Skip to main content

Advertisement

SpringerLink
Log in

Leprosy as a genetic disease

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Leprosy (Hansen’s disease) is a human infectious disease whose etiological agent, Mycobacterium leprae, was identified by G. H. A. Hansen in the 19th century. Despite the high efficacy of multidrug therapy (<0.1% annual relapse rate), transmission is persistent. In 2008, approximately 250,000 new cases were reported to the World Health Organization. Clinically, leprosy presents as either the paucibacillary (1–5 lesions) or the multibacillary (>5 lesions) subtype, highly reflective of a Th1 (cell-mediated) or Th2 (humoral) host immune response, respectively. Subsequent to Mycobacterium leprae exposure, epidemiological studies (e.g., twin studies and complex segregation analyses) maintain the importance of host genetics in susceptibility to leprosy. The results of genome-wide analyses (linkage and association) and candidate gene studies suggest an independent genetic control over both susceptibility to leprosy per se and development of clinical subtype. Moreover, the emergence of a shared genetic background between leprosy and several inflammatory/autoimmune diseases suggests that leprosy is a suitable model for studying the genetic architecture and subsequent pathogenesis of both infectious and inflammatory/autoimmune diseases. We provide the example of NOD2 (Crohn’s disease gene) and LTA (myocardial infarction gene) and the implication of a common genetic risk factor between these two diseases and leprosy. The value of leprosy as a model disease therefore extends far beyond this ancient disease to common afflictions of the 21st century.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abel L, Demenais F (1988) Detection of major genes for susceptibility to leprosy and its subtypes in a Caribbean island: Desirade island. Am J Hum Genet 42:256–266

    CAS  PubMed  Google Scholar 

  • Abel L, Vu DL, Oberti J, Nguyen VT, Van VC et al (1995) Complex segregation analysis of leprosy in southern Vietnam. Genet Epidemiol 12:63–82

    CAS  PubMed  Google Scholar 

  • Abel L, Sanchez FO, Oberti J, Thuc NV, Hoa LV et al (1998) Susceptibility to leprosy is linked to the human NRAMP1 gene. J Infect Dis 177:133–145

    CAS  PubMed  Google Scholar 

  • Abraham LJ, Kroeger KM (1999) Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol 66:562–566

    CAS  PubMed  Google Scholar 

  • Alcaïs A, Alter A, Antoni G, Orlova M, Nguyen VT et al (2007) Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nat Genet 39:517–522

    PubMed  Google Scholar 

  • Ali S, Vollaard A, Widjaja S, Surjadi C, van de Vosse E et al (2006) PARK2/PACRG polymorphisms and susceptibility to typhoid and paratyphoid fever. Clin Exp Immunol 144:425–431

    CAS  PubMed  Google Scholar 

  • Alter A, Alcais A, Abel L, Schurr E (2008) Leprosy as a genetic model for susceptibility to common infectious diseases. Hum Genet 123:227–235

    PubMed  Google Scholar 

  • Alter A, de Leseleuc L, Van Thuc N, Thai VH, Huong NT et al (2010) Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility. Hum Genet 127:337–348

    CAS  PubMed  Google Scholar 

  • Balding J, Kane D, Livingstone W, Mynett-Johnson L, Bresnihan B et al (2003) Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity. Arthritis Rheum 48:1408–1413

    CAS  PubMed  Google Scholar 

  • Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH et al (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40:955–962

    CAS  PubMed  Google Scholar 

  • Behr MA, Schurr E (2006) Mycobacteria in Crohn’s disease: a persistent hypothesis. Inflamm Bowel Dis 12:1000–1004

    PubMed  Google Scholar 

  • Berrington WR, Macdonald M, Khadge S, Sapkota BR, Janer M et al (2010) Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. J Infect Dis 201:1422–1435

