Abstract
The ancient disease of leprosy can cause severe disability and disfigurement and is still a major health concern in many parts of the world. Only a subset of those individuals exposed to the pathogen will go on to develop clinical disease and there is a broad clinical spectrum amongst leprosy sufferers. The outcome of infection is in part due to host genes that influence control of the initial infection and the host's immune response to that infection. Identification of the host genes that influence host susceptibility/resistance will enable a greater understanding of disease pathogenesis. In turn, this should facilitate development of more effective therapeutics and vaccines. So far at least a dozen genes have been implicated in leprosy susceptibility and a genome-wide linkage study has lead to the identification of at least one positional candidate. These findings are reviewed here.
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References
WHO. Leprosy Weekly Epidemiol Rec 2002 77: 1–8
Abel L, Demenais F . Detection of major genes for susceptibility to leprosy and its subtypes in a Caribbean island: Desirade island Am J Hum Genet 1988 42: 256–266
Haile RW, Iselius L, Fine PE, Morton NE . Segregation and linkage analyses of 72 leprosy pedigrees Hum Hered 1985 35: 43–52
Feitosa MF, Borecki I, Krieger H, Beiguelman B, Rao DC . The genetic epidemiology of leprosy in a Brazilian population Am J Hum Genet 1995 56: 1179–1185
Wagener DK, Schauf V, Nelson KE, Scollard D, Brown A, Smith T . Segregation analysis of leprosy in families of northern Thailand Genet Epidemiol 1988 5: 95–105
Chakravartti MR, Vogel F . A twin study on leprosy Top Hum Genet 1973 1: 1–123
de Vries RR, Fat RF, Nijenhuis LE, van Rood JJ . HLA-linked genetic control of host response to Mycobacterium leprae Lancet 1976 2: 1328–1330
Fine PE, Wolf E, Pritchard J et al. HLA-linked genes and leprosy: a family study in Karigiri, South India J Infect Dis 1979 140: 152–161
de Vries RR, Mehra NK, Vaidya MC, Gupte MD, Meera Khan P, Van Rood JJ . HLA-linked control of susceptibility to tuberculoid leprosy and association with HLA-DR types Tissue Antigens 1980 16: 294–304
van Eden W, Gonzalez NM, de Vries RR, Convit J, van Rood JJ . HLA-linked control of predisposition to lepromatous leprosy J Infect Dis 1985 151: 9–14
Dessoukey MW, el-Shiemy S, Sallam T . HLA and leprosy: segregation and linkage study Int J Dermatol 1996 35: 257–264
Xu KY, de Vries RR, Fei HM, van Leeuwen A, Chen RB, Ye GY . HLA-linked control of predisposition to lepromatous leprosy Int J Lepr Other Mycobact Dis 1985 53: 56–63
Casanova JL, Abel L . Genetic dissection of immunity to mycobacteria: the human model Annu Rev Immunol 2002 20: 581–620
Serjeantson SW . HLA and susceptibility to leprosy Immunol Rev 1983 70: 89–112
Rani R, Zaheer SA, Mukherjee R . Do human leukocyte antigens have a role to play in differential manifestation of multibacillary leprosy: a study on multibacillary leprosy patients from north India Tissue Antigens 1992 40: 124–127
Greiner J, Schleiermacher E, Smith T, Lenhard V, Vogel F . The HLA system and leprosy in Thailand Hum Genet 1978 42: 201–213
Takata H, Sada M, Ozawa S, Sekiguchi S . HLA and mycobacterial infection: increased frequency of B8 in Japanese leprosy Tissue Antigens 1978 11: 61–64
Izumi S, Sugiyama K, Matsumoto Y, Ohkawa S . Analysis of the immunogenetic background of Japanese leprosy patients by the HLA system Vox Sang 1982 42: 243–247
Kim SJ, Choi IH, Dahlberg S, Nisperos B, Kim JD, Hansen JA . HLA and leprosy in Koreans Tissue Antigens 1987 29: 146–153
Rea TH, Levan NE, Terasaki PI . Histocompatibility antigens in patients with leprosy J Infect Dis 1976 134: 615–618
