Genetics of Susceptibility to Leprosy


Leprosy is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in humans. Leprosy is also known as Hansen's disease after GA Hansen who discovered it in 1873. The infection is curable but not preventable, and remains a major global health problem, especially in the developing world. Complex segregation analysis study suggests an oligogenic model of leprosy susceptibility stating that the patients carry susceptible allele's loci. The infection in humans is influenced by genetic variation (SNPs) in the associated genes, that is, genes that contribute to the innate immune recognition of mycobacteria. Recognition of mycobacteria by the adaptive immune system, involves products of human leucocyte antigen/major histocompatibility complex genes and effector responses of the immune system. Host genetics plays an important role in determining an individual's risk of developing clinical leprosy. Host susceptibility genetic susceptibility to leprosy is complicated by the genetics of Mycobacterium leprae, interaction between gene and environmental factors, gene–gene interactions and lastly ethnicity. The host immune response influences the course of infection (host–pathogen relationship) and provides an exciting challenge to understand the genetics of disease susceptibility and immunopathogenesis of leprosy.

Key Concepts:

  • Leprosy was identified as the first devastating disease of humans causing disability by the bacterial pathogen Mycobacterium leprae.

  • Genomic data might be useful in the development of drugs and vaccines against leprosy. Despite widespread implementation of effective multidrug therapy, leprosy has not been eliminated.

  • Complex segregation analyses have suggested a predominant genetic rather than environmental model for associations in leprosy.

  • Recognition of mycobacteria by the adaptive immune system involving products of human leucocyte antigen/major histocompatibility complex genes and effector responses of the immune system (genes affecting cytokines, chemokines and immunomodulators).

  • Direct involvement of SNPs in different genes in host genetic susceptibility to leprosy.

  • Single nucleotide polymorphisms (SNPs) represent an important class of genetic variation, and SNPs within and outside coding sequences are under intense examination for possible associations or mechanistic links to disease.

  • Haplotypes are combinations of two or more polymorphisms (SNPs in this case) within a single chromosome in an individual, which can be used as genetic markers.

  • The availability of the M. leprae genome sequence and improved methodologies for molecular level diagnosis of the genetic basis of drug resistance in mycobacteria led to the development of molecular methods for drug‐susceptibility testing (DST).

Keywords: leprosy; Mycobacterium leprae; host genetics; susceptibility genes; SNPs

Figure 1.

Epidemiology of leprosy: world scenario.



Abel L, Vu DL, Oberti J et al. (1995) Complex segregation analysis of leprosy in southern Vietnam. Genetic Epidemiology 12: 63–82.

Ali S, Srivastava AK, Chopra R et al. (2013) IL12B SNPs and copy number variation in IL23R gene associated with susceptibility to leprosy. Journal of Medical Genetics 50(1): 34–42.

Alter A, Alcaïs A, Abel L and Schurr E (2008) Leprosy as a genetic model for susceptibility to common infectious diseases. Human Genetics 123: 227–235.

Barrett JC, Hansoul S, Nicolae DL et al. (2008) Genome‐wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genetics 40: 955–962.

Bhatti P, Church DM, Rutter JL, Struewing JP and Sigurdson AJ (2006) Candidate single nucleotide polymorphism selection using publicly available tools: a guide for epidemiologists. American Journal of Epidemiology 164(8): 794–804.

Browne SG (1965) The age of onset of leprosy. Indian Journal of Leprosy 33: 267–272.

Cardoso CC, Pereira AC, de Sales Marques C and Moraes MO (2011) Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome. Future Microbiology 6: 533–549.

Cargill M, Altshuler D, Ireland J et al. (1999) Characterization of single‐nucleotide polymorphisms in coding regions of human genes. Nature Genetics 22: 231–238.

Carlson CS, Eberle MA, Kruglyak L and Nickerson DA (2004) Mapping complex disease loci in whole genome association studies. Nature 429: 446–452.

Cole ST, Eiglmeier K, Parkhill J et al. (2001) Massive gene decay in the leprosy bacillus. Nature 409(6823): 1007–1011.

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

Curtiss R 3rd, Blower S, Cooper K et al. (2001) Leprosy research in the post‐genome era. Leprosy Review 72(1): 8–22.

Erdin S, Ward RM, Venner E and Lichtarge O (2010) Evolutionary trace annotation of protein function in the structural proteome. Journal of Molecular Biology 396(5): 1451–1473.

Feitosa MF, Borecki I, Krieger H, Beiguelman B and Rao DC (1995) The genetic epidemiology of leprosy in a Brazilian population. American Journal of Human Genetics 56: 1179–1185.

Gómez-Valero L, Rocha EP, Latorre A and Silva FJ (2007) Reconstructing the ancestor of Mycobacterium leprae: the dynamics of gene loss and genome reduction. Genome Research 17(8): 1178–1185.

Goulart IMB and Goulart LR (2008) Leprosy: diagnostic and control challenges for a worldwide disease. Archives of Dermatological Research 300(6): 269–290.

Gulia A, Fried I and Massone C (2010) New insights in the pathogenesis and genetics of leprosy. F1000 Medicine Reports 2: 30.

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

Halushka M, Fan J, Bentley K et al. (1999) Patterns of single‐nucleotide polymorphisms in candidate genes for blood‐pressure homeostasis. Nature Genetics 22: 239–247.

Hatta M, van Beers SM, Madjid B et al. (1995) Distribution and persistence of Mycobacterium leprae nasal carriage among a population in which leprosy is endemic in Indonesia. Transactions of the Royal Society of Tropical Medicine and Hygiene 89: 381–385.

Hill AV (2006) Aspects of genetic susceptibility to human infectious diseases. Annual Review of Genetics 40: 469–486.

