Genetic and serum markers in human host can predict leprosy susceptibility per se as well as be useful in classification and/or prediction of clinical variants and immunological responses in leprosy. Adequate and timely assessment of potential risks associated with these 38 host leprosy genes could diminish epidemiological burden and improve life quality of patients with this still prevalent mycobacterial disease. 1. Introduction In recent years, evidence has accumulated for so-called human “multidisease susceptibility genes” that play a role in several infectious and noninfectious diseases [1], and genes presumably more specific on its clinical impact when dysfunctional, that probably do not predispose to the disease per se but to a clinical phenotype when the disease is already present [2]. A decline in leprosy research, probably for the erroneous belief that the battle is won, has left unanswered questions regarding the exact mechanism of disease infection and progression. Addressing these questions could help in the final eradication of leprosy [3]. Human leprosy (or Hansen disease) is a chronic granulomatous infectious disease caused by the obligate intracellular organism Mycobacterium leprae [4, 5]. Leprosy is still an important health problem worldwide, with the highest incidences in Asia, Africa, and Latin America [6]. In 2008, ~250,000 new cases of leprosy were reported to World Health Organization [7]. The high concordance rates for leprosy infection when monozygotic and dizygotic twins are compared (84.55% versus 18.35%, resp., media of two independent reports) [7] as well as loci that are linked or associated with leprosy, reveal a strong genetic component in the susceptibility and response to the infection with M. leprae. Furthermore, complex segregation analyses suggest an oligogenic model of leprosy susceptibility, with a few major genes influencing disease and several additional genes and variations causing subtle effects on disease outcome [8]. The origin of transmission of M. leprae is mainly from untreated lepromatous patients [9] and the people most probable infected (leprosy per se) are patient’s contacts whose carry susceptibility alleles in loci 20p12 [10], TNFA [11], as well as PARK2 and PACRG genes [12]. Genetic variants in human host, mainly single nucleotide polymorphisms (SNPs) can predict susceptibility to leprosy per se and to clinical variants when leprosy is already present [2, 8, 13]. Even when death due to leprosy, caused by laryngeal obstruction, is uncommon [14], adequate and opportune detection of potential risks
References
[1]
M. Orlova, T Di Pietrantonio, and E. Schurr, “Review: genetics of infectious diseases: hidden etiologies and common pathways,” Clinical Chemistry and Laboratory Medicine, vol. 49, no. 9, pp. 1427–1437, 2011.
[2]
E. Prado Montes de Oca, J. S. Velarde-Felix, J. J. Ríos-Tostado, V. J. Picos-Cardenas, and L. E. Figuera, “SNP 668C (-44) alters a NF-κB1 putative binding site in non-coding strand of human β-defensin 1 (DEFB1) and is associated with lepromatous leprosy,” Infection, Genetics and Evolution, vol. 9, no. 4, pp. 617–625, 2009.
[3]
D. M. Scollard, “Leprosy research declines, but most of the basic questions remain unanswered,” International Journal of Leprosy and Other Mycobacterial Diseases, vol. 73, pp. 25–27, 2005.
[4]
R. L. Modlin, “The innate immune response in leprosy,” Current Opinion in Immunology, vol. 22, no. 1, pp. 48–54, 2010.
[5]
D. Montoya and R. L. Modlin, “Learning from leprosy: insight into the human innate immune response,” Advances in Immunology, vol. 105, pp. 1–24, 2010.
[6]
F. O. Vannberg, S. J. Chapman, and A. V. Hill, “Human genetic susceptibility to intracellular pathogens,” Immunological Reviews, vol. 240, no. 1, pp. 105–116, 2011.
[7]
A. Alter, A. Grant, L. Abel, A. Alcais, and E. Schurr, “Leprosy as a genetic disease,” International Mammalian Genome Society, vol. 22, no. 1-2, pp. 19–31, 2011.
[8]
C. C. Cardoso, A. C. Pereira, C. de Sales Marques, and M. O. Moraes, “Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome,” Future Microbiology, vol. 6, no. 5, pp. 533–549, 2011.
[9]
S. L. Walker and D. N. Lockwood, “The clinical and immunological features of leprosy,” British Medical Bulletin, vol. 77-78, no. 1, pp. 103–121, 2006.