Wang LM, Kimura A, Satoh M, Mineshita S . HLA linked with leprosy in southern China: HLA-linked resistance alleles to leprosy Int J Lepr Other Mycobact Dis 1999 67: 403–408
Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T . Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells Nat Immunol 2001 2: 255–260
Das H, Groh V, Kuijl C et al. MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function Immunity 2001 15: 83–93
Robinson J, Perez-Rodriguez M, Waller MJ et al. MICA sequences 2000 Immunogenetics 2001 53: 150–169
Perez-Rodriguez M, Arguello JR, Fischer G et al. Further polymorphism of the MICA gene Eur J Immunogenet 2002 29: 35–46
Rani R, Fernandez-Vina MA, Zaheer SA, Beena KR, Stastny P . Study of HLA class II alleles by PCR oligotyping in leprosy patients from north India Tissue Antigens 1993 42: 133–137
Mehra NK, Rajalingam R, Mitra DK, Taneja V, Giphart MJ . Variants of HLA-DR2/DR51 group haplotypes and susceptibility to tuberculoid leprosy and pulmonary tuberculosis in Asian Indians Int J Lepr Other Mycobact Dis 1995 63: 241–248
Schauf V, Ryan S, Scollard D et al. Leprosy associated with HLA-DR2 and DQw1 in the population of northern Thailand Tissue Antigens 1985 26: 243–247
Miyanaga K, Juji T, Maeda H, Nakajima S, Kobayashi S . Tuberculoid leprosy and HLA in Japanese Tissue Antigens 1981 18: 331–334
Joko S, Numaga J, Masuda K, Namisato M, Maeda H . [HLA class II alleles and leprosy (Hansen's disease) classified by WHO- MDT criteria] Nippon Rai Gakkai Zasshi 1996 65: 121–127
Todd JR, West BC, McDonald JC . Human leukocyte antigen and leprosy: study in northern Louisiana and review Rev Infect Dis 1990 12: 63–74
Shaw MA, Donaldson IJ, Collins A et al. Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes Genes Immun 2001 2: 196–204
Salgame P, Convit J, Bloom BR . Immunological suppression by human CD8+ T cells is receptor dependent and HLA-DQ restricted Proc Natl Acad Sci USA 1991 88: 2598–2602
Gorodezky C, Flores J, Arevalo N, Castro LE, Silva A, Rodriguez O . Tuberculoid leprosy in Mexicans is associated with HLA-DR3 Lepr Rev 1987 58: 401–406
van Eden W, de Vries RR, D'Amaro J, Schreuder I, Leiker DL, van Rood JJ . HLA-DR-associated genetic control of the type of leprosy in a population from surinam Hum Immunol 1982 4: 343–350
Ottenhoff TH, Converse PJ, Bjune G, de Vries RR . HLA antigens and neural reversal reactions in Ethiopian borderline tuberculoid leprosy patients Int J Lepr Other Mycobact Dis 1987 55: 261–266
Van Schooten WC, Elferink DG, Van Embden J, Anderson DC, De Vries RR . DR3-restricted T cells from different HLA-DR3-positive individuals recognize the same peptide (amino acids 2–12) of the mycobacterial 65-kDa heat-shock protein Eur J Immunol 1989 19: 2075–2079
Ottenhoff TH, de Vries RR . HLA class II immune response and suppression genes in leprosy Int J Lepr Other Mycobact Dis 1987 55: 521–534
Haanen JB, Ottenhoff TH, Lai AFRF, Soebono H, Spits H, de Vries RR . Mycobacterium leprae-specific T cells from a tuberculoid leprosy patient suppress HLA-DR3-restricted T cell responses to an immunodominant epitope on 65-kDa hsp of mycobacteria J Immunol 1990 145: 3898–3904
Visentainer JE, Tsuneto LT, Serra MF, Peixoto PR, Petzl-Erler ML . Association of leprosy with HLA-DR2 in a Southern Brazilian population Braz J Med Biol Res 1997 30: 51–59
Cem Mat M, Yazici H, Ozbakir F, Tuzun Y . The HLA association of lepromatous leprosy and borderline lepromatous leprosy in Turkey. A preliminary study Int J Dermatol 1988 27: 246–247
Roy S, McGuire W, Mascie-Taylor CG et al. Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy J Infect Dis 1997 176: 530–532
