Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Susceptibility to mycobacterial infections: the importance of host genetics

Genes & Immunity volume 4, pages 4–11 (2003)Cite this article

Abstract

There is substantial evidence that host genetic factors are important in determining susceptibility to mycobacteria. Several different techniques have been used to identify the genes involved. Studies of an inbred strain of mice with increased susceptibility to mycobacteria, salmonella and leishmania infections led to the identification of the natural resistance-associated macrophage protein gene (Nramp1). Case–control studies have confirmed the importance of the human equivalent of this gene, NRAMP1, and have also suggested that the major histocompatibility complex and vitamin-D receptor genes may be involved in determining human susceptibility to mycobacteria. Studies of individuals with the rare condition of increased susceptibility to disseminated bacille Calmette–Guerin and other atypical mycobacterial infections have identified several abnormalities in the genes encoding the interferon gamma receptor (IFNγR) ligand binding chain, IFNγR signal transduction chain, IFNγ signal transduction and activation of transcription-1, interleukin 12 receptor β1 subunit and interleukin 12 p40 subunit. A genome-wide linkage study has been performed to identify genes exerting a major effect on tuberculosis susceptibility in the general population. Linkages were found to markers on chromosomes 15 and X. Studies to identify the genes responsible are in progress.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Sorensen TIA, Nielsen GG, Andersen PK, Teasdale TW . Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988; 318: 727–732.

    Article  CAS  PubMed  Google Scholar 

  2. Haldane JBS . Disease and evolution. La Ricerca Sci 1949; 19 (Suppl): 68–76.

    Google Scholar 

  3. Waksman SA . The Conquest of Tuberculosis. University of California: Berkeley, 1964.

    Google Scholar 

  4. Hill AVS . Malaria resistance genes: a natural selection. Trans R Soc Med Hyg 1992; 86: 225–232.

    CAS  Google Scholar 

  5. Weatherall DJ . Host genetics and infectious disease. Parasitology 1996; 112: S23–S29.

    PubMed  Google Scholar 

  6. Murray CJL, Styblo K, Rouillon A . Tuberculosis in developing countries: burden, intervention and cost. Bull IUATLD 1990; 65: 6–24.

    CAS  Google Scholar 

  7. Dubos R, Dubos J . The White Plague: Tuberculosis, Man and Society. Little, Brown and Co.: Boston, 1952.

    Google Scholar 

  8. Motulsky AG . Metabolic polymorphisms and the role of infectious diseases in human evolution. Hum Biol 1960; 32: 28–62.

    CAS  PubMed  Google Scholar 

  9. O'Brien SJ . Ghetto legacy. Curr Biol 1991; i: 209–211.

    Google Scholar 

  10. Budd W . The nature and the mode of propagation of phthisis. Lancet 1867; ii: 451–452.

    Google Scholar 

  11. Cummins SL . Tuberculosis in the Egyptian army. Br J Tuberc 1908; ii: 35–46.

    Google Scholar 

  12. Millar JG . On the spread and prevention of tuberculosis in Pondoland, South Africa. BMJ 1908; i: 380–382.

    Google Scholar 

  13. Stead WW, Senner JW, Reddick WT, Lofgren JP . Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Engl J Med 1990; 322: 422–427.

    CAS  PubMed  Google Scholar 

  14. Kallmann FJ, Reisner D . Twin studies on the significance of genetic factors in tuberculosis. Am Rev Tuberc 1942; 47: 549–574.

    Google Scholar 

  15. Simonds B . Tuberculosis in Twins. Pitman Medical Publishing Company: London, 1963.

    Google Scholar 

  16. Comstock GW . Tuberculosis in twins: a re-analysis of the Prophit study. Am Rev Respir Dis 1978; 117: 621–624.

    CAS  PubMed  Google Scholar 

  17. Lurie MB . Hereditary, constitution and tuberculosis. An experimental study. Am Rev Tuberc 1941; 44 (suppl): 1–125.

    Google Scholar 

  18. Lurie MB . Experimental epidemiology of tuberculosis. Hereditary resistance to attack by tuberculosis and to the ensuing disease and to the effect of the concentration of tubercle bacilli upon these two phases of resistance. J Exp Med 1944; 79: 573–589.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    Article  CAS  PubMed  Google Scholar 

  20. Gros P, Skamene E, Forget A . Genetic control of natural resistance to Mycobacterium bovis BCG. J Immunol 1981; 127: 417–421.