[10]
K. Tosh, S. Meisner, M. R. Siddiqui et al., “A region of chromosome 20 is linked to leprosy susceptibility in a South Indian population,” The Journal of Infectious Diseases, vol. 186, no. 8, pp. 1190–1193, 2002.
[11]
M. A. Shaw, I. J. Donaldson, A. Collins et al., “Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes,” Genes and Immunity, vol. 2, no. 4, pp. 196–204, 2001.
[12]
M. T. Mira, A. Alcais, H. Van Thuc et al., “Susceptibility to leprosy is associated with PARK2 and PACRG,” Nature, vol. 427, no. 6975, pp. 636–640, 2004.
[13]
B. Ranque, A. Alcais, N. V. Thuc et al., “A recessive major gene controls the Mitsuda reaction in a region endemic for leprosy,” The Journal of Infectious Diseases, vol. 192, no. 8, pp. 1475–1482, 2005.
[14]
M. T. Mira, “Genetic host resistance and susceptibility to leprosy,” Microbes and Infection, vol. 8, no. 4, pp. 1124–1131, 2006.
[15]
D. S. Ridley and W. H. Jopling, “Classification of leprosy according to immunity. A five-group system,” International Journal of Leprosy and Other Mycobacterial Diseases, vol. 34, no. 3, pp. 255–273, 1966.
[16]
M. Mariano, “The experimental granuloma. A hypothesis to explain the persistence of the lesion,” Revista do Instituto de Medicina Tropical de Sao Paulo, vol. 37, no. 2, pp. 161–176, 1995.
[17]
C. L. Crawford and P. M. Hardwicke, “Experimental leprosy: a model of epithelioid cell granuloma,” International Journal of Dermatology, vol. 50, no. 3, pp. 255–261, 2011.
[18]
J. M. Davis and L. Ramakrishnan, “The role of the granuloma in expansion and dissemination of early tuberculous infection,” Cell, vol. 136, no. 1, pp. 37–49, 2009.
[19]
W. J. Britton and D. N. Lockwood, “Leprosy,” The Lancet, vol. 363, no. 9416, pp. 1209–1219, 2004.
[20]
S. L. Walker, L. Whittam, F. Vega-Lopez, and D. N. Lockwood, “Milia complicating successfully treated cutaneous leishmaniasis in three children,” The British Journal of Dermatology, vol. 155, no. 4, pp. 860–861, 2006.
[21]
E. A. Misch, W. R. Berrington, J. C. Vary Jr., and T. R. Hawn, “Leprosy and the human genome,” Microbiology and Molecular Biology Reviews, vol. 74, no. 4, pp. 589–620, 2010.
[22]
D. P. Agarwal, H. G. Benkmann, H. W. Goedde, et al., “Levels of serum β1C/β1A globulin (C3) and its polymorphism in leprosy patients and healthy controls from Ethiopia and Mali,” Humangenetik, vol. 21, no. 4, pp. 355–359, 1974.
[23]
G. Kaur, G. Sachdeva, L. K. Bhutani, and R. Bamezai, “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,” Human Genetics, vol. 100, no. 1, pp. 43–50, 1997.
[24]
J. Fitness, K. Tosh, and A. V. S. Hill, “Genetics of susceptibility to leprosy,” Genes and Immunity, vol. 3, no. 8, pp. 441–453, 2002.
[25]
I. J. de Messias-Reason, A. B. Boldt, A. C. Braga et al., “The association between mannan-binding lectin gene polymorphism and clinical leprosy: new insight into an old paradigm,” The Journal of Infectious Diseases, vol. 196, no. 9, pp. 1379–1385, 2007.
[26]
F. R. Zhang, W. Huang, S. M. Chen et al., “Genomewide association study of leprosy,” The New England Journal of Medicine, vol. 361, no. 27, pp. 2609–2618, 2009.
[27]
E. N. Sarno, G. E. Grau, L. M. Vieira, and J. A. Nery, “Serum levels of tumour necrosis factor-α and interleukin-1β during leprosy reactional states,” Clinical and Experimental Immunology, vol. 84, no. 1, pp. 103–108, 1991.
