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Genetics of leprosy: today and beyond

  • Vinicius M. Fava
  • Monica Dallmann-Sauer
  • Erwin SchurrEmail author
Review
  • 78 Downloads

Abstract

Leprosy is a chronic infectious disease of the skin and peripheral nerves that presents a strong link with the host genetic background. Different approaches in genetic studies have been applied to leprosy and today leprosy is among the infectious diseases with the greatest number of genetic risk variants identified. Several leprosy genes have been implicated in host immune response to pathogens and point to specific pathways that are relevant for host defense to infection. In addition, host genetic factors are also involved in the heterogeneity of leprosy clinical manifestations and in excessive inflammatory responses that occur in some leprosy patients. Finally, genetic studies in leprosy have provided strong evidence of pleiotropic effects between leprosy and other complex diseases, such as immune-mediated or neurodegenerative diseases. These findings not only impact on the field of leprosy and infectious diseases but also make leprosy a good model for the study of complex immune-mediated diseases. Here, we summarize recent genetic findings in leprosy susceptibility and discuss the overlap of the genetic control in leprosy with Parkinson’s disease and inflammatory bowel disease. Moreover, some limitations, challenges, and potential new avenues for future genetics studies of leprosy are also discussed in this review.

Notes

Compliance ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

References

  1. Abel L, Sanchez FO, Oberti J, Thuc NV, Van Hoa L, Lap VD et al (1998) Susceptibility to leprosy is linked to the human NRAMP1 gene. J Infect Dis 177(1):133–145.  https://doi.org/10.1086/513830 CrossRefPubMedGoogle Scholar
  2. Alcais A, Alter A, Antoni G, Orlova M, Nguyen VT, Singh M et al (2007) Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nat Genet 39(4):517–522.  https://doi.org/10.1038/ng2000 CrossRefPubMedGoogle Scholar
  3. Alemu Belachew W, Naafs B (2019) Position statement: LEPROSY: Diagnosis, treatment and follow-up. J Eur Acad Dermatol Venereol 33(7):1205–1213.  https://doi.org/10.1111/jdv.15569 CrossRefPubMedGoogle Scholar
  4. Alter A, de Leseleuc L, Van Thuc N, Thai VH, Huong NT, Ba NN et al (2010) Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility. Hum Genet 127(3):337–348.  https://doi.org/10.1007/s00439-009-0775-x CrossRefPubMedGoogle Scholar
  5. Alter A, Huong NT, Singh M, Orlova M, Van Thuc N, Katoch K et al (2011) Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India. J Infect Dis 203(9):1274–1281.  https://doi.org/10.1093/infdis/jir024 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Alter A, Fava VM, Huong NT, Singh M, Orlova M, Van Thuc N et al (2013) Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy. Hum Genet 132(1):107–116.  https://doi.org/10.1007/s00439-012-1227-6 CrossRefPubMedGoogle Scholar
  7. Alvarado-Arnez LE, Amaral EP, Sales-Marques C, Durães SM, Cardoso CC, Sarno EN et al (2015) Association of IL10 polymorphisms and leprosy: a meta-analysis. PLoS One 10(9):e0136282.  https://doi.org/10.1371/journal.pone.0136282 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Andiappan AK, Melchiotti R, Poh TY, Nah M, Puan KJ, Vigano E et al (2015) Genome-wide analysis of the genetic regulation of gene expression in human neutrophils. Nat Commun 6:7971.  https://doi.org/10.1038/ncomms8971 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Areeshi MY, Mandal RK, Dar SA, Jawed A, Wahid M, Lohani M et al (2017) Impact of TNF -308 G>A (rs1800629) gene polymorphism in modulation of leprosy risk: a reappraise meta-analysis of 14 case-control studies. Biosci Rep.  https://doi.org/10.1042/BSR20170806 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Avanzi C, Del-Pozo J, Benjak A, Stevenson K, Simpson VR, Busso P et al (2016) Red squirrels in the British Isles are infected with leprosy bacilli. Science 354(6313):744–747.  https://doi.org/10.1126/science.aah3783 CrossRefPubMedGoogle Scholar
