Current Genetic Medicine Reports

, Volume 5, Issue 3, pp 125–131 | Cite as

Human Genomics of Mycobacterium tuberculosis Infection and Disease

  • Marianna Orlova
  • Erwin SchurrEmail author
Genomics (SM Williams, Section Editor)
Part of the following topical collections:
  1. Genomics


Purpose of Review

The study of the genetic basis of tuberculosis pathogenesis has benefited from powerful technological innovations, a more structured definition of latent and clinical manifestations of the disease, and the application of functional genomic approaches. This short review aims to summarize recent advances and to provide a link with results of previous human genetic studies of tuberculosis susceptibility.

Recent Findings

Transcriptomics has been shown to be a useful tool to predict progression from latency to clinical disease while functional genomics has traced the molecular events that link pathogen-triggered gene expression and host genetics. Resistance to infection with Mycobacterium tuberculosis has been revealed to be strongly impacted by host genetics. Host genomics of clinical disease has been shown to be most powerful when focusing on carefully selected clinical entities and possibly by considering host-pathogen combinations.


Future studies need to build on the latest molecular findings to define disease subtypes to successfully elucidate the human genetic component in tuberculosis pathogenesis.


Tuberculosis Host genomics of tuberculosis Functional genomics of tuberculosis Transcript biomarkers Human genetics of infection 



Research in the authors’ laboratory is supported by grants from the Canadian Institutes of Health Research (CIHR; FDN-143332) and the National Institutes of Health (NIH; R01 AI124349).