    Google Scholar 

  21. Forget A, Skamene E, Gros P, Miailhe A-E, Turcott R . Differences in response among inbred mouse strains to infection with small doses of Mycobacterium bovis BCG. Infect Immun 1981; 32: 42–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Skamene E, Gros P, Forget A, Kongshavn PAL, St-Charles C, Taylor BA . Genetic regulation of resistance to intracellular pathogens. Nature 1982; 297: 506–509.

    CAS  PubMed  Google Scholar 

  23. Plant JE, Glynn A . Genetics of resistance to infection with Salmonella typhimurium in mice. J Infect Dis 1976; 133: 72–78.

    CAS  PubMed  Google Scholar 

  24. Plant JE, Glynn AA . Locating Salmonella resistance gene on mouse chromosome 1. Clin Exp Immunol 1979; 37: 1–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bradley DJ . Genetic control of Leishmania populations within the host. II. Genetic control of acute susceptibility of mice to L. donovani infection. Clin Exp Immunol 1977; 30: 130–140.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bradley DJ, Taylor BA, Blackwell JM, Evans EP, Freeman J . Regulation of Leishmania populations within the host. III. Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse. Clin Exp Immunol 1979; 30: 130–140.

    Google Scholar 

  27. Plant JE, Blackwell JM, O'Brien AD, Bradley DJ, Glynn AA . Are the Lsh and Ity disease resistance genes at one locus on mouse chromosome 1? Nature 1982; 297: 510–511.

    CAS  PubMed  Google Scholar 

  28. Skamene E, Gros P, Forget A, Kongshavn PAL, St-Charles C, Taylor BA . Genetic regulation of resistance to intracellular pathogens. Nature 1982; 297: 506–509.

    CAS  PubMed  Google Scholar 

  29. Brown IN, Glynn AA, Plant JE . Inbred mouse strain resistance to Mycobacterium lepraemurium follows the Ity/Lsh pattern. Immunology 1982; 47: 149–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Skamene E, Gros P, Forget A, Patel PJ, Nesbitt M . Regulation of resistance to leprosy by chromosome 1 locus in the mouse. Immunogenet 1984; 19: 117–120.

    CAS  Google Scholar 

  31. Goto Y, Buschman E, Skamene E . Regulation of host resistance to Mycobacterium intracellulare in vivo and in vitro by the Bcg gene. Immunogenet 1989; 30: 218–221.

    CAS  Google Scholar 

  32. Lissner CR, Swanson RN, O'Brien AD . Genetic control of innate resistance of mice to Salmonella typhimurium: expression of the Ity gene in peritoneal and splenic macrophages isolated in vitro. J Immunol 1983; 131: 3006–3013.

    CAS  PubMed  Google Scholar 

  33. Crocker PR, Blackwell JM, Bradley DJ . Expression of the natural resistance gene Lsh in resident liver macrophages. Infect Immun 1984; 43: 1033–1040.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Stach JL, Gros P, Forget A, Skamene E . Phenotypic expression of genetically-controlled natural resistance to Mycobacterium bovis (BCG). J Immunol 1984; 132: 888–892.

    CAS  PubMed  Google Scholar 

  35. Denis M, Forget A, Pelletier M, Gervais F, Skamene E . Killing of Mycobacterium smegmatis by macrophages from genetically susceptible and resistant mice. J Leuk Biol 1990; 47: 25–30.

    CAS  Google Scholar 

  36. Malo D, Vidal SM, Hu J, Skamene E, Gros P . High resolution linkage map in the vicinity of the host resistance locus Bcg. Genomics 1993; 16: 655–663.

    CAS  PubMed  Google Scholar 

  37. Gros P, Malo D . A reverse genetics approach to Bcg/Ity/Lsh gene cloning. Res Immunol 1989; 140: 774–777.

    CAS  PubMed  Google Scholar 

  38. Malo D, Vidal S, Lieman JH, Ward DC, Gros P . Physical delineation of the minimal chromosomal segment encompassing the murine host resistance locus Bcg. Genomics 1993; 17: 667–675.

    CAS  PubMed  Google Scholar 

  39. Vidal SM, Malo D, Vogan K, Skamene E, Gros P . Natural resistance to infection with intracellular parasites: isolation of a candidate gene for Bcg. Cell 1993; 73: 469–485.