  11. Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347(12):911–920.  https://doi.org/10.1056/NEJMra020100 CrossRefPubMedGoogle Scholar
  12. Barreiro LB, Quintana-Murci L (2010) From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11(1):17–30.  https://doi.org/10.1038/nrg2698 CrossRefPubMedGoogle Scholar
  13. Beilina A, Rudenko IN, Kaganovich A, Civiero L, Chau H, Kalia SK et al (2014) Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci USA 111(7):2626–2631.  https://doi.org/10.1073/pnas.1318306111 CrossRefPubMedGoogle Scholar
  14. Berrington WR, Macdonald M, Khadge S, Sapkota BR, Janer M, Hagge DA et al (2010) Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. J Infect Dis 201(9):1422–1435.  https://doi.org/10.1086/651559 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Bi W, Zhu L, Jing X, Liang Y, Tao E (2013) Rifampicin and Parkinson’s disease. Neurol Sci 34(2):137–141.  https://doi.org/10.1007/s10072-012-1156-0 CrossRefPubMedGoogle Scholar
  16. Blackwell JM, Jamieson SE, Burgner D (2009) HLA and infectious diseases. Clin Microbiol Rev 22(2):370–385.  https://doi.org/10.1128/CMR.00048-08(Table of Contents) CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bochud PY, Hawn TR, Siddiqui MR, Saunderson P, Britton S, Abraham I et al (2008) Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis 197(2):253–261.  https://doi.org/10.1086/524688 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G, Kerner G et al (2018) Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant. Sci Immunol 3(30):1.  https://doi.org/10.1126/sciimmunol.aau8714 CrossRefGoogle Scholar
  19. Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL, Sewell GW et al (2016) C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat Immunol 17(9):1046–1056.  https://doi.org/10.1038/ni.3532 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Camargo RM, Silva WLD, Medeiros P, Belone AFF, Latini ACP (2018) Polymorphisms in the TGFB1 and IL2RA genes are associated with clinical forms of leprosy in Brazilian population. Mem Inst Oswaldo Cruz 113(12):e180274.  https://doi.org/10.1590/0074-02760180274 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Cardoso CC, Pereira AC, Brito-de-Souza VN, Duraes SM, Ribeiro-Alves M, Nery JA et al (2011) TNF -308G>A single nucleotide polymorphism is associated with leprosy among Brazilians: a genetic epidemiology assessment, meta-analysis, and functional study. J Infect Dis 204(8):1256–1263.  https://doi.org/10.1093/infdis/jir521 CrossRefPubMedGoogle Scholar
  22. Chen Y, Du J, Zhang Z, Liu T, Shi Y, Ge X et al (2014) MicroRNA-346 mediates tumor necrosis factor alpha-induced downregulation of gut epithelial vitamin D receptor in inflammatory bowel diseases. Inflamm Bowel Dis 20(11):1910–1918.  https://doi.org/10.1097/MIB.0000000000000158 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Cobat A, Abel L, Alcais A, Schurr E (2014) A general efficient and flexible approach for genome-wide association analyses of imputed genotypes in family-based designs. Genet Epidemiol.  https://doi.org/10.1002/gepi.21842 CrossRefPubMedGoogle Scholar
  24. Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR et al (2001) Massive gene decay in the leprosy bacillus. Nature 409(6823):1007–1011.  https://doi.org/10.1038/35059006 CrossRefPubMedGoogle Scholar
  25. Consortium GT (2015) Human genomics The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 348(6235):648–660.  https://doi.org/10.1126/science.1262110 CrossRefGoogle Scholar
  26. Cunninghame Graham DS, Morris DL, Bhangale TR, Criswell LA, Syvanen AC, Ronnblom L et al (2011) Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet 7(10):e1002341.  https://doi.org/10.1371/journal.pgen.1002341 CrossRefPubMedPubMedCentralGoogle Scholar