[28]
A. R. Santos, P. N. Suffys, P. R. Vanderborght et al., “Role of tumor necrosis factor-α and interleukin-10 promoter gene polymorphisms in leprosy,” The Journal of Infectious Diseases, vol. 186, no. 11, pp. 1687–1691, 2002.
[29]
L. Hamann, O. Kumpf, R. P. Schuring et al., “Low frequency of the TIRAP S180L polymorphism in Africa, and its potential role in malaria, sepsis, and leprosy,” BMC Medical Genetics, vol. 10, article 65, 2009.
[30]
A. Alvarado-Navarro, M. Montoya-Buelna, J. F. Munoz-Valle, R. I. Lopez-Roa, C. Guillen-Vargas, and M. Fafutis-Morris, “The 3′UTR 1188 A/C polymorphism in the interleukin-12p40 gene (IL-12B) is associated with lepromatous leprosy in the west of Mexico,” Immunology Letters, vol. 118, no. 2, pp. 148–151, 2008.
[31]
S. Roy, W. McGuire, C. G. Mascie-Taylor et al., “Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy,” The Journal of Infectious Diseases, vol. 176, no. 2, pp. 530–532, 1997.
[32]
B. Ranque, V. T. Nguyen, H. T. Vu et al., “Age is an important risk factor for onset and sequelae of reversal reactions in Vietnamese patients with leprosy,” Clinical Infectious Diseases, vol. 44, no. 1, pp. 33–40, 2007.
[33]
L. Pocaterra, S. Jain, R. Reddy et al., “Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India,” The American Journal of Tropical Medicine and Hygiene, vol. 74, no. 5, pp. 868–879, 2006.
[34]
A. Alcais, M. Mira, J. L. Casanova, E. Schurr, and L. Abel, “Genetic dissection of immunity in leprosy,” Current Opinion in Immunology, vol. 17, no. 1, pp. 44–48, 2005.
[35]
D. M. Scollard, L. B. Adams, T. P. Gillis, J. L. Krahenbuhl, R. W. Truman, and D. L. Williams, “The continuing challenges of leprosy,” Clinical Microbiology Reviews, vol. 19, no. 2, pp. 338–381, 2006.
[36]
A. Sahu, T. R. Kozel, and M. K. Pangburn, “Specificity of the thioester-containing reactive site of human C3 and its significance to complement activation,” Biochemical Journal, vol. 302, part 2, pp. 429–436, 1994.
[37]
D. Ricklin, G. Hajishengallis, K. Yang, and J. D. Lambris, “Complement: a key system for immune surveillance and homeostasis,” Nature Immunology, vol. 11, no. 9, pp. 785–797, 2010.
[38]
D. Callegaro-Filho, N. Shrestha, A. E. Burdick, and P. A. Haslett, “A potential role for complement in immune evasion by Mycobacterium leprae,” Journal of Drugs in Dermatology, vol. 9, no. 11, pp. 1373–1382, 2010.
[39]
I. J. de Mesias, J. Santamaria, M. Brenden, A. Reis, and G. Mauff, “Association of C4B deficiency (C4B*Q0) with erythema nodosum in leprosy,” Clinical and Experimental Immunology, vol. 92, no. 2, pp. 284–287, 1993.
[40]
X. Liu, H. Wu, M. Byrne, S. Krane, and R. Jaenisch, “Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 5, pp. 1852–1856, 1997.
[41]
E. Prado Montes de Oca, “Human β-defensin 1: a restless warrior against allergies, infections and cancer,” International Journal of Biochemistry and Cell Biology, vol. 42, no. 6, pp. 800–804, 2010.
[42]
A. A. Kalus, L. P. Fredericks, B. M. Hacker et al., “Association of a genetic polymorphism (-44 C/G SNP) in the human DEFB1 gene with expression and inducibility of multiple β-defensins in gingival keratinocytes,” BMC Oral Health, vol. 9, article 21, 2009.
[43]
E. Prado Montes de Oca, “DEFB1 (defensin, beta 1) (8p23.1),” Atlas of Genetics and Cytogenetics in Oncology and Haematology, vol. 15, article 2, 2011.