    CAS  PubMed  Google Scholar 

  40. Barton CH, White JK, Roach TIA, Blackwell JM . NH2-terminal sequence of macrophage-expressed natural resistance-associated macrophage protein (Nramp) encodes a proline/ serine-rich putative Src homology 3-binding domain. J Exp Med 1994; 179: 1683–1687.

    CAS  PubMed  Google Scholar 

  41. Govoni G, Vidal S, Cellier M, Lepage P, Malo D, Gros P . Genomic structure, promoter sequence, and induction of expression of the mouse Nramp1 gene in macrophages. Genomics 1995; 27: 9–19.

    CAS  PubMed  Google Scholar 

  42. Vidal SM, Pinner E, Lepage P, Gauthier S, Gros P . Natural resistance to intracellular infections. Nramp1 encodes a membrane phosphoglycoprotein absent in macrophages from susceptible (Nramp1D169) mouse strains. J Immunol 1996; 157: 3559–3568.

    CAS  PubMed  Google Scholar 

  43. Malo D, Vidal S, Skamene E et al. Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites. Genomics 1994; 23: 51–61.

    CAS  PubMed  Google Scholar 

  44. Vidal S, Tremblay ML, Govoni G et al. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med 1995; 182: 655–666.

    CAS  PubMed  Google Scholar 

  45. Govoni G, Vidal S, Gauthier S, Skamene E, Malo D, Gros P . The Bcg/Ity/Lsh locus: genetic transfer of resistance to infections in C57BL/6J mice transgenic for the Nramp1G169 allele. Infect Immun 1996; 64: 2923–2929.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Cellier M, Govoni G, Vidal S et al.Human natural resistance-associated macrophage protein: cDNA cloning, chromosomal mapping, genomic organization, and tissue-specific expression. J Exp Med 1994; 180: 1741–1752.

    CAS  PubMed  Google Scholar 

  47. Blackwell JM, Barton H, White JK et al. Genomic organization and sequence of the human NRAMP gene: identification and mapping of a promoter region polymorphism. Mol Med 1995; 1: 194–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gruenheid S, Cellier M, Vidal S, Gros P . Identification and characterization of a second mouse Nramp gene. Genomics 1995; 25: 514–525.

    CAS  PubMed  Google Scholar 

  49. Dosik JK, Barton CH, Holiday DL, Krall MM, Blackwell JM, Mock BA . An Nramp-related sequence maps to mouse chromosome 17. Mammal Genome 1994; 5: 458–460.

    CAS  Google Scholar 

  50. Vidal S, Belouchi A-M, Cellier M, Beatty B, Gross P . Cloning and characterization of a second human NRAMP gene on chromosome 12q13. Mammal Genome 1995; 6: 224–230.

    CAS  Google Scholar 

  51. Kishi F, Tabuchi M . Human natural resistance-associated macrophage protein 2: gene cloning and protein identification. Biochem Biophys Res Commun 1998; 251: 775–783.

    CAS  PubMed  Google Scholar 

  52. Cellier M, Belouchi A, Gros P . Resistance to intracellular infections: comparative genomic analysis of Nramp. Trends Genet 1996; 12: 201–205.

    CAS  PubMed  Google Scholar 

  53. Supek F, Supekova L, Nelson H, Nelson N . A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria. Proc Natl Acad Sci USA 1996; 93: 5105–5110.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Gunshin H, Mackenzie B, Berger UV et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997; 388: 482–488.

    CAS  PubMed  Google Scholar 

  55. Fleming MD, Trenor CC 3rd, Su MA et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 1997; 16: 383–386.

    CAS  PubMed  Google Scholar 

  56. Fleming MD, Romano MA, Su MA Garrick LM, Garrick MD, Andrews NC . Nramp2 is mutated in the anaemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 1998; 95: 1148–1153.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Gruenheid S, Canonne-Hergaux F, Gauthier S, Hackam DJ, Grinstein S, Gros P . The iron transport protein Nramp2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J Exp Med 1999; 189: 831–841.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Tabuchi M, Yoshimori T, Yamaguchi K, Yoshida T, Kishi F . Human NRAMP2/DMT1, which mediates iron transport across membranes, is localized to late endosomes and lysosomes in Hep-2 cells. J Biol Chem 2000; 275: 22 220–22 228.