  27. da Silva MB, Portela JM, Li W, Jackson M, Gonzalez-Juarrero M, Hidalgo AS et al (2018) Evidence of zoonotic leprosy in Para, Brazilian Amazon, and risks associated with human contact or consumption of armadillos. PLoS Negl Trop Dis 12(6):e0006532.  https://doi.org/10.1371/journal.pntd.0006532 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Das S, Ghosal S, Sen R, Chakrabarti J (2014) lnCeDB: database of human long noncoding RNA acting as competing endogenous RNA. PLoS One 9(6):e98965.  https://doi.org/10.1371/journal.pone.0098965 CrossRefPubMedPubMedCentralGoogle Scholar
  29. de Leseleuc L, Orlova M, Cobat A, Girard M, Huong NT, Ba NN et al (2013) PARK2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages. PLoS Negl Trop Dis 7(1):e2015.  https://doi.org/10.1371/journal.pntd.0002015 CrossRefPubMedPubMedCentralGoogle Scholar
  30. de Messias IJ, Santamaria J, Brenden M, Reis A, Mauff G (1993) Association of C4B deficiency (C4B*Q0) with erythema nodosum in leprosy. Clin Exp Immunol 92(2):284–287CrossRefGoogle Scholar
  31. de Messias-Reason IJ, Boldt AB, Moraes Braga AC, Von Rosen Seeling Stahlke E, Dornelles L, Pereira-Ferrari L et al (2007) The association between mannan-binding lectin gene polymorphism and clinical leprosy: new insight into an old paradigm. J Infect Dis 196(9):1379–1385.  https://doi.org/10.1086/521627 CrossRefPubMedGoogle Scholar
  32. do Sacramento WS, Mazini PS, Franceschi DA, de Melo FC, Braga MA, Sell AM et al (2012) Frequencies of MICA alleles in patients from southern Brazil with multibacillary and paucibacillary leprosy. Int J Immunogenet. 39(3):210–215.  https://doi.org/10.1111/j.1744-313X.2011.01074.x CrossRefPubMedGoogle Scholar
  33. Faber WR, Jensema AJ, Goldschmidt WF (2006) Treatment of recurrent erythema nodosum leprosum with infliximab. N Engl J Med 355(7):739.  https://doi.org/10.1056/NEJMc052955 CrossRefPubMedGoogle Scholar
  34. Fava VM, Schurr E (2016) The complexity of the host genetic contribution to the human response to Mycobacterium leprae. In: Scollard DM, Gillis TP, editors. The International Textbook of Leprosy. http://www.internationaltextbookofleprosy.org/. American Leprosy Mission
  35. Fava VM, Cobat A, Van Thuc N, Latini AC, Stefani MM, Belone AF et al (2015) Association of TNFSF8 regulatory variants with excessive inflammatory responses but not leprosy per se. J Infect Dis 211(6):968–977.  https://doi.org/10.1093/infdis/jiu566 CrossRefPubMedGoogle Scholar
  36. Fava VM, Manry J, Cobat A, Orlova M, Van Thuc N, Ba NN et al (2016) A missense LRRK2 variant is a risk factor for excessive inflammatory responses in leprosy. PLoS Negl Trop Dis 10(2):e0004412.  https://doi.org/10.1371/journal.pntd.0004412 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Fava VM, Manry J, Cobat A, Orlova M, Van Thuc N, Moraes MO et al (2017a) A genome wide association study identifies a lncRna as risk factor for pathological inflammatory responses in leprosy. PLoS Genet 13(2):e1006637.  https://doi.org/10.1371/journal.pgen.1006637 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Fava VM, Sales-Marques C, Alcais A, Moraes MO, Schurr E (2017b) Age-dependent association of TNFSF15/TNFSF8 variants and leprosy type 1 reaction. Front Immunol 8:155.  https://doi.org/10.3389/fimmu.2017.00155 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Fava VM, Xu YZ, Lettre G, Van Thuc N, Orlova M, Thai VH et al (2019) Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease. Proc Natl Acad Sci USA 116(31):15616–15624.  https://doi.org/10.1073/pnas.1901805116 CrossRefPubMedGoogle Scholar
  40. Ferreira JDS, Souza Oliveira DA, Santos JP, Ribeiro C, Baeta BA, Teixeira RC et al (2018) Ticks as potential vectors of Mycobacterium leprae: use of tick cell lines to culture the bacilli and generate transgenic strains. PLoS Negl Trop Dis 12(12):e0007001.  https://doi.org/10.1371/journal.pntd.0007001 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Fitness J, Floyd S, Warndorff DK, Sichali L, Mwaungulu L, Crampin AC et al (2004) Large-scale candidate gene study of leprosy susceptibility in the Karonga district of northern Malawi. Am J Trop Med Hyg 71(3):330–340CrossRefGoogle Scholar