Joko S, Numaga J, Kawashima H, Namisato M, Maeda H . Human leukocyte antigens in forms of leprosy among Japanese patients Int J Lepr Other Mycobact Dis 2000 68: 49–56
van Eden W, de Vries RR, Mehra NK, Vaidya MC, D';Amaro J, van Rood JJ . HLA segregation of tuberculoid leprosy: confirmation of the DR2 marker J Infect Dis 1980 141: 693–701
Mehra NK, Verduijn W, Taneja V, Drabbels J, Singh SP, Giphart MJ . Analysis of HLA-DR2-associated polymorphisms by oligonucleotide hybridization in an Asian Indian population Hum Immunol 1991 32: 246–253
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
Uko GP, Lu LY, Asuquo MA et al. HLA-DRB1 leprogenic motifs in nigerian population groups Clin Exp Immunol 1999 118: 56–62
Agrewala JN, Wilkinson RJ . Influence of HLA-DR on the phenotype of CD4+ T lymphocytes specific for an epitope of the 16-kDa alpha-crystallin antigen of Mycobacterium tuberculosis Eur J Immunol 1999 29: 1753–1761
Mutis T, Cornelisse YE, Datema G, van den Elsen PJ, Ottenhoff TH, de Vries RR . Definition of a human suppressor T-cell epitope Proc Natl Acad Sci USA 1994 91: 9456–9460
Joly AL, Le Rolle AL, Gonzalez AL et al. Co-evolution of rat TAP transporters and MHC class I RT1-A molecules Curr Biol 1998 8: 169–172
Hayney MS, Poland GA, Dimanlig P, Schaid DJ, Jacobson RM, Lipsky JJ . Polymorphisms of the TAP2 gene may influence antibody response to live measles vaccine virus Vaccine 1997 15: 3–6
Barron KS, Reveille JD, Carrington M, Mann DL, Robinson MA . Susceptibility to Reiter's syndrome is associated with alleles of TAP genes Arthritis Rheum 1995 38: 684–689
Gonzalez-Escribano MF, Morales J, Garcia-Lozano JR et al. TAP polymorphism in patients with Behcet's disease Ann Rheum Dis 1995 54: 386–388
Hillarby MC, Davies EJ, Donn RP, Grennan DM, Ollier WE . TAP2D is associated with HLA-B44 and DR4 and may contribute to rheumatoid arthritis and Felty's syndrome susceptibility Clin Exp Rheumatol 1996 14: 67–70
Kaslow RA, Carrington M, Apple R et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection Nat Med 1996 2: 405–411
Daniel S, Caillat-Zucman S, Hammer J, Bach JF, van Endert PM . Absence of functional relevance of human transporter associated with antigen processing polymorphism for peptide selection J Immunol 1997 159: 2350–2357
Faucz FR, Probst CM, Petzl-Erler ML . Polymorphism of LMP2, TAP1, LMP7 and TAP2 in Brazilian Amerindians and Caucasoids: implications for the evolution of allelic and haplotypic diversity Eur J Immunogenet 2000 27: 5–16
Rajalingam R, Singal DP, Mehra NK . Transporter associated with antigen-processing (TAP) genes and susceptibility to tuberculoid leprosy and pulmonary tuberculosis Tissue Antigens 1997 49: 168–172
Engele M, Stossel E, Castiglione K et al. Induction of TNF in human alveolar macrophages as a potential evasion mechanism of virulent Mycobacterium tuberculosis J Immunol 2002 168: 1328–1337
Udalova IA, Richardson A, Denys A et al. Functional consequences of a polymorphism affecting NF-kappaB p50–p50 binding to the TNF promoter region Mol Cell Biol 2000 20: 9113–9119
Knight JC, Udalova I, Hill AV et al. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria [see comments] Nat Genet 1999 22: 145–150
Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation Proc Natl Acad Sci USA 1997 94: 3195–3199
Louis E, Franchimont D, Piron A et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans Clin Exp Immunol 1998 113: 401–406
Kroeger KM, Carville KS, Abraham LJ . The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription Mol Immunol 1997 34: 391–399
Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL . Relevance of the tumor necrosis factor alpha (TNF alpha) −308 promoter polymorphism in TNF alpha gene regulation [see comments] J Inflamm 1995 46: 32–41