[44]
R. Cagliani, M. Fumagalli, S. Riva et al., “The signature of long-standing balancing selection at the human defensin β-1 promoter,” Genome Biology, vol. 9, no. 9, article R143, 2008.
[45]
E. Prado Montes de Oca, A. García-Vargas, R. Lozano-Inocencio et al., “Association of β-defensin 1 single nucleotide polymorphisms with atopic dermatitis,” International Archives of Allergy and Immunology, vol. 142, no. 3, pp. 211–218, 2007.
[46]
E. Prado Montes de Oca, H. Rangel-Villalobos, M. P. Gallegos-Arreola, L. Sandoval, and L. E. Figuera, “SNPs in human β-defensin 1 gene (DEFB1): frequencies in a Mexican population and new PCR-RFLPs assays,” International Journal of Immunogenetics, vol. 33, no. 5, pp. 339–342, 2006.
[47]
I. de Messias-Reason, P. G. Kremsner, and J. F. Kun, “Functional haplotypes that produce normal ficolin-2 levels protect against clinical leprosy,” The Journal of Infectious Diseases, vol. 199, no. 6, pp. 801–804, 2009.
[48]
S. Kulkarni, M. P. Martin, and M. Carrington, “The Yin and Yang of HLA and KIR in human disease,” Seminars in Immunology, vol. 20, no. 6, pp. 343–352, 2008.
[49]
G. Fabozzi, G. Modiano, F. Poccia, F. Visca, and F. Ascenzi, “Is there an answer? Is there a genetic basis for human susceptibility to leprosy?” IUBMB Life, vol. 57, pp. 119–121, 2005.
[50]
U. Shankarkumar, K. Ghosh, S. Badakere, and D. Mohanty, “Novel HLA class I alleles associated with Indian leprosy patients,” Journal of Biomedicine and Biotechnology, vol. 2003, no. 3, pp. 208–211, 2003.
[51]
M. Kocak, M. Balci, B. Pence, and N. Kundakci, “Associations between human leukocyte antigens and leprosy in the Turkish population,” Clinical and Experimental Dermatology, vol. 27, no. 3, pp. 235–239, 2002.
[52]
L. M. Wang, A. Kimura, M. Satoh, and S. Mineshita, “HLA linked with leprosy in southern China; HLA-linked resistance alleles to leprosy,” International Journal of Leprosy and Other Mycobacterial Diseases, vol. 67, no. 4, pp. 403–408, 1999.
[53]
J. R. Schoenborn and C. B. Wilson, “Regulation of interferon-γ during innate and adaptive immune responses,” Advances in Immunology, vol. 96, pp. 41–101, 2007.
[54]
E. P. Sampaio, A. L. Moreira, G. Kaplan et al., “Mycobacterium leprae-induced interferon-γ production by household contacts of leprosy patients: association with the development of active disease,” The Journal of Infectious Diseases, vol. 164, no. 5, pp. 990–993, 1991.
[55]
C. C. Cardoso, A. C. Pereira, V. N. Brito-De-Souza et al., “IFNG +874 T？>？A single nucleotide polymorphism is associated with leprosy among Brazilians,” Human Genetics, vol. 128, no. 5, pp. 481–490, 2010.
[56]
R. M. Teles, S. R. Krutzik, M. T. Ochoa, R. B. Oliveira, E. N. Sarno, and R. L. Modlin, “Interleukin-4 regulates the expression of CD209 and subsequent uptake of Mycobacterium leprae by Schwann cells in human leprosy,” Infection and Immunity, vol. 78, no. 11, pp. 4634–4643, 2010.
[57]
D. Yang, H. Song, W. Xu, et al., “Interleukin 4-590T/C Polymorphism and Susceptibility to Leprosy,” Genetic Testing and Molecular Biomarkers. In press.
[58]
M. D. Howell, N. Novak, T. Bieber et al., “Interleukin-10 downregulates anti-microbial peptide expression in atopic dermatitis,” The Journal of Investigative Dermatology, vol. 125, no. 4, pp. 738–745, 2005.