  42. Gaschignard J, Quentin BV, Jais JP, Cobat A, Alcais A (2015) Implicit hypotheses are hidden power droppers in family-based association studies of secondary outcomes. Open J Stat 5(1):35–45.  https://doi.org/10.4236/ojs.2015.51005 CrossRefGoogle Scholar
  43. Gaschignard J, Grant AV, Thuc NV, Orlova M, Cobat A, Huong NT et al (2016) Pauci- and multibacillary leprosy: two distinct, genetically neglected diseases. PLoS Negl Trop Dis 10(5):e0004345.  https://doi.org/10.1371/journal.pntd.0004345 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Grant AV, Alter A, Huong NT, Orlova M, Van Thuc N, Ba NN et al (2012) Crohn’s disease susceptibility genes are associated with leprosy in the Vietnamese population. J Infect Dis 206(11):1763–1767.  https://doi.org/10.1093/infdis/jis588 CrossRefPubMedGoogle Scholar
  45. Grant AV, Cobat A, Van Thuc N, Orlova M, Huong NT, Gaschignard J et al (2014) CUBN and NEBL common variants in the chromosome 10p13 linkage region are associated with multibacillary leprosy in Vietnam. Hum Genet.  https://doi.org/10.1007/s00439-014-1430-8 CrossRefPubMedGoogle Scholar
  46. Haapasalo K, Koskinen LLE, Suvilehto J, Jousilahti P, Wolin A, Suomela S et al (2018) The psoriasis risk allele HLA-C*06:02 shows evidence of association with chronic or recurrent streptococcal tonsillitis. Infect Immun 86(10):e00304–e00318.  https://doi.org/10.1128/IAI.00304-18 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Han B, Pouget JG, Slowikowski K, Stahl E, Lee CH, Diogo D et al (2016) A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases. Nat Genet 48(7):803–810.  https://doi.org/10.1038/ng.3572 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Hirata J, Hosomichi K, Sakaue S, Kanai M, Nakaoka H, Ishigaki K et al (2019) Genetic and phenotypic landscape of the major histocompatibilty complex region in the Japanese population. Nat Genet 51(3):470–480.  https://doi.org/10.1038/s41588-018-0336-0 CrossRefPubMedGoogle Scholar
  49. Hsieh NK, Chu CC, Lee NS, Lee HL, Lin M (2010) Association of HLA-DRB1*0405 with resistance to multibacillary leprosy in Taiwanese. Hum Immunol 71(7):712–716.  https://doi.org/10.1016/j.humimm.2010.03.007 CrossRefPubMedGoogle Scholar
  50. Hui KY, Fernandez-Hernandez H, Hu J, Schaffner A, Pankratz N, Hsu NY et al (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci Transl Med 10(423):1.  https://doi.org/10.1126/scitranslmed.aai7795 CrossRefGoogle Scholar
  51. Imhann F, Vich Vila A, Bonder MJ, Fu J, Gevers D, Visschedijk MC et al (2018) Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 67(1):108–119.  https://doi.org/10.1136/gutjnl-2016-312135 CrossRefPubMedGoogle Scholar
  52. International HIVCS, Pereyra F, Jia X, McLaren PJ, Telenti A, deBakker PI et al (2010) The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science. 330(6010):1551–1557.  https://doi.org/10.1126/science.1195271 CrossRefGoogle Scholar
  53. Jaillon S, Berthenet K, Garlanda C (2019) Sexual dimorphism in innate immunity. Clin Rev Allergy Immunol 56(3):308–321.  https://doi.org/10.1007/s12016-017-8648-x CrossRefPubMedGoogle Scholar
  54. Jarduli LR, Sell AM, Reis PG, Sippert EA, Ayo CM, Mazini PS et al (2013) Role of HLA, KIR, MICA, and cytokines genes in leprosy. Biomed Res Int 2013:989837.  https://doi.org/10.1155/2013/989837 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491(7422):119–124.  https://doi.org/10.1038/nature11582 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Kalia LV, Lang AE, Hazrati LN, Fujioka S, Wszolek ZK, Dickson DW et al (2015) Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol 72(1):100–105.  https://doi.org/10.1001/jamaneurol.2014.2704 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Kerner G, Ramirez-Alejo N, Seeleuthner Y, Yang R, Ogishi M, Cobat A et al (2019) Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry. Proc Natl Acad Sci USA 116(21):10430–10434.  https://doi.org/10.1073/pnas.1903561116 CrossRefPubMedGoogle Scholar