Somoskovi A, Zissel G, Seitzer U, Gerdes J, Schlaak M, Muller Quernheim J . Polymorphisms at position −308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis Cytokine 1999 11: 882–887
Kaijzel EL, Bayley JP, van Krugten MV et al. Allele-specific quantification of tumor necrosis factor alpha (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals Genes Immun 2001 2: 135–144
Stuber F, Udalova IA, Book M et al. −308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter J Inflamm 1995 46: 42–50
Nadal D, Leppert D, Frei K, Gallo P, Lamche H, Fontana A . Tumour necrosis factor-alpha in infectious meningitis Arch Dis Child 1989 64: 1274–1279
Cabrera M, Shaw MA, Sharples C et al. Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis J Exp Med 1995 182: 1259–1264
Conway DJ, Holland MJ, Bailey RL et al. Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid Infect Immun 1997 65: 1003–1006
McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria Nature 1994 371: 508–510
Sashio H, Tamura K, Ito R et al. Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn's disease, respectively Immunogenetics 2002 53: 1020–1027
Santos AR, Almeida AS, Suffys PN et al. Tumor necrosis factor promoter polymorphism (TNF2) seems to protect against development of severe forms of leprosy in a pilot study in Brazilian patients Int J Lepr Other Mycobact Dis 2000 68: 325–327
Moraes MO, Duppre NC, Suffys PN et al. Tumor necrosis factor-alpha promoter polymorphism TNF2 is associated with a stronger delayed-type hypersensitivity reaction in the skin of borderline tuberculoid leprosy patients Immunogenetics 2001 53: 45–47
Khanolkar-Young S, Rayment N, Brickell PM et al. Tumour necrosis factor-alpha (TNF-alpha) synthesis is associated with the skin and peripheral nerve pathology of leprosy reversal reactions Clin Exp Immunol 1995 99: 196–202
Kaplan G . Cytokine regulation of disease progression in leprosy and tuberculosis Immunobiology 1994 191: 564–568
Skoff AM, Lisak RP, Bealmear B, Benjamins JA . TNF-alpha and TGF-beta act synergistically to kill Schwann cells J Neurosci Res 1998 53: 747–756
Sarno EN, Santos AR, Jardim MR et al. Pathogenesis of nerve damage in leprosy: genetic polymorphism regulates the production of TNF alpha Lepr Rev 2000 71 (Suppl) S154–S158 discussion S158–S160
Jongeneel CV, Briant L, Udalova IA, Sevin A, Nedospasov SA, Cambon-Thomsen A . Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended HLA haplotypes Proc Natl Acad Sci USA 1991 88: 9717–9721
Fanning GC, Bunce M, Black CM, Welsh KI . Polymerase chain reaction haplotyping using 3′ mismatches in the forward and reverse primers: application to the biallelic polymorphisms of tumor necrosis factor and lymphotoxin alpha Tissue Antigens 1997 50: 23–31
de Messias IJ, Santamaria J, Brenden M, Reis A, Mauff G . Association of C4B deficiency (C4B*Q0) with erythema nodosum in leprosy Clin Exp Immunol 1993 92: 284–287
Vanbuskirk A, Crump BL, Margoliash E, Pierce SK . A peptide binding protein having a role in antigen presentation is a member of the HSP70 heat shock family J Exp Med 1989 170: 1799–1809
Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H . HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway J Biol Chem 2002 277: 15107–15112
Asea A, Rehli M, Kabingu E et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4 J Biol Chem 2002 277: 15028–15034
Laroia G, Cuesta R, Brewer G, Schneider RJ . Control of mRNA decay by heat shock–ubiquitin–proteasome pathway Science 1999 284: 499–502
Cascino I, Sorrentino R, Tosi R . Strong genetic association between HLA-DR3 and a polymorphic variation in the regulatory region of the HSP70-1 gene Immunogenetics 1993 37: 177–182