    CAS  PubMed  Google Scholar 

  • Bochud PY, Sinsimer D, Aderem A, Siddiqui MR, Saunderson P et al (2009) Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy. Eur J Clin Microbiol Infect Dis 28:1055–1065

    CAS  PubMed  Google Scholar 

  • Boraska V, Zeggini E, Groves CJ, Rayner NW, Skrabic V et al (2009) Family-based analysis of tumor necrosis factor and lymphotoxin-alpha tag polymorphisms with type 1 diabetes in the population of South Croatia. Hum Immunol 70:195–199

    CAS  PubMed  Google Scholar 

  • Casanova JL, Abel L (2007) Human genetics of infectious diseases: a unified theory. EMBO J 26:915–922

    CAS  PubMed  Google Scholar 

  • Chakravartti M, Vogel F (1973) A twin study on leprosy. In: Becker PE, Lenz W, Vogel F, Wendt GG (eds) Topics in human genetics. Georg Thieme, Stuttgart

    Google Scholar 

  • Chaudhury S, Hazra SK, Saha B, Mazumder B, Biswas PC et al (1994) An eight-year field trial on antileprosy vaccines among high-risk household contacts in the Calcutta metropolis. Int J Lepr Other Mycobact Dis 62:389–394

    CAS  PubMed  Google Scholar 

  • Cobat A, Gallant CJ, Simkin L, Black GF, Stanley K et al (2009) Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J Exp Med 206(12):2583–2591

    CAS  PubMed  Google Scholar 

  • Cobat A, Orlova M, Alcaïs A, Schurr E (2010) Genetics of susceptibility and resistance to infection. In: Kaufmann SHE, Kabelitz D (eds) Immunology of infection (methods in microbiology). Academic Press, New York

    Google Scholar 

  • Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR et al (2001) Massive gene decay in the leprosy bacillus. Nature 409:1007–1011

    CAS  PubMed  Google Scholar 

  • Convit J, Sampson C, Zuniga M, Smith PG, Plata J et al (1992) Immunoprophylactic trial with combined Mycobacterium leprae/BCG vaccine against leprosy: preliminary results. Lancet 339:446–450

    CAS  PubMed  Google Scholar 

  • Cooke G, Hill A (2008) Tuberculosis, leprosy and other mycobacterial diseases. In: McNicholl JM, Hill AVS, Kaslow RA (eds) Genetic susceptibility to infectious diseases. Oxford University Press, New York

    Google Scholar 

  • Cooney R, Jewell D (2009) The genetic basis of inflammatory bowel disease. Dig Dis 27:428–442

    PubMed  Google Scholar 

  • De La Vega FM, Isaac H, Collins A, Scafe CR, Halldorsson BV et al (2005) The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern. Genome Res 15:454–462

    Google Scholar 

  • Eleftherohorinou H, Wright V, Hoggart C, Hartikainen AL, Jarvelin MR et al (2009) Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases. PLoS One 4:e8068

    PubMed  Google Scholar 

  • Feitosa MF, Borecki I, Krieger H, Beiguelman B, Rao DC (1995) The genetic epidemiology of leprosy in a Brazilian population. Am J Hum Genet 56:1179–1185

    CAS  PubMed  Google Scholar 

  • Fitness J, Tosh J, Hill AVS (2002) Genetics of susceptibility to leprosy. Genes Immun 3:441–453

    CAS  PubMed  Google Scholar 

  • Fulco TO, Lopes UG, Sarno EN, Sampaio EP, Saliba AM (2007) The proteasome function is required for Mycobacterium leprae-induced apoptosis and cytokine secretion. Immunol Lett 110:82–85

    CAS  PubMed  Google Scholar 

  • Gallant CJ, Malik S, Jabado N, Cellier M, Simkin L et al (2007) Reduced in vitro functional activity of human NRAMP1 (SLC11A1) allele that predisposes to increased risk of pediatric tuberculosis disease. Genes Immun 8:691–698