[59]
J. Yu, N. Mookherjee, K. Wee et al., “Host defense peptide LL-37, in synergy with inflammatory mediator IL-1β, augments immune responses by multiple pathways,” The Journal of Immunology, vol. 179, no. 11, pp. 7684–7691, 2007.
[60]
D. L. Jack, N. J. Klein, and M. W. Turner, “Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis,” Immunological Reviews, vol. 180, pp. 86–99, 2001.
[61]
S. Thiel, T. Vorup-Jensen, C. M. Stover et al., “A second serine protease associated with mannan-binding lectin that activates complement,” Nature, vol. 386, no. 6624, pp. 506–510, 1997.
[62]
D. L. Jack and M. W. Turner, “Anti-microbial activities of mannose-binding lectin,” Biochemical Society Transactions, vol. 31, no. 4, pp. 753–757, 2003.
[63]
L. N. Dornelles, L. Pereira-Ferrari, and I. Messias-Reason, “Mannan-binding lectin plasma levels in leprosy: deficiency confers protection against the lepromatous but not the tuberculoid forms,” Clinical and Experimental Immunology, vol. 145, no. 3, pp. 463–468, 2006.
[64]
B. R. Sapkota, M. Macdonald, W. R. Berrington et al., “Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes,” Human Immunology, vol. 71, no. 10, pp. 992–998, 2010.
[65]
L. R. Vasconcelos, J. P. Fonseca, R. F. Carmo et al., “Mannose-binding lectin serum levels in patients with leprosy are influenced by age and MBL2 genotypes,” International Journal of Infectious Diseases, vol. 15, no. 8, pp. e551–e557, 2011.
[66]
M. R. Siddiqui, S. Meisner, K. Tosh et al., “A major susceptibility locus for leprosy in India maps to chromosome 10p13,” Nature Genetics, vol. 27, no. 4, pp. 439–441, 2001.
[67]
L. S. Schlesinger, T. M. Kaufman, S. Iyer, S. R. Hull, and L. K. Marchiando, “Differences in mannose receptor-mediated uptake of lipoarabinomannan from virulent and attenuated strains of Mycobacterium tuberculosis by human macrophages,” The Journal of Immunology, vol. 157, no. 10, pp. 4568–4575, 1996.
[68]
A. Alter, L. de Leseleuc, N. Van Thuc et al., “Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility,” Human Genetics, vol. 127, no. 3, pp. 337–348, 2010.
[69]
R. Cooney, J. Baker, O. Brain et al., “NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation,” Nature Medicine, vol. 16, no. 1, pp. 90–97, 2010.
[70]
S. H. Wong, A. V. Hill, and F. O. Vannberg, “Genomewide association study of leprosy,” The New England Journal of Medicine, vol. 362, no. 15, pp. 1446–1447, 2010.
[71]
E. Schurr, A. Alcais, L. de Leseleuc, and L. Abel, “Genetic predisposition to leprosy: a major gene reveals novel pathways of immunity to Mycobacterium leprae,” Seminars in Immunology, vol. 18, no. 6, pp. 404–410, 2006.
[72]
M. T. Mira, A. Alcais, N. Van Thuc et al., “Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population,” Nature Genetics, vol. 33, no. 3, pp. 412–415, 2003.
[73]
N. Jabado, A. Jankowski, S. Dougaparsad, V. Picard, S. Grinstein, and P. Gros, “Natural resistance to intracellular infections: natural resistance—associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane,” Journal of Experimental Medicine, vol. 192, no. 9, pp. 1237–1248, 2000.
[74]
S. Gruenheid and P. Gros, “Genetic susceptibility to intracellular infections: nramp1, macrophage function and divalent cations transport,” Current Opinion in Microbiology, vol. 3, no. 1, pp. 43–48, 2000.
[75]
B. Ranque, A. Alter, M. Mira et al., “Genomewide linkage analysis of the granulomatous mitsuda reaction implicates chromosomal regions 2q35 and 17q21,” The Journal of Infectious Diseases, vol. 196, no. 8, pp. 1248–1252, 2007.
[76]
E. Bouzigon, E. Corda, H. Aschard et al., “Effect of 17q21 variants and smoking exposure in early-onset asthma,” The New England Journal of Medicine, vol. 359, no. 19, pp. 1985–1994, 2008.