Compliance with Ethical Standards

Conflict of Interest

Both authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    World Health Organization. Global tuberculosis report 2016.Google Scholar
  2. 2.
    Abel L, El-Baghdadi J, Bousfiha AA, Casanova JL, Schurr E. Human genetics of tuberculosis: a long and winding road. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1645):20130428.CrossRefGoogle Scholar
  3. 3.
    Quach H, Quintana-Murci L. Living in an adaptive world: genomic dissection of the genus Homo and its immune response. J Exp Med. 2017;214(4):877–94.CrossRefPubMedGoogle Scholar
  4. 4.
    Lin PL, Ford CB, Coleman MT, Myers AJ, Gawande R, Ioerger T, et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med. 2014;20(1):75–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Lin PL, Maiello P, Gideon HP, Coleman MT, Cadena AM, Rodgers MA, et al. PET CT identifies reactivation risk in cynomolgus macaques with latent M. tuberculosis. PLoS Pathog. 2016;12(7):e1005739.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Esmail H, Lai RP, Lesosky M, Wilkinson KA, Graham CM, Coussens AK, et al. Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-D-glucose positron emission and computed tomography. Nat Med. 2016;22(10):1090–3.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Barreiro LB, Quintana-Murci L. From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet. 2010;11(1):17–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Manry J, Laval G, Patin E, Fornarino S, Itan Y, Fumagalli M, et al. Evolutionary genetic dissection of human interferons. J Exp Med. 2011;208(13):2747–59.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Nedelec Y, Sanz J, Baharian G, Szpiech ZA, Pacis A, Dumaine A, et al. Genetic ancestry and natural selection drive population differences in immune responses to pathogens. Cell. 2016;167(3):657–69.e21.CrossRefPubMedGoogle Scholar
  10. 10.
    Deschamps M, Laval G, Fagny M, Itan Y, Abel L, Casanova JL, et al. Genomic signatures of selective pressures and introgression from archaic hominins at human innate immunity genes. Am J Hum Genet. 2016;98(1):5–21.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Quach H, Rotival M, Pothlichet J, Loh YE, Dannemann M, Zidane N, et al. Genetic adaptation and neandertal admixture shaped the immune system of human populations. Cell. 2016;167(3):643–56.e17.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sams AJ, Dumaine A, Nedelec Y, Yotova V, Alfieri C, Tanner JE, et al. Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans. Genome Biol. 2016;17(1):246.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cadena AM, Flynn JL, Fortune SM. The importance of first impressions: early events in Mycobacterium tuberculosis infection influence outcome. MBio. 2016;7(2):e00342–16.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Barreiro LB, Tailleux L, Pai AA, Gicquel B, Marioni JC, Gilad Y. Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection. Proc Natl Acad Sci U S A. 2012;109(4):1204–9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    • Pacis A, Tailleux L, Morin AM, Lambourne J, MacIsaac JL, Yotova V, et al. Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res. 2015;25(12):1801–11. Demonstration of epigenetic remodelling of dendritic cells by Mtb. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Blischak JD, Tailleux L, Mitrano A, Barreiro LB, Gilad Y. Mycobacterial infection induces a specific human innate immune response. Sci Rep. 2015;5.Google Scholar
  17. 17.
    Berry MP, Graham CM, McNab FW, Xu Z, Bloch SA, Oni T, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature. 2010;466(7309):973–7.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Maertzdorf J, Repsilber D, Parida SK, Stanley K, Roberts T, Black G, et al. Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun. 2011;12(1):15–22.CrossRefPubMedGoogle Scholar
  19. 19.
    Kaforou M, Wright VJ, Oni T, French N, Anderson ST, Bangani N, et al. Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study. PLoS Med. 2013;10(10):e1001538.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Anderson ST, Kaforou M, Brent AJ, Wright VJ, Banwell CM, Chagaluka G, et al. Diagnosis of childhood tuberculosis and host RNA expression in Africa. N Engl J Med. 2014;370(18):1712–23.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Blankley S, Graham CM, Levin J, Turner J, Berry MP, Bloom CI, et al. A 380-gene meta-signature of active tuberculosis compared with healthy controls. Eur Respir J. 2016;47(6):1873–6.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    • Zak DE, Penn-Nicholson A, Scriba TJ, Thompson E, Suliman S, Amon LM, et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet. 2016;387(10035):2312–22. Description of a blood transcriptomics signature for progression to clinical disease. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Blankley S, Graham CM, Turner J, Berry MP, Bloom CI, Xu Z, et al. The transcriptional signature of active tuberculosis reflects symptom status in extra-pulmonary and pulmonary tuberculosis. PLoS One. 2016;11(10):e0162220.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Seshadri C, Sedaghat N, Campo M, Peterson G, Wells RD, Olson GS, et al. Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection. PLoS One. 2017;12(4):e0175844.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Verrall AJ, Netea MG, Alisjahbana B, Hill PC, van Crevel R. Early clearance of Mycobacterium tuberculosis: a new frontier in prevention. Immunology. 2014;141(4):506–13.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ma N, Zalwango S, Malone LL, Nsereko M, Wampande EM, Thiel BA, et al. Clinical and epidemiological characteristics of individuals resistant to M. tuberculosis infection in a longitudinal TB household contact study in Kampala, Uganda. BMC Infect Dis. 2014;14:352.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Jepson A, Fowler A, Banya W, Singh M, Bennett S, Whittle H, et al. Genetic regulation of acquired immune responses to antigens of Mycobacterium tuberculosis: a study of twins in West Africa. Infect Immun. 2001;69(6):3989–94.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cobat A, Gallant CJ, Simkin L, Black GF, Stanley K, Hughes J, et al. High heritability of antimycobacterial immunity in an area of hyperendemicity for tuberculosis disease. J Infect Dis. 2010;201(1):15–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Cobat A, Barrera LF, Henao H, Arbelaez P, Abel L, Garcia LF, et al. Tuberculin skin test reactivity is dependent on host genetic background in Colombian tuberculosis household contacts. Clin Infect Dis. 2012;54(7):968–71.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tao L, Zalwango S, Chervenak K, Thiel B, Malone LL, Qiu F, et al. Genetic and shared environmental influences on interferon-gamma production in response to Mycobacterium tuberculosis antigens in a Ugandan population. Am J Trop Med Hyg. 2013;89(1):169–73.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Thye T, Vannberg FO, Wong SH, Owusu-Dabo E, Osei I, Gyapong J, et al. Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nat Genet. 2010;42(9):739–41.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sveinbjornsson G, Gudbjartsson DF, Halldorsson BV, Kristinsson KG, Gottfredsson M, Barrett JC, et al. HLA class II sequence variants influence tuberculosis risk in populations of European ancestry. Nat Genet. 2016;48(3):318–22.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Stein CM, Zalwango S, Malone LL, Won S, Mayanja-Kizza H, Mugerwa RD, et al. Genome scan of M. tuberculosis infection and disease in Ugandans. PLoS One. 2008;3(12):e4094.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    • Cobat A, Gallant CJ, Simkin L, Black GF, Stanley K, Hughes J, et al. Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J Exp Med. 2009;206(12):2583–91. Identification of two major loci controlling TST-intensity and negativity. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cobat A, Poirier C, Hoal E, Boland-Auge A, de La Rocque F, Corrard F, et al. Tuberculin skin test negativity is under tight genetic control of chromosomal region 11p14-15 in settings with different tuberculosis endemicities. J Infect Dis. 2015;211(2):317–21.CrossRefPubMedGoogle Scholar