Rajalingam R, Mehra NK, Singal DP . Polymorphism in heat-shock protein 70-1 (HSP70-1) gene promoter region and susceptibility to tuberculoid leprosy and pulmonary tuberculosis in Asian Indians Indian J Exp Biol 2000 38: 658–662
Cascino I, D'Alfonso S, Cappello N et al. Gametic association of HSP70-1 promoter region alleles and their inclusion in extended HLA haplotypes Tissue Antigens 1993 42: 62–66
Vidal S, Gros P, Skamene E . Natural resistance to infection with intracellular parasites: molecular genetics identifies Nramp1 as the Bcg/Ity/Lsh locus J Leukoc Biol 1995 58: 382–390
Brown IN, Glynn AA, Plant J . Inbred mouse strain resistance to Mycobacterium lepraemurium follows the Ity/Lsh pattern Immunology 1982 47: 149–156
Skamene E, Gros P, Forget A, Patel PJ, Nesbitt MN . Regulation of resistance to leprosy by chromosome 1 locus in the mouse Immunogenetics 1984 19: 117–124
Goto Y, Buschman E, Skamene E . Regulation of host resistance to Mycobacterium intracellulare in vivo and in vitro by the Bcg gene Immunogenetics 1989 30: 218–221
Blackwell JM, Roberts CW, Roach TI, Alexander J . Influence of macrophage resistance gene Lsh/Ity/Bcg (candidate Nramp) on Toxoplasma gondii infection in mice Clin Exp Immunol 1994 97: 107–112
Puliti M, Radzioch D, Mazzolla R, Barluzzi R, Bistoni F, Blasi E . Influence of the Bcg locus on macrophage response to the dimorphic fungus Candida albicans Infect Immun 1995 63: 4170–4173
Leclercq V, Lebastard M, Belkaid Y, Louis J, Milon G . The outcome of the parasitic process initiated by Leishmania infantum in laboratory mice: a tissue-dependent pattern controlled by the Lsh and MHC loci J Immunol 1996 157: 4537–4545
North RJ, LaCourse R, Ryan L, Gros P . Consequence of Nramp1 deletion to Mycobacterium tuberculosis infection in mice Infect Immun 1999 67: 5811–5814
Medina E, Rogerson BJ, North RJ . The Nramp1 antimicrobial resistance gene segregates independently of resistance to virulent Mycobacterium tuberculosis Immunology 1996 88: 479–481
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
Wyllie S, Seu P, Goss JA . The natural resistance-associated macrophage protein 1 Slc11a1 (formerly Nramp1) and iron metabolism in macrophages Microbes Infect 2002 4: 351–359
Jabado N, Jankowski A, Dougaparsad S, Picard V, Grinstein S, Gros P . Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane J Exp Med 2000 192: 1237–1248
Blackwell JM, Searle S, Goswami T, Miller EN . Understanding the multiple functions of Nramp1 Microbes Infect 2000 2: 317–321
Lang T, Prina E, Sibthorpe D, Blackwell JM . Nramp1 transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on antigen processing and presentation Infect Immun 1997 65: 380–386
Kaye PM, Blackwell JM . Lsh antigen presentation and the development of CMI Res Immunol 1989 140: 810–815 discussion 815–822
Soo SS, Villarreal-Ramos B, Anjam Khan CM, Hormaeche CE, Blackwell JM . Genetic control of immune response to recombinant antigens carried by an attenuated Salmonella typhimurium vaccine strain: Nramp1 influences T-helper subset responses and protection against leishmanial challenge Infect Immun 1998 66: 1910–1917
Liu J, Fujiwara TM, 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
White JK, Shaw MA, Barton CH et al. Genetic and physical mapping of 2q35 in the region of the NRAMP and IL8R genes: identification of a polymorphic repeat in exon 2 of NRAMP Genomics 1994 24: 295–302
Buu NT, Cellier M, Gros P, Schurr E . Identification of a highly polymorphic length variant in the 3'UTR of NRAMP1 Immunogenetics 1995 42: 428–429
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
Shaw MA, Clayton D, Atkinson SE et al. Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35 J Med Genet 1996 33: 672–677