[77]
M. F. Moffatt, I. G. Gut, F. Demenais et al., “A large-scale, consortium-based genomewide association study of asthma,” The New England Journal of Medicine, vol. 363, no. 13, pp. 1211–1221, 2010.
[78]
A. Binia, N. Khorasani, P. K. Bhavsar et al., “Chromosome 17q21 SNP and severe asthma,” Journal of Human Genetics, vol. 56, no. 1, pp. 97–98, 2011.
[79]
L. Abel, F. O. Sánchez, J. Oberti et al., “Susceptibility to leprosy is linked to the human NRAMP1 gene,” The Journal of Infectious Diseases, vol. 177, no. 1, pp. 133–145, 1998.
[80]
S. J. Meisner, S. Mucklow, G. Warner, S. O. Sow, C. Lienhardt, and A. V. S. Hill, “Association of nramp1 polymorphism with leprosy type but not susceptibility to leprosy per se in West Africans,” The American Journal of Tropical Medicine and Hygiene, vol. 65, no. 6, pp. 733–735, 2001.
[81]
F. R. Ferreira, L. R. Goulart, H. D. Silva, and I. M. B. Goulart, “Susceptibility to leprosy may be conditioned by an interaction between the NRAMP1 promoter polymorphisms and the lepromin response,” International Journal of Leprosy and Other Mycobacterial Diseases, vol. 72, no. 4, pp. 457–467, 2004.
[82]
T. Kawai and S. Akira, “The role of pattern-recognition receptors in innate immunity: update on toll-like receptors,” Nature Immunology, vol. 11, no. 5, pp. 373–384, 2010.
[83]
C. M. Johnson, E. A. Lyle, K. O. Omueti et al., “Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy,” The Journal of Immunology, vol. 178, no. 12, pp. 7520–7524, 2007.
[84]
E. A. Misch, M. Macdonald, C. Ranjit et al., “Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction,” Plos Neglected Tropical Diseases, vol. 2, no. 5, Article ID e231, 2008.
[85]
E. A. Misch and T. R. Hawn, “Toll-like receptor polymorphisms and susceptibility to human disease,” Clinical Science, vol. 114, no. 5-6, pp. 347–360, 2008.
[86]
R. P. Schilling, L. Hamann, W. R. Faber et al., “Polymorphism N248S in the human Toll-like receptor 1 gene is related to leprosy and leprosy reactions,” The Journal of Infectious Diseases, vol. 199, no. 12, pp. 1816–1819, 2009.
[87]
D. M. Bowdish, K. Sakamoto, M. J. Kim et al., “MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis,” Plos Pathogens, vol. 5, no. 6, Article ID e1000474, 2009.
[88]
S. R. Krutzik, M. T. Ochoa, P. A. Sieling et al., “Activation and regulation of Toll-like receptors 2 and 1 in human leprosy,” Nature Medicine, vol. 9, no. 5, pp. 525–532, 2003.
[89]
N. Mikita, N. Kanazawa, M. Ozaki et al., “No involvement of non-synonymous TLR2 polymorphisms in Japanese leprosy patients,” Journal of Dermatological Science, vol. 54, no. 1, pp. 48–49, 2009.
[90]
T. J. Kang and G. T. Chae, “Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients,” FEMS Immunology and Medical Microbiology, vol. 31, no. 1, pp. 53–58, 2001.
[91]
D. Malhotra, V. Relhan, B. S. Reddy, and R. Bamezai, “TLR2 Arg677Trp polymorphism in leprosy: revisited,” Human Genetics, vol. 116, no. 5, pp. 413–415, 2005.
[92]
R. B. Oliveira, M. T. Ochoa, P. A. Sieling et al., “Expression of toll-like receptor 2 on human schwann cells: a mechanism of nerve damage in leprosy,” Infection and Immunity, vol. 71, no. 3, pp. 1427–1433, 2003.
[93]
P. Y. Bochud, T. R. Hawn, M. R. Siddiqui et al., “Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy,” The Journal of Infectious Diseases, vol. 197, no. 2, pp. 253–261, 2008.
