Genetics of Susceptibility to Tuberculosis


There is an increasing body of evidence showing that tuberculosis (TB) susceptibility is partially influenced by human genetic factors. Early evidence came from twin studies, observation of differences in susceptibility between ethnic groups, animal models and segregation analysis. Both candidate gene and genome‐wide studies have been conducted to search for genes underlying this susceptibility, and there has been very little consistency in the results across these studies. This inconsistency may be partially explained by the complexity of TB as a phenotype, differences across populations in both population genetic parameters as well as patterns of Mycobacterium tuberculosis strain variation, and interacting factors such as HIV, age, sex and other genes. Future studies are needed to further examine these factors as well as the immune response underlying TB pathogenesis.

Key Concepts:

  • Several types of studies provide evidence for a role of human genetics in susceptibility to tuberculosis (TB).

  • There have been numerous candidate gene studies conducted, and 10 genome‐wide studies conducted, but there is little overlap in the results of these studies.

  • Studies of TB genetics are extremely sensitive to phenotype definition in both cases and controls.

  • There are many aspects of the design of previous studies that make them difficult to compare.

  • Several aspects of TB require further study, including the role of variable strain virulence, immune response to TB, and the role of rare variants and copy number variants.

Keywords: infectious disease; genetic susceptibility; immunity; genetic epidemiology; Mycobacterium tuberculosis; gene–environment interaction; complex trait; TB

Figure 1.

Approaches to genetic epidemiological studies of TB.

Figure 2.

Factors that influence TB susceptibility. Many factors act independently and in concert in their influence on TB susceptibility. In this figure, red single‐headed arrows represent independent effects on TB susceptibility and other factors, and blue double‐headed arrows represent interaction effects. For example, host genetics not only have independent effects on TB susceptibility, but also may interact with the genetics of the bacterium, HIV positivity and perhaps even epidemiological risk factors for transmission of M. tuberculosis.



Adams LA, Moller M, Nebel A et al. (2011) Polymorphisms in MC3R promoter and CTSZ 3′UTR are associated with tuberculosis susceptibility. European Journal of Human Genetics 19: 676–681.

Baker AR, Zalwango S, Malone LL et al. (2011) Genetic susceptibility to tuberculosis associated with cathepsin Z haplotype in a Ugandan household contact study. Human Immunology 72: 426–430.

Bellamy R (1998) Genetics and pulmonary medicine. 3. Genetic susceptibility to tuberculosis in human populations. Thorax 53: 588–593.

Bellamy R (2000) Identifying genetic susceptibility factors for tuberculosis in Africans: a combined approach using a candidate gene study and a genome‐wide screen. Clinical Science (London) 98: 245–250.

Berrington WR and Hawn TR (2007) Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter? Immunological Reviews 219: 167–186.

Blackwell J, Barton C, White J et al. (2004) Genomic organizaton and sequence of the human NRAMP gene: identification and mapping of a promotor region polymorphism. Molecular Medicine 1: 194–205.

Caws M, Thwaites G, Dunstan S et al. (2008) The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathogens 4: e1000034.

Comas I and Gagneux S (2009) The past and future of tuberculosis research. PLoS Pathogens 5: e1000600.

Comstock G (1978) Tuberculosis in twins: a re‐analysis of the Prophit study. American Review of Respiratory Disease 117: 621–624.

Comstock G (1982) Epidemiology of tuberculosis. American Review of Respiratory Disease 125: 8–15.

Cooke GS, Campbell SJ, Bennett S et al. (2008) Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis. American Journal of Respiratory and Critical Care Medicine 178: 203–207.

Cooke GS, Campbell SJ, Sillah J et al. (2006) Polymorphism within the interferon gamma/receptor complex is associated with pulmonary tuberculosis. American Journal of Respiratory and Critical Care Medicine 174: 339–343.

Crowle A and Elkins N (1990) Relative permissiveness of macrophages from black and white people for virulent tubercle bacilli. Infection and Immunity 58: 632–638.

El Baghdadi J, Remus N, Benslinane A et al. (2004) Variants of the human NRAMP1 gene and susceptibility to tuberculosis in Morocco. International Journal of Tuberculosis and Lung Disease 7: 599–602.

Flynn J, Goldstein M, Chan J et al. (1995) Tumor necrosis factor‐alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2: 561–572.

Gagneux S, Deriemer K, Van T et al. (2006) Variable host‐pathogen compatibility in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the USA 103: 2869–2873.

Hindorff LA, Sethupathy P, Junkins HA et al. (2009) Potential etiologic and functional implications of genome‐wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of the USA 106: 9362–9367.

Jamieson S, Miller E, Black G et al. (2004) Evidence for a cluster of genes on chromosome 17q11‐q21 controlling susceptibility to tuberculosis and leprosy in Brazilians. Genes and Immunity 5: 46–57.

Kallmann F and Reisner D (1943) Twin studies on the significance of genetic factors in tuberculosis. American Review of Tuberculosis 47: 549–574.

Kramnik I, Dietrick W, Demant P and Bloom B (2000) Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the USA 97: 8560–8565.

Leung KH, Yip SP, Wong WS et al. (2007) Sex‐ and age‐dependent association of SLC11A1 polymorphisms with tuberculosis in Chinese: a case control study. BMC Infectious Diseases 7: 19.