    Google Scholar 

  59. Gruenheid S, Pinner E, Desjardins M, Gros P . Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome. J Exp Med 1997; 185: 717–730.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Atkinson PGP, Blackwell JM, Barton CH . Nramp1 locus encodes a 65 kDa interferon-γ-inducible protein in murine macrophages. Biochem J 1997; 325: 779–786.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Gomes MS, Appelberg R . Evidence for a link between iron metabolism and Nramp1 gene function in innate resistance against Mycobacterium avium. Immunology 1998; 95: 165–168.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gordeuk VR, McLaren CE, MacPhail AP, Deichsel G, Bothwell TH . Associations of iron overload in Africa with hepatocellular carcinoma and tuberculosis: Strachan's 1929 thesis revisited. Blood 1996; 87: 3470–3476.

    CAS  PubMed  Google Scholar 

  63. Agranoff D, Monahan IM, Mangan JA, Butcher PD, Krishna S . Mycobacterium tuberculosis expresses a novel pH-dependent divalent cation transporter belonging to the Nramp family. J Exp Med 1999; 190: 717–724.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu J, Fujiwara M, Buu NT et al. Identification of polymorphisms and sequence variants in the human homologue of the mouse natural resistance-associated macrophage protein gene. Am J Hum Genet 1995; 56: 845–853.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Abel L, Sanchez FO, Oberti J et al. Susceptibility to leprosy is linked to the human NRAMP1 gene. J Infect Dis 1998; 177: 133–145.

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  67. Greenwood CM, Fujiwara TM, Boothroyd LJ et al. Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am J Hum Genet 2000; 67: 405–416.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Roger M, Levee G, Chanteau S, Gicquel B, Schurr E . No evidence for linkage between leprosy susceptibility and the human natural resistance-associated macrophage protein 1 (NRAMP1) gene in French Polynesia. Int J Leprosy 1997; 65: 197–202.

    CAS  Google Scholar 

  69. Bellamy R, Beyers N, McAdam KPWJ et al. Genetic susceptibility to tuberculosis in Africans: a genome-wide scan. Proc Natl Acad Sci USA 2000; 97: 8005–8009.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Medina E, North RJ . Evidence inconsistent with a role for the Bcg gene (Nramp1) in resistance of mice to infection with virulent Mycobacterium tuberculosis. J Exp Med 1996; 183: 1045–1051.

    CAS  PubMed  Google Scholar 

  71. Bellamy R, Ruwende C, Corrah T, McAdam KPWJ, Whittle HC, Hill AVS . Variation in the human NRAMP1 gene and human tuberculosis in an African population. N Engl J Med 1998; 338: 640–644.

    CAS  PubMed  Google Scholar 

  72. Gao P-S, Fujishima S, Mao X-Q et al. Genetic variants of NRAMP1 and active tuberculosis in Japanese populations. Clin Genet 2000; 58: 74–76.

    CAS  PubMed  Google Scholar 

  73. Ryu S, Park YK, Bai GH, Kim SJ, Park SN, Kang S . 3′UTR polymorphisms in the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans. Int J Tuberc Lung Dis 2000; 4: 577–580.

    CAS  PubMed  Google Scholar 

  74. Cervino AC, Lakiss S, Sow O, Hill AV . Allelic association between the NRAMP1 gene and susceptibility to tuberculosis in Guinea-Conakry. Ann Hum Genet 2000; 64: 507–512.

    CAS  PubMed  Google Scholar 

  75. Meisner SJ, Mucklow S, Warner G, Sow SO, Lienhardt C, Hill AV . Association of NRAMP1 polymorphism with leprosy type but not susceptibility per se in West Africans. Am J Trop Med Hyg 2001; 65: 733–735.

    CAS  PubMed  Google Scholar 

  76. Searle S, Blackwell JM . Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet 1999; 36: 295–299.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Levin M, Newport MJ, D'Souza S et al. Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene? Lancet 1995; 345: 79–83.

    CAS  PubMed  Google Scholar 

  78. Newport MJ, Huxley CM, Huston S et al. A mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 1996; 335: 1941–1949.

    CAS  PubMed  Google Scholar 

  79. Casanova J-L, Blanche S, Emile J-F et al. Idiopathic disseminated bacillus Calmette–Guerin infection: a French national retrospective study. Pediatrics 1996; 98: 774–778.