[94]
P. Y. Bochud, D. Sinsimer, A. Aderem et al., “Polymorphisms in toll-like receptor 4 (TLR4) are associated with protection against leprosy,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 28, no. 9, pp. 1055–1065, 2009.
[95]
P. T. Liu, S. Stenger, H. Li et al., “Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response,” Science, vol. 311, no. 5768, pp. 1770–1773, 2006.
[96]
P. T. Liu, S. Stenger, D. H. Tang, and R. L. Modlin, “Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin,” The Journal of Immunology, vol. 179, no. 4, pp. 2060–2063, 2007.
[97]
A. R. Martineau, S. M. Newton, K. A. Wilkinson et al., “Neutrophil-mediated innate immune resistance to mycobacteria,” The Journal of Clinical Investigation, vol. 117, no. 7, pp. 1988–1994, 2007.
[98]
A. R. Martineau, K. A. Wilkinson, S. M. Newton et al., “IFN-γ- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37,” The Journal of Immunology, vol. 178, no. 11, pp. 7190–7198, 2007.
[99]
S. Roy, A. Frodsham, B. Saha, S. K. Hazra, C. G. N. Mascie-Taylor, and A. V. S. Hill, “Association of vitamin D receptor genotype with leprosy type,” The Journal of Infectious Diseases, vol. 179, no. 1, pp. 187–191, 1999.
[100]
J. S. Velarde Felix, S. G. Cazarez Salazar, R. Castro Velazquez, J. G. Rendon Maldonado, and H. Rangel Villalobos, “Association between the TaqI polymorphism of Vitamin D Receptor gene and lepromatous leprosy in a Mexican population sample,” Salud Publica de Mexico, vol. 51, no. 1, pp. 59–61, 2009.
[101]
W. O. Cookson, B. Ubhi, R. Lawrence et al., “Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci,” Nature Genetics, vol. 27, no. 4, pp. 372–373, 2001.
[102]
E. Prado Montes de Oca, Human b-defensin 1 (DEFB1) polymorphisms in leprosy susceptibility, Ph.D. thesis, Guadalajara University, 2007.
[103]
J. M. Jones, J. C. Morrell, and S. J. Gould, “Identification and characterization of HAOX1, HAOX2, and HAOX3, three human peroxisomal 2-hydroxy acid oxidases,” The Journal of Biological Chemistry, vol. 275, no. 17, pp. 12590–12597, 2000.
[104]
S. T. Cole, K. Eiglmeier, J. Parkhill et al., “Massive gene decay in the leprosy bacillus,” Nature, vol. 409, no. 6823, pp. 1007–1011, 2001.
[105]
P. Visca, G. Fabozzi, M. Milani, M. Bolognesi, and P. Ascenzi, “Nitric oxide and Mycobacterium leprae pathogenicity,” IUBMB Life, vol. 54, no. 3, pp. 95–99, 2002.
[106]
P. Visca, G. Fabozzi, A. Petrucca et al., “The truncated hemoglobin from Mycobacterium lepraeq,” Biochemical and Biophysical Research Communications, vol. 294, no. 5, pp. 1064–1070, 2002.
[107]
K. A. Mattos, V. G. C. Oliveira, H. D'Avila et al., “TLR6-driven lipid droplets in Mycobacterium leprae-infected Schwann cells: immunoinflammatory platforms associated with bacterial persistence,” The Journal of Immunology, vol. 187, no. 5, pp. 2548–2558, 2011.
[108]
G. N. López Campos, W. Li, and E. Prado Montes de Oca, “A novel in silico method for transcriptional impact assessment of polymorphisms in eukaryotes: variants in human antimicrobial peptides promoters as an example,” submitted.
[109]
E. N. Miller, S. E. Jamieson, M. Fakiola et al., “Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians,” Genes and Immunity, vol. 5, no. 1, pp. 63–67, 2004.
[110]
T. Gillis, V. Vissa, M. Matsuoka et al., “Characterisation of short tandem repeats for genotyping Mycobacterium leprae,” Leprosy Review, vol. 80, no. 3, pp. 250–260, 2009.