    CAS  PubMed  Google Scholar 

  • Greenstein RJ (2003) Is Crohn’s disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne’s disease. Lancet Infect Dis 3:507–514

    PubMed  Google Scholar 

  • Greenstein RJ, Greenstein AJ (1995) Is there clinical, epidemiological and molecular evidence for two forms of Crohn’s disease? Mol Med Today 1:343–348

    CAS  PubMed  Google Scholar 

  • Gruenheid S, Gros P (2000) Genetic susceptibility to intracellular infections: Nramp1, macrophage function and divalent cations transport. Curr Opin Microbiol 3:43–48

    CAS  PubMed  Google Scholar 

  • Gupte M, Vallishayee R, Anantharaman D, Nagaraju B, Sreevatsa et al (1998) Comparative leprosy vaccine trial in south India. Indian J Lepr 70:369–388

    CAS  PubMed  Google Scholar 

  • Hackam DJ, Rotstein OD, Zhang W, Gruenheid S, Gros P et al (1998) Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J Exp Med 188:351–364

    CAS  PubMed  Google Scholar 

  • Haile RW, Iselius L, Fine PE, Morton NE (1985) Segregation and linkage analyses of 72 leprosy pedigrees. Hum Hered 35:43–52

    CAS  PubMed  Google Scholar 

  • Halsall JA, Osborne JE, Pringle JH, Hutchinson PE (2005) Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis. Pharmacogenet Genomics 15:349–355

    CAS  PubMed  Google Scholar 

  • Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S et al (2001) Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 357:1925–1928

    CAS  PubMed  Google Scholar 

  • Hansen GA (1875) On the etiology of leprosy. Br Foreign Med-Chir Rev 55:459–489

    Google Scholar 

  • Hatta M, van Beers SM, Madjid B, Djumadi A, de Wit MY et al (1995) Distribution and persistence of Mycobacterium leprae nasal carriage among a population in which leprosy is endemic in Indonesia. Trans R Soc Trop Med Hyg 89:381–385

    CAS  PubMed  Google Scholar 

  • Helgadottir A, Manolescu A, Helgason A, Thorleifsson G, Thorsteinsdottir U et al (2006) A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet 38:68–74

    CAS  PubMed  Google Scholar 

  • Hill AV (2006) Aspects of genetic susceptibility to human infectious diseases. Annu Rev Genet 40:469–486

    CAS  PubMed  Google Scholar 

  • Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P et al (1991) Common West African HLA antigens are associated with protection from severe malaria. Nature 352:595–600

    CAS  PubMed  Google Scholar 

  • Hiroi S, Harada H, Nishi H, Satoh M, Nagai R et al (1999) Polymorphisms in the SOD2 and HLA-DRB1 genes are associated with nonfamilial idiopathic dilated cardiomyopathy in Japanese. Biochem Biophys Res Commun 261:332–339

    CAS  PubMed  Google Scholar 

  • Holloway JW, Barton SJ, Holgate ST, Rose-Zerilli MJ, Sayers I (2008) The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility. Allergy 63:1046–1053

    CAS  PubMed  Google Scholar 

  • Horton R, Wilming L, Rand V, Lovering RC, Bruford EA et al (2004) Gene map of the extended human MHC. Nat Rev Genet 5:889–899

    CAS  PubMed  Google Scholar 

  • Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603

    CAS  PubMed  Google Scholar 

  • International Leprosy Association (2002) Report of the International Leprosy Association Technical Forum: epidemiology and control. Int J Lepr 70(suppl):1–62

    Google Scholar 

  • International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A, Sawcer S, Lander ES et al (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851–862

    CAS  PubMed  Google Scholar 

  • Jabado N, Jankowski A, Dougaparsad S, Picard V, Grinstein S et al (2000) 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 192:1237–1248

    CAS  PubMed  Google Scholar 

  • Jamieson SE, Miller EN, Black GF, Peacock CS, Cordell HJ et al (2004) Evidence for a cluster of genes on chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians. Genes Immun 5:46–57