  36. 36.
    Cobat A, Hoal EG, Gallant CJ, Simkin L, Black GF, Stanley K, et al. Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis. Clin Infect Dis. 2013;57(7):963–70.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Jabot-Hanin F, Cobat A, Feinberg J, Grange G, Remus N, Poirier C, et al. Major loci on chromosomes 8q and 3q control interferon gamma production triggered by bacillus Calmette-Guerin and 6-kDa early secretory antigen target, respectively, in various populations. J Infect Dis. 2016;213(7):1173–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Alcais A, Quintana-Murci L, Thaler DS, Schurr E, Abel L, Casanova JL. Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity? Ann N Y Acad Sci. 2010;1214:18–33.CrossRefPubMedGoogle Scholar
  39. 39.
    de Beaucoudrey L, Samarina A, Bustamante J, Cobat A, Boisson-Dupuis S, Feinberg J, et al. Revisiting human IL-12Rbeta1 deficiency: a survey of 141 patients from 30 countries. Medicine (Baltimore). 2010;89(6):381–402.CrossRefGoogle Scholar
  40. 40.
    Boisson-Dupuis S, El Baghdadi J, Parvaneh N, Bousfiha A, Bustamante J, Feinberg J, et al. IL-12Rbeta1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey. PLoS One. 2011;6(4):e18524.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Alcais A, Fieschi C, Abel L, Casanova JL. Tuberculosis in children and adults: two distinct genetic diseases. J Exp Med. 2005;202(12):1617–21.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Malik S, Abel L, Tooker H, Poon A, Simkin L, Girard M, et al. Alleles of the NRAMP1 gene are risk factors for pediatric tuberculosis disease. Proc Natl Acad Sci U S A. 2005;102(34):12183–8.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    • Grant AV, El Baghdadi J, Sabri A, El Azbaoui S, Alaoui-Tahiri K, Abderrahmani Rhorfi I, et al. Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region. Am J Hum Genet. 2013;92(3):407–14. Positional identification of TOX as early onset TB susceptibility gene. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Uren C, Henn BM, Franke A, Wittig M, van Helden PD, Hoal EG, et al. A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility. PLoS One. 2017;12(4):e0174738.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Thye T, Owusu-Dabo E, Vannberg FO, van Crevel R, Curtis J, Sahiratmadja E, et al. Common variants at 11p13 are associated with susceptibility to tuberculosis. Nat Genet. 2012;44(3):257–9.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Chimusa ER, Zaitlen N, Daya M, Moller M, van Helden PD, Mulder NJ, et al. Genome-wide association study of ancestry-specific TB risk in the South African Coloured population. Hum Mol Genet. 2014;23(3):796–809.CrossRefPubMedGoogle Scholar
  47. 47.
    Mahasirimongkol S, Yanai H, Mushiroda T, Promphittayarat W, Wattanapokayakit S, Phromjai J, et al. Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis. J Hum Genet. 2012;57(6):363–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Curtis J, Luo Y, Zenner HL, Cuchet-Lourenco D, Wu C, Lo K, et al. Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat Genet. 2015;47(5):523–7.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Png E, Alisjahbana B, Sahiratmadja E, Marzuki S, Nelwan R, Balabanova Y, et al. A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians. BMC Med Genet. 2012;13:5.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Grant AV, Sabri A, Abid A, Abderrahmani Rhorfi I, Benkirane M, Souhi H, et al. A genome-wide association study of pulmonary tuberculosis in Morocco. Hum Genet. 2016;135(3):299–307.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Shi C, Sakuma M, Mooroka T, Liscoe A, Gao H, Croce KJ, et al. Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function. Blood. 2008;112(12):4699–711.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Tokuoka SM, Kita Y, Shindou H, Shimizu T. Alkylglycerol monooxygenase as a potential modulator for PAF synthesis in macrophages. Biochem Biophys Res Commun. 2013;436(2):306–12.CrossRefPubMedGoogle Scholar
  53. 53.
    Tientcheu LD, Koch A, Ndengane M, Andoseh G, Kampmann B, Wilkinson RJ. Immunological consequences of strain variation within the Mycobacterium tuberculosis complex. Eur J Immunol. 2017;47(3):432–45.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Di Pietrantonio T, Hernandez C, Girard M, Verville A, Orlova M, Belley A, et al. Strain-specific differences in the genetic control of two closely related mycobacteria. PLoS Pathog. 2010;6(10):e1001169.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Di Pietrantonio T, Schurr E. Host-pathogen specificity in tuberculosis. Adv Exp Med Biol. 2013;783:33–44.CrossRefPubMedGoogle Scholar
  56. 56.
    • Sobota RS, Stein CM, Kodaman N, Scheinfeldt LB, Maro I, Wieland-Alter W, et al. A locus at 5q33.3 confers resistance to tuberculosis in highly susceptible individuals. Am J Hum Genet. 2016;98(3):514–24. Use of a highly selected phenotype to identify strong genetic TB resistance markers. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    • Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell. 2012;148(3):434–46. Identifcation of a genetic polymorphism for treatment stratification of TBM patients. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Thuong NTT, Heemskerk D, Tram TTB, Thao LTP, Ramakrishnan L, Ha VTN, et al. Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis. J Infect Dis. 2017;215(7):1020–8.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    van Laarhoven A, Dian S, Ruesen C, Hayati E, Damen M, Annisa J, et al. Clinical parameters, routine inflammatory markers, and LTA4H genotype as predictors of mortality among 608 patients with tuberculous meningitis in Indonesia. J Infect Dis. 2017;215(7):1029–39.CrossRefPubMedGoogle Scholar
  60. 60.
    Fava VM, Schurr E. Evaluating the impact of LTA4H genotype and immune status on survival from tuberculous meningitis. J Infect Dis. 2017;215(7):1011–3.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Program in Infectious Diseases and Immunity in Global HealthThe Research Institute of the McGill University Health CentreMontréalCanada
  2. 2.McGill International TB CentreMcGill UniversityMontrealCanada
  3. 3.Departments of Medicine and Human GeneticsMcGill UniversityMontrealCanada

Personalised recommendations