Volume 71, Issue 3
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Twenty-seven polymorphisms from 12 genes have been investigated for association with tuberculosis (TB) in up to 514 cases and 913 controls from Karonga district, northern Malawi. Homozygosity for the complement receptor 1 (CR1) Q1022H polymorphism was associated with susceptibility to TB in this population (odds ratio [OR] = 3.12, 95% Confidence interval [CI] = 1.13–8.60, = 0.028). This association was not observed among human immunodeficiency virus (HIV)–positive TB cases, suggesting either chance association or that HIV status may influence genetic associations with TB susceptibility. Heterozygosity for a newly studied CAAA insertion/deletion polymorphism in the 3′-untranslated region of solute carrier family 11, member 1 (SLC11A1, formerly NRAMP1) was associated with protection against TB in both HIV-positive (OR = 0.70, 95% CI = 0.49–0.99, = 0.046) and HIV-negative (OR = 0.65, 95% CI = 0.46–0.92, = 0.014) TB cases, suggesting that the SLC11A1 protein may have a role in innate TB immune responses that influence susceptibility even in immunocompromised individuals. However, associations of other variants of SCLA11A with TB reported from other populations were not replicated in Malawi. Furthermore, associations with vitamin D receptor, interferon-γ, and mannose-binding lectin observed elsewhere were not observed in this Karonga study. Genetic susceptibility to TB in Africans appears polygenic. The relevant genes and variants may vary significantly between populations, and may be affected by HIV infection status.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C, 2003. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 163 : 1009–1021. [Google Scholar]
  2. Bloom BR, Small PM, 1998. The evolving relation between humans and Mycobacterium tuberculosis. N Engl J Med 338 : 677–678. [Google Scholar]
  3. Bellamy R, 2003. Interferon-gamma and host susceptibility to tuberculosis. Am J Respir Crit Care Med 167 : 946–947. [Google Scholar]
  4. Marquet S, Schurr E, 2001. Genetics of susceptibility to infectious diseases: tuberculosis and leprosy as examples. Drug Metab Dispos 29 : 479–483. [Google Scholar]
  5. Shaw MA, Collins A, Peacock CS, Miller EN, Black GF, Sibthorpe D, Lins-Lainson Z, Shaw JJ, Ramos F, Silveira F, Blackwell JM, 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. Tuber Lung Dis 78 : 35–45. [Google Scholar]
  6. Gao PS, Fujishima S, Mao XQ, Remus N, Kanda M, Enomoto T, Dake Y, Bottini N, Tabuchi M, Hasegawa N, Yamaguchi K, Tiemessen C, Hopkin JM, Shirakawa T, Kishi F, 2000. Genetic variants of NRAMP1 and active tuberculosis in Japanese populations. International Tuberculosis Genetics Team. Clin Genet 58 : 74–76. [Google Scholar]
  7. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV, 1998. Variations in the NRAMP1 gene and susceptibility to tuberculosis in west Africans. N Engl J Med 338 : 640–644. [Google Scholar]
  8. Ryu S, Park YK, Bai GH, Kim SJ, Park SN, Kang S, 2000. 3′UTR polymorphisms in the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans. Int J Tuberc Lung Dis 4 : 577–580. [Google Scholar]
  9. Cervino AC, Lakiss S, Sow O, Hill AV, 2000. Allelic association between the NRAMP1 gene and susceptibility to tuberculosis in Guinea-Conakry. Ann Hum Genet 64 : 507–512. [Google Scholar]
  10. Greenwood CM, Fujiwara TM, Boothroyd LJ, Miller MA, Frappier D, Fanning EA, Schurr E, Morgan K, 2000. Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am J Hum Genet 67 : 405–416. [Google Scholar]
  11. Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, Hill AV, 1999. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 179 : 721–724. [Google Scholar]