    CAS  PubMed  Google Scholar 

  • Janeway CA, Travers P, Walport M, Shlomchik M (2001) Immunobiology. Garland Science, New York and London

    Google Scholar 

  • Jawaheer D, Li W, Graham RR, Chen W, Damle A et al (2002) Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet 71:585–594

    CAS  PubMed  Google Scholar 

  • Jeyanathan M, Boutros-Tadros O, Radhi J, Semret M, Bitton A et al (2007) Visualization of Mycobacterium avium in Crohn’s tissue by oil-immersion microscopy. Microbes Infect 9:1567–1573

    CAS  PubMed  Google Scholar 

  • Johnson CM, Lyle EA, Omueti KO, Stepensky VA, Yegin O et al (2007) Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J Immunol 178:7520–7524

    CAS  PubMed  Google Scholar 

  • Jones L, Moszer I, Cole ST (2001) Leproma: a Mycobacterium leprae genome browser. Lepr Rev 72:470–477

    CAS  PubMed  Google Scholar 

  • Kabesch M, Peters W, Carr D, Leupold W, Weiland SK et al (2003) Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol 111:813–817

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Kirchheimer WF, Storrs EE (1971) Attempts to establish the armadillo (Dasypus novemcinctus Linn.) as a model for the study of leprosy. I. Report of lepromatoid leprosy in an experimentally infected armadillo. Int J Lepr Other Mycobact Dis 39:693–702

    CAS  PubMed  Google Scholar 

  • Klatser PR, van Beers S, Madjid B, Day R, de Wit MY (1993) Detection of Mycobacterium leprae nasal carriers in populations for which leprosy is endemic. J Clin Microbiol 31:2947–2951

    CAS  PubMed  Google Scholar 

  • Klein J, Sato A (2000a) The HLA system. First of two parts. N Engl J Med 343:702–709

    CAS  PubMed  Google Scholar 

  • Klein J, Sato A (2000b) The HLA system. Second of two parts. N Engl J Med 343:782–786

    CAS  PubMed  Google Scholar 

  • Knight JC, Kwiatkowski D (1999) Inherited variability of tumor necrosis factor production and susceptibility to infectious disease. Proc Assoc Am Physicians 111:290–298

    CAS  PubMed  Google Scholar 

  • Knight JC, Keating BJ, Kwiatkowski DP (2004) Allele-specific repression of lymphotoxin-[alpha] by activated B cell factor-1. Nat Genet 36:394–399

    CAS  PubMed  Google Scholar 

  • Kocak M, Balci M, Pence B, Kundakci N (2002) Associations between human leukocyte antigens and leprosy in the Turkish population. Clin Exp Dermatol 27:235–239

    CAS  PubMed  Google Scholar 

  • Kotb M, Norrby-Teglund A, McGeer A, El-Sherbini H, Dorak MT et al (2002) An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nat Med 8:1398–1404

    CAS  PubMed  Google Scholar 

  • Krutzik SR, Ochoa MT, Sieling PA, Uematsu S, Ng YW et al (2003) Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 9:525–532

    CAS  PubMed  Google Scholar 

  • Krutzik SR, Tan B, Li H, Ochoa MT, Liu PT et al (2005) TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat Med 11:653–660

    CAS  PubMed  Google Scholar 

  • Kulkarni S, Martin MP, Carrington M (2008) The Yin and Yang of HLA and KIR in human disease. Semin Immunol 20:343–352

    CAS  PubMed  Google Scholar 

  • Lang HL, Jacobsen H, Ikemizu S, Andersson C, Harlos K et al (2002) A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 3:940–943

    CAS  PubMed  Google Scholar 

  • Lazaro FP, Werneck RI, Mackert CC, Cobat A, Prevedello FC et al (2010) A major gene controls leprosy susceptibility in a hyperendemic isolated population from north of Brazil. J Infect Dis 201:1598–1605