    CAS  PubMed  Google Scholar 

  80. Jouanguy E, Altare F, Lamhamedi S et al. Interferon-γ-receptor deficiency in an infant with fatal bacille Calmette–Guerin infection. N Engl J Med 1996; 335: 1956–1961.

    CAS  PubMed  Google Scholar 

  81. Pierre-Audigier C, Jouanguy E, Lamhamedi S et al. Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon γ receptor deficiency. Clin Infect Dis 1997; 24: 982–984.

    CAS  PubMed  Google Scholar 

  82. Altare F, Jouanguy E, Lamhamedi-Cherradi S et al. A causative relationship between mutant IFNγR1 alleles and impaired cellular response to IFNγ in a compound heterozygous child. Am J Hum Genet 1998; 62: 723–726.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Holland SM, Dorman SE, Kwon A et al. Abnormal regulation of interferon-γ, interleukin-12, and tumour necrosis factor-α in human interferon-γ receptor 1 deficiency. J Infect Dis 1228; 178: 1095–1104.

    Google Scholar 

  84. Roesler J, Kofink B, Wendisch J et al. Listeria monocytogenes and recurrent mycobacterial infections in a child with complete interferon-γ-receptor (IFNγR1) deficiency: mutational analysis and evaluation of therapeutic options. Exp Haematol 1999; 27: 1368–1374.

    CAS  Google Scholar 

  85. Cunningham JA, Kellner JD, Bridge PJ et al. Disseminated bacille Calmette–Guerin infection in an infant with a novel deletion in the interferon-γ-receptor gene. Int J Tuberc Lung Dis 2000; 4: 719–749.

    Google Scholar 

  86. Jouanguy E, Dupuis S, Pallier A et al. In a novel form of IFNγ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ. J Clin Invest 2000; 105: 1429–1436.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Allende LM, Lopez-Goyenes A, Paz-Artal E et al. A point mutation in a domain of gamma interferon receptor 1 provokes severe imunodeficiency. Clin Diagn Lab Immunol 2001; 8: 133–137.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Jouanguy E, Lamhamedi-Cherradi S, Altare F et al. Partial interferon-γ receptor 1 deficiency in a child with tuberculoid bacillus Calmette–Guerin infection and a sibling with clinical tuberculosis. J Clin Invest 1997; 100: 2658–2664.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Jouanguy E, Lamhamedi-Cherradi S, Lammas D et al. A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet 1999; 21: 370–378.

    CAS  PubMed  Google Scholar 

  90. Villela A, Picard C, Jouanguy E et al. Recurrent Mycobacterium avium osteomyelitis associated with a novel dominant interferon gamma receptor mutation. Pediatrics 2001; 107: e47.

    Google Scholar 

  91. Dorman SE, Holland SM . Mutation in the signal-transducing chain of the interferon-γ receptor and susceptibility to mycobacterial infection. J Clin Invest 1998; 101: 2364–2369.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Doffinger R, Jouanguy E, Dupuis S et al. Partial interferon-γ receptor signaling chain deficiency in a patient with bacille Calmette–Guerin and Mycobacterium abscessus infection. J Infect Dis 2000; 181: 379–384.

    CAS  PubMed  Google Scholar 

  93. Dupuis S, Dargemont C, Fieschi C et al. Impairment of mycobacterial but not viral immunity by a germline STAT1 mutation. Science 200; 293: 300–303.

    Google Scholar 

  94. Altare F, Durandy A, Lammas D et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 1998; 280: 1432–1435.

    CAS  PubMed  Google Scholar 

  95. de Jong R, Altare F, Haagen I-A et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 1998; 280: 1435–1438.

    Google Scholar 

  96. Verhagen CE, de Boer T, Smits HH et al. Residual type 1 immunity in patients genetically deficient for interleukin 12 receptor β1 (IL12Rβ1): evidence for an IL12Rβ1-independent pathway of IL-12 responsiveness in human T cells. J Exp Med 2000; 192: 517–528.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Aksu G, Trpan C, Cavuolu C et al. Mycobacterium fortuitum-chelonae complex infection in a child with complete interleukin-12 receptor β1 deficiency. Pediatr Infect Dis J 2001; 20: 551–553.