Lurie M (1941) Heredity, constitution and tuberculosis: An experimental study. American Review of Tuberculosis 44: 1–125.

Ma X, Liu Y, Gowen BB et al. (2007) Full‐exon resequencing reveals toll‐like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS ONE 2: e1318.

Mahasirimongkol S, Yanai H, Mushiroda T et al. (2012) Genome‐wide association studies of tuberculosis in Asians identify distinct at‐risk locus for young tuberculosis. Journal of Human Genetics 10: 426.

Mahasirimongkol S, Yanai H, Nishida N et al. (2009) Genome‐wide SNP‐based linkage analysis of tuberculosis in Thais. Genes & Immunity 10: 77–83.

Malik S, Abel L, Tooker H et al. (2005) Alleles of the NRAMP1 gene are risk factors for pediatric tuberculosis disease. Proceedings of the National Academy of Sciences of the USA 102: 12183–12188.

Miller E, Jamieson S, Joberty C et al. (2004) Genome‐wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes & Immunity 5: 63–67.

Möller M, de Wit E and Hoal EG (2010) Past, present and future directions in human genetic susceptibility to tuberculosis. FEMS Immunology & Medical Microbiology 58: 3–26.

Motsinger‐Reif AA, Antas PR, Oki NO et al. (2010) Polymorphisms in IL‐1beta, vitamin D receptor Fok1, and Toll‐like receptor 2 are associated with extrapulmonary tuberculosis. BMC Medical Genetics 11: 37.

Pacheco AG, Cardoso CC and Moraes MO (2008) IFNG +874T/A, IL10 ‐1082G/A and TNF ‐308G/A polymorphisms in association with tuberculosis susceptibility: a meta‐analysis study. Human Genetics 123: 477–484.

Png E, Alisjahbana B, Sahiratmadja E et al. (2012) A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians. BMC Medical Genetics 13: 5.

Randhawa AK, Shey MS, Keyser A et al. (2011) Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. PLoS Pathogens 7: e1002174.

Raviglione M, Snider D and Kochi A (1995) Global epidemiology of tuberculosis: Morbidity and mortality of a worldwide epidemic. Journal of the American Medical Association 273: 220–226.

Shaw MA, Collins A, Peacock CS et al. (1997) Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA. Tubercle and Lung Disease 78: 35–45.

Stein CM (2011) Genetic epidemiology of tuberculosis susceptibility: impact of study design. PLoS Pathogens 7(1): e1001189.

Stein CM and Baker AR (2011) Tuberculosis as a complex trait: impact of genetic epidemiological study design. Mammalian Genome 22: 91–99.

Stein CM, Zalwango S, Chiunda AB et al. (2007) Linkage and association analysis of candidate genes for TB and TNFalpha cytokine expression: evidence for association with IFNGR1, IL‐10, and TNF receptor 1 genes. Human Genetics 121: 663–673.

Stein CM, Zalwango S, Malone LL et al. (2008) Genome scan of M. tuberculosis infection and disease in Ugandans. PLoS ONE 3: e4094.

Thuong NT, Dunstan SJ, Chau TT et al. (2008) Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. PLoS Pathogens 4: e1000229.

Thye T, Owusu‐Dabo E, Vannberg FO et al. (2012) Common variants at 11p13 are associated with susceptibility to tuberculosis. Nature Genetics 44: 257–259.

Thye T, Vannberg FO, Wong SH et al. (2010) Genome‐wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nature Genetics 42: 739–741.

Velez DR, Hulme WF, Myers JL et al. (2009a) Association of SLC11A1 with tuberculosis and interactions with NOS2A and TLR2 in African‐Americans and Caucasians. International Journal of Tuberculosis and Lung Disease 13: 1068–1076.

Velez DR, Hulme WF, Myers JL et al. (2009b) NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African‐Americans. Human Genetics 126: 643–653.

Wang X, Xiao H, Lan H, Mao C and Chen Q (2011) Lack of association between the P2×7 receptor A1513C polymorphism and susceptibility to pulmonary tuberculosis: a meta‐analysis. Respirology 16: 790–795.

Wheeler E, Miller EN, Peacock CS et al. (2006) Genome‐wide scan for loci influencing quantitative immune response traits in the Belem family study: comparison of methods and summary of results. Annals of Human Genetics 70: 78–97.

de Wit E, van der Merwe L, Van Helden PD and Hoal EG (2011) Gene‐gene interaction between tuberculosis candidate genes in a South African population. Mammalian Genome 22: 100–110.

Zhang J, Chen Y, Nie XB et al. (2011) Interleukin‐10 polymorphisms and tuberculosis susceptibility: a meta‐analysis. International Journal of Tuberculosis and Lung Disease 15: 594–601.

Further Reading

Bodmer W and Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nature Genetics 40: 695–701.

Chapman SJ and Hill AV (2012) Human genetic susceptibility to infectious disease. Nature Reviews Genetics 13: 175–188.

McCarroll SA and Altshuler DM (2007) Copy‐number variation and association studies of human disease. Nature Genetics 39: S37–S42.

McCarthy MI, Abecasis GR, Cardon LR et al. (2008) Genome‐wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics 9: 356–369.

Moller M and Hoal EG (2010) Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis. Tuberculosis (Edinburgh) 90: 71–83.

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Stein, Catherine M(Aug 2012) Genetics of Susceptibility to Tuberculosis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023886]