    PubMed  Google Scholar 

  • Lincoln MR, Montpetit A, Cader MZ, Saarela J, Dyment DA et al (2005) A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet 37:1108–1112

    CAS  PubMed  Google Scholar 

  • Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G et al (2000) Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 342:1560–1567

    CAS  PubMed  Google Scholar 

  • MacDonald KS, Fowke KR, Kimani J, Dunand VA, Nagelkerke NJ et al (2000) Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 infection. J Infect Dis 181:1581–1589

    CAS  PubMed  Google Scholar 

  • Malhotra D, Darvishi K, Lohra M, Kumar H, Grover C et al (2005a) Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population. Eur J Hum Genet 14:438–442

    Google Scholar 

  • Malhotra D, Relhan V, Reddy BS, Bamezai R (2005b) TLR2 Arg677Trp polymorphism in leprosy: revisited. Hum Genet 116:413–415

    CAS  PubMed  Google Scholar 

  • Malo D, Vogan K, Vidal S, Hu J, Cellier M et al (1994) Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites. Genomics 23:51–61

    CAS  PubMed  Google Scholar 

  • McInturff JE, Modlin RL, Kim J (2005) The role of toll-like receptors in the pathogenesis and treatment of dermatological disease. J Invest Dermatol 125:1–8

    CAS  PubMed  Google Scholar 

  • Mehra NK, Singh P, Sood P, Kaur G (2010) MHC and non-MHC genes in tuberculosis and leprosy. In: Mehra NK (ed) The HLA complex in biology and medicine: a resource book. Jaypee Bros. Medical Publishers, New Delhi, pp 386–405

    Google Scholar 

  • Meisner SJ, Mucklow S, Warner G, Sow SO, Lienhardt C et al (2001) Association of NRAMP1 polymorphism with leprosy type but not susceptibility to leprosy per se in west Africans. Am J Trop Med Hyg 65:733–735

    CAS  PubMed  Google Scholar 

  • Meyer CG, May J, Stark K (1998) Human leukocyte antigens in tuberculosis and leprosy. Trends Microbiol 6:148–154

    CAS  PubMed  Google Scholar 

  • Migita O, Noguchi E, Koga M, Jian Z, Shibasaki M et al (2005) Haplotype analysis of a 100 kb region spanning TNF-LTA identifies a polymorphism in the LTA promoter region that is associated with atopic asthma susceptibility in Japan. Clin Exp Allergy 35:790–796

    CAS  PubMed  Google Scholar 

  • Miller EN, Jamieson SE, Joberty C, Fakiola M, Hudson D et al (2004) Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun 5:63–67

    CAS  PubMed  Google Scholar 

  • Mira MT (2006) Genetic host resistance and susceptibility to leprosy. Microbes Infect 8:1124–1131

    CAS  PubMed  Google Scholar 

  • Mira MT, Alcais A, Van Thuc N, Thai VH, Huong NT et al (2003) Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet 33:412–415

    CAS  PubMed  Google Scholar 

  • Mira MT, Alcais A, Van Thuc N, Moraes MO, Di Flumeri C et al (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427:636–640

    CAS  PubMed  Google Scholar 

  • Misch EA, Hawn TR (2008) Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci (Lond) 114:347–360

    Google Scholar 

  • Misch EA, Macdonald M, Ranjit C, Sapkota BR, Wells RD et al (2008) Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl Trop Dis 2:e231

    PubMed  Google Scholar 

  • Mishina D, Katsel P, Brown ST, Gilberts EC, Greenstein RJ (1996) On the etiology of Crohn disease. Proc Natl Acad Sci USA 93:9816–9820

    CAS  PubMed  Google Scholar 

  • Moegling A (1935) Die Epidemiologie der Lûbecker Säuglingstuberkulose. Arbeiten ad Reichsges-Amt 69:1–24