    CAS  PubMed  Google Scholar 

  98. Altare F, Ensser A, Breiman A et al. IL-12 receptor β1 deficiency in a patient with abdominal tuberculosis. J Infect 2001; 184: 231–236.

    CAS  Google Scholar 

  99. Sakai T, Matsuoka M, Aoki M et al. Missense mutation of the interleukin-12 receptor β1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection. Blood 2001; 97: 2688–2694.

    CAS  PubMed  Google Scholar 

  100. Altare F, Lammas D, Revy P et al. Inherited interleukin 12 deficiency in a child with bacille Calmette–Guerin and Salmonella enteritidis disseminated infection. J Clin Invest 1998; 102: 2035–2040.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Picard C, Fieschi C, Altare F et al. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet 2002; 70: 336–348.

    CAS  PubMed  Google Scholar 

  102. Dupuis S, Doffinger R, Picard C et al. Human interferon-γ-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol Rev 2000; 178: 129–137.

    CAS  PubMed  Google Scholar 

  103. Dowling GB, Prosser-Thomas EW . Treatment of lupus vulgaris with calciferol. Lancet 1946; i: 919–922.

    Google Scholar 

  104. Rook GAW, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J . Vitamin D3, gamma interferon, and control of Mycobacterium tuberculosis by human monocytes. Immunology 1986; 57: 159–163.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Tsoukas CD, Provvedini DM, Manolagas SC . 1,25-dihydroxy-vitamin D3: a novel immunoregulatory hormone. Science 1984; 224: 1438–1440.

    CAS  PubMed  Google Scholar 

  106. Lemire JM, Adams JS, Sakai R, Jordan SC . 1α,25-dihydroxy-vitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 1984; 74: 657–661.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Rook GAW, Taverne J, Leveton C, Steele J . The role of gamma-interferon, vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis. Immunology 1987; 62: 229–234.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Denis M . Killing of Mycobacterium tuberculosis within human monocytes: activation by cytokines and calcitriol. Clin Exp Immunol 1991; 84: 200–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Cadranel J, Hance AJ, Milleron B, Paillard F, Akoun GM, Garabedian M . The production of 1,25(OH)2D3 by cells recovered by bronchoalveolar lavage and the role of this metabolite in calcium homeostasis. Am Rev Resp Dis 1988; 138: 984–989.

    CAS  PubMed  Google Scholar 

  110. Strachan DP, Powell KJ, Thaker A, Millard FJC, Maxwell JD . Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians. Thorax 1995; 50: 175–180.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Davies PDO, Brown RC, Woodhead JS . Serum concentrations of vitamin D metabolites in untreated tuberculosis. Thorax 1985; 40: 187–190.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Grange JM, Davies PDO, Brown RC, Woodhead JS, Kardjito T . A study of vitamin D levels in Indonesian patients with untreated pulmonary tuberculosis. Tubercle 1985; 66: 187–191.

    CAS  PubMed  Google Scholar 

  113. Reichel H, Koeffler HP, Tobler A, Norman AW . 1α,25-dihydroxyvitamin D3 inhabits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci USA 1987; 84: 3385–3389.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC . 1,25 dihydroxyvitamin D3 receptors in human leukocytes. Science 1983; 221: 1181–1183.

    CAS  PubMed  Google Scholar 

  115. Kitajima I, Maruyama I, Matsubara H, Osame M, Igata A . Immune dysfunction in hypophosphataemic vitamin D-resistant rickets: immunoregulatory reaction of 1α(OH) vitamin D3 . Clin Immunol Immunopathol 1989; 53: 24–31.

    CAS  PubMed  Google Scholar 

  116. Morrison NA, Yeoman R, Kelly PJ, Eisman JA . Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA 1992; 89: 6665–6669.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Morrison NA, Qi JC, Tokita A et al. Prediction of bone density from vitamin D receptor alleles. Nature 1994; 367: 284–287.

    CAS  PubMed  Google Scholar 

  118. Howard G, Nguyen T, Morrison N et al. Genetic influences on bone density: physiological correlates of vitamin D receptor gene alleles in premenopausal women. J Clin Endocrinol Metab 1995; 80: 2800–2805.