Hugot JP, Laurent‐Puig P, Gower‐Rousseau C et al. (1996) Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 379: 821–823.

Hugot J‐P, Chamaillard M, Zouali H et al. (2001) Association of NOD2 leucine‐rich repeat variants with susceptibility to Crohn's disease. Nature 411: 599–603.

Jacobson RR and Krahenbuhl JL (1999) Leprosy. Lancet 353: 655–660.

John AS, Rao PS, Kundu R and Raju MS (2005) Leprosy among adolescents in Kolkata, India. Indian Journal of Leprosy 77: 247–253.

Lalande JD and Behr MA (2010) Mycobacteria in Crohn's disease: how innate immune deficiency may result in chronic inflammation. Expert Review of Clinical Immunology 6: 633–641.

Liu H, Irwanto A, Tian H et al. (2012) Identification of IL18RAP/IL18R1 and IL12B as leprosy risk genes demonstrates shared pathogenesis between inflammation and infectious diseases. American Journal of Human Genetics 91(5): 935–941.

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

Miller EN, Jamieson SE, Joberty C et al. (2004) Genome‐wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes and Immunity 5: 63–67.

Ng PC and Henikoff S (2006) Predicting the effects of amino‐acid substitutions on protein function. Annual Review of Genomics and Human Genetics 7: 61–80.

NLEP (2011) ‘Progress Report for the year 2010‐11 ending on 31st March 2011’, Central Leprosy Division, Directorate General of Health Services, New Delhi.

Pinheiro RO, de Souza Salles J, Sarno EN and Sampaio EP (2012) Mycobacterium leprae‐host‐cell interactions and genetic determinants in leprosy: an overview. Future Microbiology 6(2): 217–230.

Prokunina L and Alarcon‐Riquelme ME (2004) Regulatory SNPs in complex diseases: their identification and functional validation. Expert Reviews in Molecular Medicine 6(10): 1–15.

Prokunina L, Castillejo‐Lopez C, Oberg F et al. (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nature Genetics 32: 666–669.

Ranque B, Alcais A, Thuc NV et al. (2005) A recessive major genecontrols the Mitsuda reaction in a region endemic for leprosy. Journal of Infectious Diseases 192: 1475–1482.

Rignall TR, Baker JO, McCarter SL et al. (2002) Effect of single‐active‐site cleft mutation on product specificity in a thermostable bacterial cellulase. Applied Biochemistry and Biotechnology 98–100: 383–394.

Roy S, Frodsham A, Saha B et al. (1999) Association of vitamin D receptor genotype with leprosy type. Journal of Infectious Diseases 179: 187–191.

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

Sundaramurthi JC, Ramanandan P, Brindha S et al. (2011) DDTRP: database of drug targets for resistant pathogens. Bioinformation 7: 98–101.

Todd JA (2010) D'oh! Genes and environment cause Crohn's disease. Cell 141: 1114–1116.

Ung MU, Lu B and McCammon JA (2006) E230Q Mutation of the catalytic subunit of cAMP‐dependent protein kinase affects local structure and the binding of peptide inhibitor. Biopolymers 81: 428–439.

Van Brakel WH and Officer A (2008) Approaches and tools for measuring disability in low and middle‐income countries. Leprosy Review 79: 50–64.

Walker SL and Lockwood DN (2007) Leprosy. Clinics in Dermatology 25: 165–172.

Wang Z and Moult J (2001) SNPs, protein structure, and disease. Human Mutation 7: 263–270.

Wong SH, Gochhait S, Malhotra D et al. (2010) Leprosy and the adaptation of human toll‐like receptor 1. PLoS Pathogens 6: e1000979.

WHO (2008) Enhanced global strategy for further reducing the disease burden due to leprosy (plan period: 2011–2015). New Delhi: World Health Organization Regional Office for South‐East Asia.

WHO – World Health Organization (2011) Leprosy update. Weekly Epidemiological Record 36: 389–400.

Yue P and Moult J (2006) Identification and analysis of deleterious human SNPs. Journal of Molecular Biology 356(5): 1263–1274.

Zhang F, Liu H, Chen S et al. (2011) Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nature Genetics 43: 1247–1251.

Zhang FR, Huang W, Chen SM et al. (2009) Genome wide association study of leprosy. New England Journal of Medicine 361: 2609–2618.

Further Reading

Bhat RM and Prakash C (2012) Leprosy: an overview of pathophysiology. Interdisciplinary Perspectives on Infectious Diseases 2012: 181089.

Britton WJ and Lockwood DN (2004) Leprosy. Lancet 363(9416): 1209–1.

Coeytaux A, Truffert A, Mueller Y, Antille C and Jackson Y (2007) Leprosy, a neurologic disease. Revue Médicale Suisse 3(110): 1178, 1180–1184.

De Vries Jan L and Perry Barbara H (1984) Leprosy case detection rates by age, sex, and polar type under leprosy control conditions. American Journal of Medical Epidemiology 121(3): 403–413.

Fitness J, Tosh K and Hil AVS (2002) Genetics of susceptibility to leprosy. Genes and Immunity 3: 441–453.

Hartzell JD, Zapor M, Peng S and Straight T (2004) Leprosy: a case series and review. Southern Medical Journal 97: 1252–1256.

Priyanka MS and Rahul MS (2008) Occular manifestations of leprosy. Indian Journal for the Practicing Doctor 4: 6.

Rodrigues LC and Lockwood DNJ (2011) Leprosy now: epidemiology, progress, challenges, and research gaps. Lancet Infectious Diseases 11: 464–470.

Williams DL and Gillis TP (2012) Drug‐resistant leprosy: monitoring and current status. Leprosy Review 83: 269–281.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Priya Doss C, George, Dev, Sreyashi, and Das, Anubrita(Sep 2013) Genetics of Susceptibility to Leprosy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025037]