    Google Scholar 

  • Moffatt MF, Schou C, Faux JA, Abecasis GR, James A et al (2001) Association between quantitative traits underlying asthma and the HLA-DRB1 locus in a family-based population sample. Eur J Hum Genet 9:341–346

    CAS  PubMed  Google Scholar 

  • Mohamed Ali P, Ramanujam K (1966) Leprosy in twins. Int J Lepr 34:405–407

    Google Scholar 

  • Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF et al (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450:887–892

    CAS  PubMed  Google Scholar 

  • Nishi H, Koga Y, Koyanagi T, Harada H, Imaizumi T et al (1995) DNA typing of HLA class II genes in Japanese patients with dilated cardiomyopathy. J Mol Cell Cardiol 27:2385–2392

    CAS  PubMed  Google Scholar 

  • Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606

    CAS  PubMed  Google Scholar 

  • Oksenberg JR, Barcellos LF, Cree BA, Baranzini SE, Bugawan TL et al (2004) Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 74:160–167

    CAS  PubMed  Google Scholar 

  • Oliveira RB, Ochoa MT, Sieling PA, Rea TH, Rambukkana A et al (2003) Expression of Toll-like receptor 2 on human Schwann cells: a mechanism of nerve damage in leprosy. Infect Immun 71:1427–1433

    CAS  PubMed  Google Scholar 

  • Orlova M, Schurr E (2010) Genetic architecture of mycobacterial diseases. In: Mehra NK (ed) The HLA complex in biology and medicine: a resource book. Jaypee Bros. Medical Publishers, New Delhi, pp 365–385

    Google Scholar 

  • Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R et al (2002) Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32:650–654

    CAS  PubMed  Google Scholar 

  • Park BS, Park JS, Lee DY, Youn JI, Kim IG (1999) Vitamin D receptor polymorphism is associated with psoriasis. J Invest Dermatol 112:113–116

    CAS  PubMed  Google Scholar 

  • Poon AH, Laprise C, Lemire M, Montpetit A, Sinnett D et al (2004) Association of vitamin D receptor genetic variants with susceptibility to asthma and atopy. Am J Respir Crit Care Med 170:967–973

    PubMed  Google Scholar 

  • PROCARDIS Consortium (2004) A trio family study showing association of the lymphotoxin-alpha N26 (804A) allele with coronary artery disease. Eur J Hum Genet 12:770–774

    Google Scholar 

  • Raby BA, Lazarus R, Silverman EK, Lake S, Lange C et al (2004) Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med 170:1057–1065

    PubMed  Google Scholar 

  • Rahman P, Bartlett S, Siannis F, Pellett FJ, Farewell VT et al (2003) CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet 73:677–681

    CAS  PubMed  Google Scholar 

  • Reis AF, Hauache OM, Velho G (2005) Vitamin D endocrine system and the genetic susceptibility to diabetes, obesity and vascular disease. A review of evidence. Diabetes Metab 31:318–325

    CAS  PubMed  Google Scholar 

  • Roach DR, Briscoe H, Saunders B, France MP, Riminton S et al (2001) Secreted lymphotoxin-{{alpha}} is essential for the control of an intracellular bacterial infection. J Exp Med 193:239–246

    CAS  PubMed  Google Scholar 

  • Roach D, Briscoe H, Saunders B, Britton W (2005) Independent protective effects for tumor necrosis factor and lymphotoxin alpha in the host response to Listeria monocytogenes infection. Infect Immun 73:4787–4792

    CAS  PubMed  Google Scholar 

  • Saadi A, Gao G, Li H, Wei C, Gong Y et al (2009) Association study between vitamin D receptor gene polymorphisms and asthma in the Chinese Han population: a case-control study. BMC Med Genet 10:71

    PubMed  Google Scholar 

  • Saeki H, Asano N, Tsunemi Y, Takekoshi T, Kishimoto M et al (2002) Polymorphisms of vitamin D receptor gene in Japanese patients with psoriasis vulgaris. J Dermatol Sci 30:167–171