    CAS  PubMed  Google Scholar 

  119. Spector TD, Keen RW, Arden NK et al. Influence of vitamin D receptor genotype on bone mineral density in pre-menopausal women: a twin study in Britain. BMJ 1995; 310: 1357–1360.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Eisman JA . Vitamin D receptor gene variants: implications for therapy. Curr Opin Genet Dev 1996; 6: 361–365.

    CAS  PubMed  Google Scholar 

  121. Riggs BL . Vitamin-D receptor genotypes and bone mineral density. N Engl J Med 1997; 337: 125–126.

    CAS  PubMed  Google Scholar 

  122. Bellamy R, Ruwende C, Corrah T et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 1999; 179: 722–724.

    Google Scholar 

  123. Wilkinson RJ, Llewelyn M, Toossi Z et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis amongst Gujarati Asians in west London. Lancet 2000; 355: 618–621.

    CAS  PubMed  Google Scholar 

  124. Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CGN, Hill AVS . Association of vitamin D receptor genotype with leprosy type. J Infect Dis 1999; 179: 187–191.

    CAS  PubMed  Google Scholar 

  125. Singh SPN, Mehra NK, Dingley HB, Pande JN, Vaidya MC . Human leukocyte antigen (HLA)-linked control of susceptibility to tuberculosis and association with HLA-DR types. J Infect Dis 1983; 148: 676–681.

    CAS  PubMed  Google Scholar 

  126. Bothamley GH, Beck JS, Schreuder GMT et al. Association of tuberculosis and tuberculosis-specific antibody levels with HLA. J Infect Dis 1989; 159: 549–555.

    CAS  PubMed  Google Scholar 

  127. Todd JR, West BC, McDonald JC . Human leukocyte antigen and leprosy: study in Northern Louisana and review. Rev Infect Dis 1990; 12: 63–74.

    CAS  PubMed  Google Scholar 

  128. Brahmajothi V, Pitchappan RM, Kakkanaiah VN et al. Association of pulmonary tuberculosis and HLA in South India. Tubercle 1991; 72: 123–132.

    CAS  PubMed  Google Scholar 

  129. Cox RA, Downs M, Neimes RE, Ognibene AJ, Yamashita TS, Ellner JJ . Immunogenetic analysis of human tuberculosis. J Infect Dis 1988; 158: 1302–1308.

    CAS  PubMed  Google Scholar 

  130. Goldfield AE, Delgado JC, Thim S et al. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 1998; 279: 226–228.

    Google Scholar 

  131. Zerva L, Cizman B, Mehra NK et al. Arginine at positions 13 or 70–71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy. J Exp Med 1996; 183: 829–836.

    CAS  PubMed  Google Scholar 

  132. Roy S, McGuire W, Mascie-Taylor CGN et al. Tumour necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. J Infect Dis 1997; 176: 530–532.

    CAS  PubMed  Google Scholar 

  133. Penrose LS . The general purpose sib-pair linkage test. Ann Eugen 1953; 18: 120–124.

    CAS  PubMed  Google Scholar 

  134. Heffernan JF, Nunn AJ, Peto J, Fox W . Pulmonary tuberculosis in Scotland: a national sample survey and follow-up (1968–1970). 1 The characteristics of the patients notified in 1968. Tubercle 1975; 56: 253–267.

    CAS  PubMed  Google Scholar 

  135. Hinman AR, Judd JM, Kolnick JP, Daitch PB . Changing risks in tuberculosis. Am J Epidemiol 1976; 103: 486–497.

    CAS  PubMed  Google Scholar 

  136. Kustner HGV . Trends in four major communicable diseases. S Afr Med J 1979; 55: 460–473.

    CAS  PubMed  Google Scholar 

  137. Rieder HL, Kelly GD, Bloch AB, Cauthen GM, Snider DE . Tuberculosis diagnosed at death in the United States. Chest 1991; 100: 678–681.

    CAS  PubMed  Google Scholar 

  138. Medical Research Council Cardiothoracic Epidemiology Group . National survey of notifications of tuberculosis in England and Wales in 1988. Thorax 1992; 47: 770–775.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Medicine, Singleton Hospital, Swansea, South Wales, UK

    R Bellamy

Authors
  1. R Bellamy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Bellamy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bellamy, R. Susceptibility to mycobacterial infections: the importance of host genetics. Genes Immun 4, 4–11 (2003). https://doi.org/10.1038/sj.gene.6363915

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6363915

Keywords

This article is cited by

Search

Advanced search

Quick links