  58. Kim EW, Teles RMB, Haile S, Liu PT, Modlin RL (2018) Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae. PLoS Negl Trop Dis 12(7):e0006608.  https://doi.org/10.1371/journal.pntd.0006608 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Krause-Kyora B, Nutsua M, Boehme L, Pierini F, Pedersen DD, Kornell SC et al (2018) Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans. Na Commun 9(1):1569.  https://doi.org/10.1038/s41467-018-03857-x CrossRefGoogle Scholar
  60. Lahiri A, Hedl M, Yan J, Abraham C (2017) Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. Nature Commun 8:15614.  https://doi.org/10.1038/ncomms15614 CrossRefGoogle Scholar
  61. Liu H, Irwanto A, Tian H, Fu X, Yu Y, Yu G et al (2012) Identification of IL18RAP/IL18R1 and IL12B as leprosy risk genes demonstrates shared pathogenesis between inflammation and infectious diseases. Am J Hum Genet 91(5):935–941.  https://doi.org/10.1016/j.ajhg.2012.09.010 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Liu H, Bao F, Irwanto A, Fu X, Lu N, Yu G et al (2013) An association study of TOLL and CARD with leprosy susceptibility in Chinese population. Hum Mol Genet 22(21):4430–4437.  https://doi.org/10.1093/hmg/ddt286 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Liu H, Irwanto A, Fu X, Yu G, Yu Y, Sun Y et al (2015a) Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy. Nat Genet.  https://doi.org/10.1038/ng.3212 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A et al (2015b) Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 47(9):979–986.  https://doi.org/10.1038/ng.3359 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Liu H, Wang Z, Li Y, Yu G, Fu X, Wang C et al (2017) Genome-wide analysis of protein-coding variants in leprosy. J Invest Dermatol.  https://doi.org/10.1016/j.jid.2017.08.004 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Manry J, Nedelec Y, Fava VM, Cobat A, Orlova M, Thuc NV et al (2017) Deciphering the genetic control of gene expression following Mycobacterium leprae antigen stimulation. PLoS Genet 13(8):e1006952.  https://doi.org/10.1371/journal.pgen.1006952 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Marques Cde S, Brito-de-Souza VN, Guerreiro LT, Martins JH, Amaral EP, Cardoso CC et al (2013) Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection. J Infect Dis 208(1):120–129.  https://doi.org/10.1093/infdis/jit133 CrossRefPubMedGoogle Scholar
  68. Matheoud D, Sugiura A, Bellemare-Pelletier A, Laplante A, Rondeau C, Chemali M et al (2016) Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166(2):314–327.  https://doi.org/10.1016/j.cell.2016.05.039 CrossRefPubMedGoogle Scholar
  69. Matheoud D, Cannon T, Voisin A, Penttinen AM, Ramet L, Fahmy AM et al (2019) Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1(−/−) mice. Nature.  https://doi.org/10.1038/s41586-019-1405-y CrossRefPubMedGoogle Scholar
  70. Matzaraki V, Kumar V, Wijmenga C, Zhernakova A (2017) The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol 18(1):76.  https://doi.org/10.1186/s13059-017-1207-1 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Misch EA, Macdonald M, Ranjit C, Sapkota BR, Wells RD, Siddiqui MR et al (2008) Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl Trop Dis 2(5):e231.  https://doi.org/10.1371/journal.pntd.0000231 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Neumann Ada S, Dias Fde A, Ferreira Jda S, Fontes AN, Rosa PS, Macedo RE et al (2016) Experimental Infection of Rhodnius prolixus (Hemiptera, Triatominae) with Mycobacterium leprae indicates potential for leprosy transmission. PLoS One 11(5):e0156037.  https://doi.org/10.1371/journal.pone.0156037 CrossRefPubMedGoogle Scholar