[111]
M. Matsuoka, A. V. Gonzalez, I. Estrada, C. Carreno-Martinez, and M. Fafutis-Morris, “Various genotypes of Mycobacterium leprae from Mexico reveal distinct geographic distribution,” Leprosy Review, vol. 80, no. 3, pp. 322–326, 2009.
[112]
M. Monot, N. Honore, T. Garnier et al., “Comparative genomic and phylogeographic analysis of Mycobacterium leprae,” Nature Genetics, vol. 41, no. 12, pp. 1282–1289, 2009.
[113]
Y. C. Shin, H. Lee, G. P. Walsh, J. D. Kim, and S. N. Cho, “Variable numbers of TTC repeats in Mycobacterium leprae DNA from leprosy patients and use in strain differentiation,” Journal of Clinical Microbiology, vol. 38, no. 12, pp. 4535–4538, 2000.
[114]
N. A. Groathouse, B. Rivoire, H. Kim et al., “Multiple polymorphic loci for molecular typing of strains of Mycobacterium leprae,” Journal of Clinical Microbiology, vol. 42, no. 4, pp. 1666–1672, 2004.
[115]
M. Monot, N. Honore, T. Garnier et al., “On the origin of leprosy,” Science, vol. 308, no. 5724, pp. 1040–1042, 2005.
[116]
M. Matsuoka, L. Zhang, M. F. Morris, P. Legua, and C. Wiens, “Polymorphism in the rpoT gene in Mycobacterium leprae isolates obtained from Latin American countries and its possible correlation with the spread of leprosy,” FEMS Microbiology Letters, vol. 243, no. 2, pp. 311–315, 2005.
[117]
M. Matsuoka, Y. Suzuki, I. E. Garcia et al., “Possible mode of emergence for drug-resistant leprosy is revealed by an analysis of samples from Mexico,” Japanese Journal of Infectious Diseases, vol. 63, no. 6, pp. 412–416, 2010.
[118]
M. Matsuoka, “Drug resistance in leprosy,” Japanese Journal of Infectious Diseases, vol. 63, no. 1, pp. 1–7, 2010.
[119]
D. Altshuler, M. J. Daly, and E. S. Lander, “Genetic mapping in human disease,” Science, vol. 322, no. 5903, pp. 881–888, 2008.
[120]
E. Prado Montes de Oca and W. Li, “Human β-defensin 1 (DEFB1) alleles and genotypes frequencies probably impact atopic dermatitis ethnic susceptibility,” International Journal of Dermatology. In press.
[121]
E. Prado Montes de Oca, “Genome-Wide Association Studies (GWAS) are not “complete genome” association studies,” unpublished.
[122]
L. Rew, M. Kaur, A. McMillan, M. MacKert, and D. Bonevac, “Systematic review of psychosocial benefits and harms of genetic testing,” Issues in Mental Health Nursing, vol. 31, no. 10, pp. 631–645, 2010.
[123]
1000 Genomes Project Consortium, “1000 Genomes: a deep catalog of human genetic variation,” August 2011, http://www.1000genomes.org.
[124]
1000 Genomes Project Consortium, “A map of human genome variation from population-scale sequencing,” Nature, vol. 467, no. 7319, pp. 1061–1073, 2010.
[125]
M. R. Kohonen-Corish, J. Y. Al-Aama, A. D. Auerbach et al., “How to catch all those mutations-the report of the third human variome project meeting, UNESCO Paris, May 2010,” Human Mutation, vol. 31, no. 12, pp. 1374–1381, 2010.
[126]
E. Prado Montes de Oca, “Antimicrobial peptide elicitors: potential strategy against infections,” Gaceta Medica de Mexico, vol. 145, no. 3, pp. 241–243, 2009.
[127]
R. Raqib, P. Sarker, P. Bergman et al., “Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 24, pp. 9178–9183, 2006.
[128]
P. Sarker, S. Ahmed, S. Tiash et al., “Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy,” PLoS One, vol. 6, Article ID e20637, 2011.
[129]
W. J. Velden, T. M. van Iersel, N. M. Blijlevens, and J. P. Donnelly, “Safety and tolerability of the antimicrobial peptide human lactoferrin 1-11 (hLF1-11),” BMC Medicine, vol. 7, article 44, 2009.