Singal DP, Li J, Zhu Y, Zhang G . NRAMP1 gene polymorphisms in patients with rheumatoid arthritis Tissue Antigens 2000 55: 44–47
Sanjeevi CB, Miller EN, Dabadghao P et al. Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis Arthritis Rheum 2000 43: 1397–1404
Hofmeister A, Neibergs HL, Pokorny RM, Galandiuk S . The natural resistance-associated macrophage protein gene is associated with Crohn's disease Surgery 1997 122: 173–178 discussion 178–179
Kojima Y, Kinouchi Y, Takahashi S, Negoro K, Hiwatashi N, Shimosegawa T . Inflammatory bowel disease is associated with a novel promoter polymorphism of natural resistance-associated macrophage protein 1 (NRAMP1) gene Tissue Antigens 2001 58: 379–384
Esposito L, Hill NJ, Pritchard LE et al. Genetic analysis of chromosome 2 in type 1 diabetes: analysis of putative loci IDDM7, IDDM12, and IDDM13 and candidate genes NRAMP1 and IA-2 and the interleukin-1 gene cluster. IMDIAB Group Diabetes 1998 47: 1797–1799
Maliarik MJ, Chen KM, Sheffer RG et al. The natural resistance-associated macrophage protein gene in African Americans with sarcoidosis Am J Respir Cell Mol Biol 2000 22: 672–675
Marquet S, Sanchez FO, Arias M et al. Variants of the human NRAMP1 gene and altered human immunodeficiency virus infection susceptibility J Infect Dis 1999 180: 1521–1525
Blackwell JM . Modern genetics and leprosy susceptibility Lepr Rev 2001 72: 352–356
Gao PS, Fujishima S, Mao XQ et al. Genetic variants of NRAMP1 and active tuberculosis in Japanese populations. International Tuberculosis Genetics Team Clin Genet 2000 58: 74–76
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 Tuber Lung Dis 1997 78: 35–45
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
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
Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV . Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans N Engl J Med 1998 338: 640–644
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
Bellamy R, Beyers N, McAdam KP et al. Genetic susceptibility to tuberculosis in Africans: a genome-wide scan Proc Natl Acad Sci USA 2000 97: 8005–8009
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
Shaw MA, Atkinson S, Dockrell H et al. An RFLP map for 2q33–q37 from multicase mycobacterial and leishmanial disease families: no evidence for an Lsh/Ity/Bcg gene homologue influencing susceptibility to leprosy Ann Hum Genet 1993 57: (Pt 4) 251–271
Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV . Association of vitamin D receptor genotype with leprosy type J Infect Dis 1999 179: 187–191
Meisner SJ, Mucklow S, Warner G, Sow SO, Lienhardt C, Hill AV . Association of NRAMP1 polymorphism with leprosy type but not susceptibility to leprosy per se in west Africans Am J Trop Med Hyg 2001 65: 733–735
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 Lepr Other Mycobact Dis 1997 65: 197–202
Alcais A, Sanchez FO, Thuc NV et al. Granulomatous reaction to intradermal injection of lepromin (Mitsuda reaction) is linked to the human NRAMP1 gene in Vietnamese leprosy sibships J Infect Dis 2000 181: 302–308
Kaur G, Sachdeva G, Bhutani LK, Bamezai R . Association of polymorphism at COL3A and CTLA4 loci on chromosome 2q31–33 with the clinical phenotype and in-vitro CMI status in healthy and leprosy subjects: a preliminary study Hum Genet 1997 100: 43–50
Holopainen PM, Partanen JA . Technical note: linkage disequilibrium and disease-associated CTLA4 gene polymorphisms J Immunol 2001 167: 2457–2458
Chistiakov DA, Savost'anov KV, Nosikov VV . CTLA4 gene polymorphisms are associated with, and linked to, insulin-dependent diabetes mellitus in a Russian population BMC Genet 2001 2: 6