  12. Selvaraj P, Narayanan PR, Reetha AM, 1999. Association of functional mutant homozygotes of the mannose binding protein gene with susceptibility to pulmonary tuberculosis in India. Tuber Lung Dis 79 : 221–227. [Google Scholar]
  13. Hoal-Van Helden EG, Epstein J, Victor TC, Hon D, Lewis LA, Beyers N, Zurakowski D, Ezekowitz AB, van Helden PD, 1999. Mannose-binding protein B allele confers protection against tuberculous meningitis. Pediatr Res 45 : 459–464. [Google Scholar]
  14. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV, 2000. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 61 : 863–866. [Google Scholar]
  15. Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG, 2003. Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet 361 : 1871–1872. [Google Scholar]
  16. Lio D, Marino V, Serauto A, Gioia V, Scola L, Crivello A, Forte GI, Colonna-Romano G, Candore G, Caruso C, 2002. Genotype frequencies of the +874T→A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Eur J Immunogenet 29 : 371–374. [Google Scholar]
  17. Fitness J, Floyd S, Warndorff DK, Sichali L, Mwaungulu L, Crampin AC, Fine PEM, Hill AVS, 2004. Large-scale candidate gene study of leprosy susceptibility in the Karonga District of northern Malawi. Am J Trop Med Hyg 71 : 330–340. [Google Scholar]
  18. Kang TJ, Chae GT, 2001. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol 31 : 53–58. [Google Scholar]
  19. Glynn JR, Jenkins PA, Fine PE, Ponnighaus JM, Sterne JA, Mkandwire PK, Nyasulu S, Bliss L, Warndorff DK, 1995. Patterns of initial and acquired antituberculosis drug resistance in Karonga District, Malawi. Lancet 345 : 907–910. [Google Scholar]
  20. Ponninghaus JM, Fine PE, Bliss L, Sliney IJ, Bradley DJ, Rees RJ, 1987. The Lepra Evaluation Project (LEP), an epidemiological study of leprosy in Northern Malawi. I. Methods. Lepr Rev 58 : 359–375. [Google Scholar]
  21. Crampin AC, Mwinuka V, Malema SS, Glynn JR, Fine PE, 2001. Field-based random sampling without a sampling frame: control selection for a case-control study in rural Africa. Trans R Soc Trop Med Hyg 95 : 481–483. [Google Scholar]
  22. Glynn JR, Warndorff DK, Malema SS, Mwinuka V, Ponnighaus JM, Crampin AC, Fine PE, 2000. Tuberculosis: associations with HIV and socioeconomic status in rural Malawi. Trans R Soc Trop Med Hyg 94 : 500–503. [Google Scholar]
  23. Fitness J, Tosh K, Hill AV, 2002. Genetics of susceptibility to leprosy. Genes Immun 3 : 441–453. [Google Scholar]
  24. Marquet S, Sanchez FO, Arias M, Rodriguez J, Paris SC, Skamene E, Schurr E, Garcia LF, 1999. Variants of the human NRAMP1 gene and altered human immunodeficiency virus infection susceptibility. J Infect Dis 180 : 1521–1525. [Google Scholar]
  25. Schlesinger LS, Horwitz MA, 1990. Phagocytosis of leprosy bacilli is mediated by complement receptors CR1 and CR3 on human monocytes and complement component C3 in serum. J Clin Invest 85 : 1304–1314. [Google Scholar]
  26. Hirsch CS, Ellner JJ, Russell DG, Rich EA, 1994. Complement receptor-mediated uptake and tumor necrosis factor-alpha-mediated growth inhibition of Mycobacterium tuberculosis by human alveolar macrophages. J Immunol 152 : 743–753. [Google Scholar]
  27. Xiang L, Rundles JR, Hamilton DR, Wilson JG, 1999. Quantitative alleles of CR1: coding sequence analysis and comparison of haplotypes in two ethnic groups. J Immunol 163 : 4939–4945. [Google Scholar]
  28. Bellamy R, Ruwende C, McAdam KP, Thursz M, Sumiya M, Summerfield J, Gilbert SC, Corrah T, Kwiatkowski D, Whittle HC, Hill AV, 1998. Mannose binding protein deficiency is not associated with malaria, hepatitis B carriage nor tuberculosis in Africans. QJM 91 : 13–18. [Google Scholar]
