis: a long and winding road

Abstract

Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.

Keywords: Mendelian predisposition; complex genetic predisposition; genetic variant; latent tuberculosis infection; primary tuberculosis; pulmonary tuberculosis.

Figure 1.

A schematic of the natural history of human infection by M. tuberculosis, and the subsequent development of clinical TB. Despite sustained high-level exposure, a substantial proportion of subjects (approx. 10–20%) do not become infected, and hence never develop disease. About 5% of infected individuals develop clinical TB within 2 years of infection; this ‘primary’ TB is particularly common in children, and could be associated with extrapulmonary disease. The remaining persons infected with M. tuberculosis develop latent TB infection (LTBI). Only a minority of subjects with LTBI (approx. 5–10%) develop clinical TB during their lifetime, typically owing to reactivation of the original infection. (Online version in colour.)