Kristiansen OP, Larsen ZM, Pociot F . CTLA-4 in autoimmune diseases–a general susceptibility gene to autoimmunity? Genes Immun 2000 1: 170–184
Morrison NA, Qi JC, Tokita A et al. Prediction of bone density from vitamin D receptor alleles Nature 1994 367: 284–287
Hughes MR, Malloy PJ, Kieback DG et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets Science 1988 242: 1702–1705
Lorentzon M, Lorentzon R, Nordstrom P . Vitamin D receptor gene polymorphism is associated with birth height, growth to adolescence, and adult stature in healthy caucasian men: a cross-sectional and longitudinal study J Clin Endocrinol Metab 2000 85: 1666–1670
Vidal M, Ramana CV, Dusso AS . Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription Mol Cell Biol 2002 22: 2777–2787
Alroy I, Towers TL, Freedman LP . Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor Mol Cell Biol 1995 15: 5789–5799
Towers TL, Freedman LP . Granulocyte-macrophage colony-stimulating factor gene transcription is directly repressed by the vitamin D3 receptor. Implications for allosteric influences on nuclear receptor structure and function by a DNA element J Biol Chem 1998 273: 10338–10348
Cippitelli M, Santoni A . Vitamin D3: a transcriptional modulator of the interferon-gamma gene Eur J Immunol 1998 28: 3017–3030
D'Ambrosio D, Cippitelli M, Cocciolo MG et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene J Clin Invest 1998 101: 252–262
Cippitelli M, Fionda C, Di Bona D et al. Negative regulation of CD95 ligand gene expression by vitamin D3 in T lymphocytes J Immunol 2002 168: 1154–1166
Rescigno M, Piguet V, Valzasina B et al. Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1beta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses J Exp Med 2000 192: 1661–1668
Morrison NA, Yeoman R, Kelly PJ, Eisman JA . Contribution of transacting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin Proc Natl Acad Sci USA 1992 89: 6665–6669
Verbeek W, Gombart AF, Shiohara M, Campbell M, Koeffler HP . Vitamin D receptor: no evidence for allele-specific mRNA stability in cells which are heterozygous for the Taq I restriction enzyme polymorphism Biochem Biophys Res Commun 1997 238: 77–80
Mocharla H, Butch AW, Pappas AA et al. Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: lack of correspondence with common allelic variants J Bone Miner Res 1997 12: 726–733
Simmons JD, Mullighan C, Welsh KI, Jewell DP . Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility Gut 2000 47: 211–214
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: 721–724
Wilkinson RJ, Llewelyn M, Toossi Z et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study Lancet 2000 355: 618–621
Gelder CM, Hart KW, Williams OM et al. Vitamin D receptor gene polymorphisms and susceptibility to Mycobacterium malmoense pulmonary disease J Infect Dis 2000 181: 2099–2102
Selvaraj P, Narayanan PR, Reetha AM . Association of vitamin D receptor genotypes with the susceptibility to pulmonary tuberculosis in female patients & resistance in female contacts Indian J Med Res 2000 111: 172–179
Ingles SA, Haile RW, Henderson BE et al. Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies Cancer Epidemiol Biomarkers Prev 1997 6: 93–98
Jurutka PW, Remus LS, Whitfield GK et al. The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB Mol Endocrinol 2000 14: 401–420
Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ . Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis J Immunol 1999 163: 3920–3927
Lien E, Sellati TJ, Yoshimura A et al. Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products J Biol Chem 1999 274: 33419–33425
Underhill DM, Ozinsky A, Smith KD, Aderem A . Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages Proc Natl Acad Sci USA 1999 96: 14459–14463