  29. Kube D, Platzer C, von Knethen A, Straub H, Bohlen H, Hafner M, Tesch H, 1995. Isolation of the human interleukin 10 promoter. Characterization of the promoter activity in Burkitt’s lymphoma cell lines. Cytokine 7 : 1–7. [Google Scholar]
  30. Rees LE, Wood NA, Gillespie KM, Lai KN, Gaston K, Mathieson PW, 2002. The interleukin-10-1082 G/A polymorphism: allele frequency in different populations and functional significance. Cell Mol Life Sci 59 : 560–569. [Google Scholar]
  31. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P, 1999. Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 42 : 1101–1108. [Google Scholar]
  32. Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP, 2001. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 166 : 3915–3922. [Google Scholar]
  33. Fernandez-Reyes D, Craig AG, Kyes SA, Peshu N, Snow RW, Berendt AR, Marsh K, Newbold CI, 1997. A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya. Hum Mol Genet 6 : 1357–1360. [Google Scholar]
  34. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O’Riordan J, Stanford J, 1986. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57 : 159–163. [Google Scholar]
  35. Barber Y, Rubio C, Fernandez E, Rubio M, Fibla J, 2001. Host genetic background at CCR5 chemokine receptor and vitamin D receptor loci and human immunodeficiency virus (HIV) type 1 disease progression among HIV-seropositive injection drug users. J Infect Dis 184 : 1279–1288. [Google Scholar]
  36. Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ, 1999. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 163 : 3920–3927. [Google Scholar]
  37. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM, 2001. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345 : 1098–1104. [Google Scholar]
  38. Blackwell JM, Black GF, Peacock CS, Miller EN, Sibthorpe D, Gnananandha D, Shaw JJ, Silveira F, Lins-Lainson Z, Ramos F, Collins A, Shaw MA, 1997. Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study. Philos Trans R Soc Lond B Biol Sci 352 : 1331–1345. [Google Scholar]
  39. Goldfeld AE, Delgado JC, Thim S, Bozon MV, Uglialoro AM, Turbay D, Cohen C, Yunis EJ, 1998. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 279 : 226–228. [Google Scholar]
  40. Selvaraj P, Sriram U, Mathan Kurian S, Reetha AM, Narayanan PR, 2001. Tumour necrosis factor alpha (−238 and −308) and beta gene polymorphisms in pulmonary tuberculosis: haplo-type analysis with HLA-A, B and DR genes. Tuberculosis (Edinb) 81 : 335–341. [Google Scholar]
  41. Roach DR, Briscoe H, Saunders B, France MP, Riminton S, Britton WJ, 2001. Secreted lymphotoxin-alpha is essential for the control of an intracellular bacterial infection. J Exp Med 193 : 239–246. [Google Scholar]
  42. Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, Tsunoda T, Sato H, Hori M, Nakamura Y, Tanaka T, 2002. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32 : 650–654. [Google Scholar]
  43. Carrington M, Nelson G, O’Brien SJ, 2001. Considering genetic profiles in functional studies of immune responsiveness to HIV-1. Immunol Lett 79 : 131–140. [Google Scholar]
  44. Al-Sharif FM, Makki RF, Ollier WE, Hajeer AH, 1999. A new microsatellite marker within the promoter region of the MIP-1A gene. Immunogenetics 49 : 740–741. [Google Scholar]
  45. Saukkonen JJ, Bazydlo B, Thomas M, Strieter RM, Keane J, Kornfeld H, 2002. Beta-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth. Infect Immun 70 : 1684–1693. [Google Scholar]

Data & Media loading...

  • Received : 28 Aug 2003
  • Accepted : 11 Mar 2004

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error