    CAS  PubMed  Google Scholar 

  • Schurr E, Gros P (2009) A common genetic fingerprint in leprosy and Crohn’s disease? N Engl J Med 361:2666–2668

    CAS  PubMed  Google Scholar 

  • Scollard DM, Joyce MP, Gillis TP (2006) Development of leprosy and type 1 leprosy reactions after treatment with infliximab: a report of 2 cases. Clin Infect Dis 43:e19–e22

    CAS  PubMed  Google Scholar 

  • Shankarkumar U (2004) HLA associations in leprosy patients from Mumbai, India. Lepr Rev 75:79–85

    CAS  PubMed  Google Scholar 

  • Sharma S, Sharma A, Kumar S, Sharma SK, Ghosh B (2006) Association of TNF haplotypes with asthma, serum IgE levels, and correlation with serum TNF-alpha levels. Am J Respir Cell Mol Biol 35:488–495

    CAS  PubMed  Google Scholar 

  • Shaw MA, Donaldson IJ, Collins A, Peacock CS, Lins-Lainson Z et al (2001) Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes. Genes Immun 2:196–204

    CAS  PubMed  Google Scholar 

  • Shaw MH, Reimer T, Kim YG, Nunez G (2008) NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Curr Opin Immunol 20:377–382

    CAS  PubMed  Google Scholar 

  • Shepard CC (1960) The experimental disease that follows the injection of human leprosy bacilli into footpads of mice. J Exp Med 112:445–454

    CAS  PubMed  Google Scholar 

  • Shields ED, Russell DA, Pericak-Vance MA (1987) Genetic epidemiology of the susceptibility to leprosy. J Clin Invest 79:1139–1143

    CAS  PubMed  Google Scholar 

  • Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S et al (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302–305

    CAS  PubMed  Google Scholar 

  • Shin HD, Yang SW, Kim DH, Park Y (2008) Independent association of tumor necrosis factor polymorphism with type 1 diabetes susceptibility. Ann NY Acad Sci 1150:76–85

    CAS  PubMed  Google Scholar 

  • Siddiqui MR, Meisner S, Tosh K, Balakrishnan K, Ghei S et al (2001) A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 27:439–441

    CAS  PubMed  Google Scholar 

  • Smith DG (1979) The genetic hypothesis for susceptibility to lepromatous leprosy. Hum Genet 50:163–177

    CAS  PubMed  Google Scholar 

  • Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y et al (2005) Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci USA 102:18676–18681

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Thursz M, Yallop R, Goldin R, Trepo C, Thomas HC (1999) Influence of MHC class II genotype on outcome of infection with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research. Lancet 354:2119–2124

    CAS  PubMed  Google Scholar 

  • Tobin DM, Vary JC Jr, Ray JP, Walsh GS, Dunstan SJ et al (2010) The lta4 h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140:717–730

    CAS  PubMed  Google Scholar 

  • Via M, De Giacomo A, Corvol H, Eng C, Seibold MA et al (2010) The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos. Clin Exp Allergy 40:582–589

    CAS  PubMed  Google Scholar 

  • Vidal SM, Pinner E, Lepage P, Gauthier S, Gros P (1996) Natural resistance to intracellular infections: Nramp1 encodes a membrane phosphoglycoprotein absent in macrophages from susceptible (Nramp1 D169) mouse strains. J Immunol 157:3559–3568

    CAS  PubMed  Google Scholar 

  • Vyakarnam A, Sidebottom D, Murad S, Underhill JA, Easterbrook PJ et al (2004) Possession of human leucocyte antigen DQ6 alleles and the rate of CD4 T-cell decline in human immunodeficiency virus-1 infection. Immunology 112:136–142

    CAS  PubMed  Google Scholar 

  • Wagener DK, Schauf V, Nelson KE, Scollard D, Brown A et al (1988) Segregation analysis of leprosy in families of northern Thailand. Genet Epidemiol 5:95–105