  73. Nishimura T, Tamizu E, Uno S, Uwamino Y, Fujiwara H, Nishio K et al (2017) hsa-miR-346 is a potential serum biomarker of Mycobacterium avium complex pulmonary disease activity. J Infect Chemother 23(10):703–708.  https://doi.org/10.1016/j.jiac.2017.07.015 CrossRefPubMedGoogle Scholar
  74. Ridley DS, Jopling WH (1966) Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 34(3):255–273PubMedGoogle Scholar
  75. Sales-Marques C, Salomao H, Fava VM, Alvarado-Arnez LE, Amaral EP, Cardoso CC et al (2014) NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians. Hum Genet 133(12):1525–1532.  https://doi.org/10.1007/s00439-014-1502-9 CrossRefPubMedGoogle Scholar
  76. Sales-Marques C, Cardoso CC, Alvarado-Arnez LE, Illaramendi X, Sales AM, Hacker MA et al (2017) Genetic polymorphisms of the IL6 and NOD2 genes are risk factors for inflammatory reactions in leprosy. PLoS Negl Trop Dis 11(7):e0005754.  https://doi.org/10.1371/journal.pntd.0005754 CrossRefPubMedPubMedCentralGoogle Scholar
  77. Santos AR, Suffys PN, Vanderborght PR, Moraes MO, Vieira LM, Cabello PH et al (2002) Role of tumor necrosis factor-alpha and interleukin-10 promoter gene polymorphisms in leprosy. J Infect Dis 186(11):1687–1691.  https://doi.org/10.1086/345366 CrossRefPubMedGoogle Scholar
  78. Savica R, Grossardt BR, Bower JH, Ahlskog JE, Rocca WA (2016) Time trends in the incidence of Parkinson disease. JAMA Neurol 73(8):981–989.  https://doi.org/10.1001/jamaneurol.2016.0947 CrossRefPubMedPubMedCentralGoogle Scholar
  79. Schuenemann VJ, Avanzi C, Krause-Kyora B, Seitz A, Herbig A, Inskip S et al (2018) Ancient genomes reveal a high diversity of Mycobacterium leprae in medieval Europe. PLoS Pathog 14(5):e1006997CrossRefGoogle Scholar
  80. Schurz H, Salie M, Tromp G, Hoal EG, Kinnear CJ, Moller M (2019) The X chromosome and sex-specific effects in infectious disease susceptibility. Hum Genom 13(1):2.  https://doi.org/10.1186/s40246-018-0185-z CrossRefGoogle Scholar
  81. Semaan N, Frenzel L, Alsaleh G, Suffert G, Gottenberg JE, Sibilia J et al (2011) miR-346 controls release of TNF-alpha protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization. PLoS One 6(5):e19827.  https://doi.org/10.1371/journal.pone.0019827 CrossRefPubMedPubMedCentralGoogle Scholar
  82. Shimoda K, Tsutsui H, Aoki K, Kato K, Matsuda T, Numata A et al (2002) Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice. Blood 99(6):2094–2099.  https://doi.org/10.1182/blood.v99.6.2094 CrossRefPubMedGoogle Scholar
  83. Shu Y, Ming J, Zhang P, Wang Q, Jiao F, Tian B (2016) Parkinson-related LRRK2 mutation R1628P enables Cdk5 phosphorylation of LRRK2 and upregulates its kinase activity. PLoS One 11(3):e0149739.  https://doi.org/10.1371/journal.pone.0149739 CrossRefPubMedPubMedCentralGoogle Scholar
  84. Soares CT, Trombone APF, Fachin LRV, Rosa PS, Ghidella CC, Ramalho RF et al (2017) Differential expression of microRNAs in leprosy skin lesions. Front Immunol 8:1035.  https://doi.org/10.3389/fimmu.2017.01035 CrossRefPubMedPubMedCentralGoogle Scholar
  85. Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J et al (2017) T cells from patients with Parkinson’s disease recognize alpha-synuclein peptides. Nature 546(7660):656–661.  https://doi.org/10.1038/nature22815 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Tay Y, Kats L, Salmena L, Weiss D, Tan SM, Ala U et al (2011) Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147(2):344–357.  https://doi.org/10.1016/j.cell.2011.09.029 CrossRefPubMedPubMedCentralGoogle Scholar
  87. Teles RMB, Kelly-Scumpia KM, Sarno EN, Rea TH, Ochoa MT, Cheng G et al (2015) IL-27 suppresses antimicrobial activity in human leprosy. J Investig Dermatol 135(10):2410–2417.  https://doi.org/10.1038/jid.2015.195 CrossRefPubMedGoogle Scholar
  88. Tian C, Hromatka BS, Kiefer AK, Eriksson N, Noble SM, Tung JY et al (2017) Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nature communications. 8(1):599.  https://doi.org/10.1038/s41467-017-00257-5 CrossRefPubMedPubMedCentralGoogle Scholar