Thoma-Uszynski S, Stenger S, Takeuchi O et al. Induction of direct antimicrobial activity through mammalian toll-like receptors Science 2001 291: 1544–15447
Kang TJ, Chae GT . Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients FEMS Immunol Med Microbiol 2001 31 53–58
Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA . A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection Infect Immun 2000 68: 6398–6401
Garred P, Madsen HO, Kurtzhals JA et al. Diallelic polymorphism may explain variations of the blood concentration of mannan-binding protein in Eskimos, but not in black Africans Eur J Immunogenet 1992 19: 403–412
Garred P, Harboe M, Oettinger T, Koch C, Svejgaard A . Dual role of mannan-binding protein in infections: another case of heterosis? Eur J Immunogenet 1994 21: 125–131
Hoal-Van Helden EG, Epstein J, Victor TC et al. Mannose-binding protein B allele confers protection against tuberculous meningitis Pediatr Res 1999 45: (Pt 1) 459–464
Garred P, Richter C, Andersen AB et al. Mannan-binding lectin in the sub-Saharan HIV and tuberculosis epidemics Scand J Immunol 1997 46: 204–208
Bellamy R, Ruwende C, McAdam KP et al. Mannose binding protein deficiency is not associated with malaria hepatitis B carriage nor tuberculosis in Africans Qjm 1998 91: 13–18
Schorey JS, Carroll MC, Brown EJ . A macrophage invasion mechanism of pathogenic mycobacteria Science 1997 277: 1091–1093
Selvaraj P, Narayanan PR, Reetha AM . Association of functional mutant homozygotes of the mannose binding protein gene with susceptibility to pulmonary tuberculosis in India Tuber Lung Dis 1999 79: 221–227
Marquet S, Abel L, Hillaire D et al. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31–q33 Nat Genet 1996 14: 181–184
Muller-Myhsok B, Stelma FF, Guisse-Sow F et al. Further evidence suggesting the presence of a locus, on human chromosome 5q31–q33, influencing the intensity of infection with Schistosoma mansoni Am J Hum Genet 1997 61: 452–454
Garcia A, Marquet S, Bucheton B et al. Linkage analysis of blood Plasmodium falciparum levels: interest of the 5q31–q33 chromosome region Am J Trop Med Hyg 1998 58: 705–709
Cookson WO, Ubhi B, Lawrence R et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci Nat Genet 2001 27: 372–373
Nair RP, Henseler T, Jenisch S et al. Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan Hum Mol Genet 1997 6: 1349–1356
Trembath RC, Clough RL, Rosbotham JL et al. Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis Hum Mol Genet 1997 6: 813–820
Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247
Siddiqui MR, Meisner S, Tosh K et al. A major susceptibility locus for leprosy in India maps to chromosome 10p13 Nat Genet 2001 27: 439–441
Taylor ME, Drickamer K . Structural requirements for high affinity binding of complex ligands by the macrophage mannose receptor J Biol Chem 1993 268: 399–404
Schlesinger LS, Hull SR, Kaufman TM . Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages J Immunol 1994 152: 4070–4079
Prigozy TI, Sieling PA, Clemens D et al. The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules Immunity 1997 6: 187–197
Tosh K, Meisner S, Siddiqui MR, Balakrishnan K, Ghei S, Golding M et al. A region of chromosome 20 is linked to leprosy susceptibility in a South Indian population J Infect Dis 2002 186: (8)
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Fitness, J., Tosh, K. & Hill, A. Genetics of susceptibility to leprosy. Genes Immun 3, 441–453 (2002). https://doi.org/10.1038/sj.gene.6363926
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DOI: https://doi.org/10.1038/sj.gene.6363926
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