    CAS  PubMed  Google Scholar 

  • Wang LM, Kimura A, Satoh M, Mineshita S (1999) HLA linked with leprosy in southern China: HLA-linked resistance alleles to leprosy. Int J Lepr Other Mycobact Dis 67:403–408

    CAS  PubMed  Google Scholar 

  • Weidinger S, Klopp N, Rummler L, Wagenpfeil S, Baurecht HJ et al (2005) Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults. Clin Exp Allergy 35:866–872

    CAS  PubMed  Google Scholar 

  • Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

    Google Scholar 

  • Wheeler E, Miller EN, Peacock CS, Donaldson IJ, Shaw MA et al (2006) Genome-wide scan for loci influencing quantitative immune response traits in the Belem family study: comparison of methods and summary of results. Ann Hum Genet 70:78–97

    CAS  PubMed  Google Scholar 

  • WHO (2008) Global leprosy situation, beginning of 2008. Wkly Epidemiol Rec 83:293–300

    Google Scholar 

  • Wong SH, Hill AV, Vannberg FO (2010) Genomewide association study of leprosy. N Engl J Med 362:1446–1447 (author reply 1447–1448)

    CAS  PubMed  Google Scholar 

  • Yang SK, Lee SG, Cho YK, Lim J, Lee I et al (2006) Association of TNF-alpha/LTA polymorphisms with Crohn’s disease in Koreans. Cytokine 35:13–20

    PubMed  Google Scholar 

  • Yee LJ, Thursz MR (2004) Genetic diversity in the major histocompatibility complex and the immune response to infectious diseases. In: Bellamy R (ed) Susceptibility to infectious diseases: the importance of host genetics (advances in molecular and cellular microbiology). Cambridge University Press, Cambridge

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zhang FR, Huang W, Chen SM, Sun LD, Liu H et al (2009) Genomewide association study of leprosy. N Engl J Med 361:2609–2618

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

A. Alcaïs was supported the Agence Nationale de la Recherche (ANR) of the Ministere Francais de l’Education Nationale de la Recherche et de la Technologie. A. Grant was supported in part by the Fondation pour la Recherche Médicale (FRM). Work in the laboratories of the authors was supported by grants from the Canadian Institutes of Health Research and MAGRALEPRE from the l’Ordre de Malte. E. Schurr is a Chercheur National du Fonds de la Recherche en Santé du Québec and an International Research Scholar of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Research Institute of the McGill University Health Centre, McGill Centre for the Study of Host Resistance, Department of Medicine, McGill University, Montreal, QC, Canada

    Andrea Alter & Erwin Schurr

  2. Research Institute of the McGill University Health Centre, McGill Centre for the Study of Host Resistance, Department of Human Genetics, McGill University, Montreal, QC, Canada

    Andrea Alter & Erwin Schurr

  3. Laboratoire de Génétique des Maladies Infectieuses, Institut National de la Santé et de la Recherche Médicale, U550, 75015, Paris, France

    Audrey Grant, Laurent Abel & Alexandre Alcaïs

  4. Faculté Médicine Necker, Université Paris René Descartes, 75015, Paris, France

    Audrey Grant, Laurent Abel & Alexandre Alcaïs

  5. St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 11065, USA

    Laurent Abel & Alexandre Alcaïs

  6. Montreal General Hospital Research Institute, 1650 Cedar Avenue, Room L11-521, Montreal, QC, H3G 1A4, Canada

    Erwin Schurr

Authors
  1. Andrea Alter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Audrey Grant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurent Abel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandre Alcaïs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erwin Schurr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erwin Schurr.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alter, A., Grant, A., Abel, L. et al. Leprosy as a genetic disease. Mamm Genome 22, 19–31 (2011). https://doi.org/10.1007/s00335-010-9287-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-010-9287-1

Keywords

Search

Navigation