  89. Tosh K, Ravikumar M, Bell JT, Meisner S, Hill AV, Pitchappan R (2006) Variation in MICA and MICB genes and enhanced susceptibility to paucibacillary leprosy in South India. Hum Mol Genet 15(19):2880–2887.  https://doi.org/10.1093/hmg/ddl229 CrossRefPubMedGoogle Scholar
  90. Truman RW, Singh P, Sharma R, Busso P, Rougemont J, Paniz-Mondolfi A et al (2011) Probable zoonotic leprosy in the southern United States. N Engl J Med 364(17):1626–1633.  https://doi.org/10.1056/NEJMoa1010536 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Vanderborght PR, Pacheco AG, Moraes ME, Antoni G, Romero M, Verville A et al (2007) HLA-DRB1*04 and DRB1*10 are associated with resistance and susceptibility, respectively, in Brazilian and Vietnamese leprosy patients. Genes Immun 8(4):320–324.  https://doi.org/10.1038/sj.gene.6364390 CrossRefPubMedGoogle Scholar
  92. Wang Z, Sun Y, Fu X, Yu G, Wang C, Bao F et al (2016) A large-scale genome-wide association and meta-analysis identified four novel susceptibility loci for leprosy. Nat Commun 7:13760.  https://doi.org/10.1038/ncomms13760 CrossRefPubMedPubMedCentralGoogle Scholar
  93. Wang Z, Mi Z, Wang H, Sun L, Yu G, Fu X et al (2018a) Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy. Clin Genet 94(2):259–263.  https://doi.org/10.1111/cge.13376 CrossRefPubMedGoogle Scholar
  94. Wang D, Fan Y, Malhi M, Bi R, Wu Y, Xu M et al (2018b) Missense variants in HIF1A and LACC1 contribute to leprosy risk in Han Chinese. Am J Hum Genet 102(5):794–805.  https://doi.org/10.1016/j.ajhg.2018.03.006 CrossRefPubMedPubMedCentralGoogle Scholar
  95. Wong SH, Gochhait S, Malhotra D, Pettersson FH, Teo YY, Khor CC et al (2010a) Leprosy and the adaptation of human toll-like receptor 1. PLoS Pathog 6:e1000979.  https://doi.org/10.1371/journal.ppat.1000979 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Wong SH, Hill AV, Vannberg FO (2010b) Genomewide association study of leprosy. N Engl J Med 362(15):1446–1447.  https://doi.org/10.1056/NEJMc1001451(author reply 7-8) CrossRefPubMedGoogle Scholar
  97. Zerva L, Cizman B, Mehra NK, Alahari SK, Murali R, Zmijewski CM 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(3):829–836CrossRefGoogle Scholar
  98. Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y et al (2009a) Genomewide association study of leprosy. N Engl J Med 361(27):2609–2618.  https://doi.org/10.1056/NEJMoa0903753 CrossRefPubMedGoogle Scholar
  99. Zhang F, Liu H, Chen S, Wang C, Zhu C, Zhang L et al (2009b) Evidence for an association of HLA-DRB1*15 and DRB1*09 with leprosy and the impact of DRB1*09 on disease onset in a Chinese Han population. BMC Med Genet 10:133.  https://doi.org/10.1186/1471-2350-10-133 CrossRefPubMedPubMedCentralGoogle Scholar
  100. Zhang F, Liu H, Chen S, Low H, Sun L, Cui Y et al (2011) Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nat Genet 43(12):1247–1251.  https://doi.org/10.1038/ng.973 CrossRefPubMedGoogle Scholar
  101. Zhang X, Cheng Y, Zhang Q, Wang X, Lin Y, Yang C et al (2019) Meta-analysis identifies major histocompatiblity complex loci in or near HLA-DRB1, HLA-DQA1, HLA-C as associated with leprosy in Chinese Han population. J Investig Dermatol. 139(4):957–960.  https://doi.org/10.1016/j.jid.2018.09.029 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Vinicius M. Fava
    • 1
    • 2
  • Monica Dallmann-Sauer
    • 1
    • 2
    • 3
  • Erwin Schurr
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Program in Infectious Diseases and Immunity in Global HealthThe Research Institute of the McGill University Health CentreMontrealCanada
  2. 2.McGill International TB CentreMontrealCanada
  3. 3.Department of Human Genetics, Faculty of MedicineMcGill UniversityMontrealCanada
  4. 4.Department of Medicine, Faculty of MedicineMcGill UniversityMontrealCanada

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