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HLA-DRB1*04 and DRB1*10 are associated with resistance and susceptibility, respectively, in Brazilian and Vietnamese leprosy patients

Abstract

The host genetic background has been considered one of the factors that influence leprosy outcome, a chronic infectious disease caused by Mycobacterium leprae. Genome scans demonstrated that the 6p21 region is associated with leprosy and a substantial number of population-based studies analyzing human leukocyte antigen (HLA) class II loci suggested association of HLA-DR with leprosy. However, some studies lacked robustness as they had limited power. Indeed, experimental designs require increased sample size to achieve adequate power, as well as replication studies with independent samples for confirmation of previous findings. In this work, we analyzed the influence of the HLA-DRB1 locus on leprosy susceptibility per se and disease type using a case–control design carried out in Brazilians (578 cases and 691 controls) and a replication study based on a family design in a Vietnamese population (n=194 families). The results showed that HLA-DRB1*10 is associated with susceptibility to leprosy and HLA-DRB1*04 is associated with resistance, both in the Brazilian and Vietnamese populations suggesting that these alleles play an important role in the activation of cellular immune responses against M. leprae.

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References

  1. Kaplan G, Cohen ZA . Regulation of cell-mediated immunity in lepromatous leprosy. Lep Rev 1986; 57: 199–202.

    Google Scholar 

  2. Ridley DS, Jopling WH . Classification of leprosy according to immunity – a five group system. Int J Lepr 1966; 34: 255–273.

    CAS  Google Scholar 

  3. van de Vosse E, Hoeve MA, Ottenhoff TH . Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae. Lancet Infect Dis 2004; 4: 739–749.

    Article  CAS  Google Scholar 

  4. Sampaio EP, Moraes MO, Pessolani CVF, Sarno EN . The role of Th1 responses in Mycobacterium leprae infection. In: Kotb M, Calandra T (eds). Cytokines and Chemokines in Infectious Diseases Handbook. Humana Press: NJ, 2003, pp 163–188.

    Chapter  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Beiguelman B . Some remarks on the genetics of leprosy resistance. Acta Genet Med Gemellol (Roma) 1968; 17: 584–594.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Santos AR, Suffys PN, Vanderborght PR, Moraes MO, Vieira LM, Cabello PH et al. Role of tumor necrosis factor-alpha and interleukin-10 promoter gene polymorphisms in leprosy. J Infect Dis 2002; 11: 1687–1691.

    Article  Google Scholar 

  10. Roy S, McGuire W, Mascie Taylor CG, Saha B, Hazra SK, Hill AV et al. Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. J Infect Dis 1997; 176: 530–532.

    Article  CAS  Google Scholar 

  11. De Vries RRP, van Eden W, Ottenhoff THM . HLA class II immune response genes and products in leprosy. Prog Allergy 1985; 36: 95.

    CAS  PubMed  Google Scholar 

  12. Ottenhoff TH, Neuteboom S, Elferink DG, de Vries RR . Molecular localization and polymorphism of HLA class II restriction determinants defined by Mycobacterium leprae-reactive helper T cell clones from leprosy patients. J Exp Med 1986; 164: 1923–1939.

    Article  CAS  Google Scholar 

  13. Moraes MO, Cardoso CC, Vanderborght PR, Pacheco AG . Genetics of host response in leprosy. Lep Rev 2006; 7: 189–202.

    Google Scholar 

  14. De Vries RRP, Mehra MK, Vaidya MC, Gupte MD, Khan PM, Van Rood JJ . HLA-linked control of susceptibility to tuberculoid leprosy and association with HLA-DR types. Tissue Antigens 1980; 16: 89–112.

    Google Scholar 

  15. Schauf V, Ryan S, Scollard D, Jonasson O, Brown A, Nelson K et al. Leprosy associated with HLA-DR2 and DQw1 in the population of northern Thailand. Tissue Antigens 1985; 26: 243–247.

    Article  CAS  Google Scholar 

  16. Visentainer JE, Tsuneto LT, Serra MF, Peixoto PR, Petzl-Erler ML . Association of leprosy with HLA-DR2 in a Southern Brazilian population. Braz J Med Biol Res 1997; 30: 51–59.

    Article  CAS  Google Scholar 

  17. Rani R, Fernandez-Vina MA, Zaheer SA, Beena KR, Stastny P . Study of HLA class II alleles by PCR oligotyping in leprosy patients from north India. Tissue Antigens 1993; 42: 133–137.

    Article  CAS  Google Scholar 

  18. van Eden W, de Vries RR, D'Amaro J, Schreuder I, Leiker DL, van Rood JJ . HLA-DR-associated genetic control of the type of leprosy in a population from surinam. Hum Immunol 1982; 4: 343–350.

    Article  CAS  Google Scholar 

  19. Gorodezky C, Flores J, Arevalo N, Castro LE, Silva A, Rodriguez O . Tuberculoid leprosy in Mexicans is associated with HLA-DR3. Lepr Rev 1987; 58: 401–406.

    CAS  PubMed  Google Scholar 

  20. Mitra DK, Rajalingam R, Taneja V, Bhattacharyya BC, Mehra NK . HLA-DR polymorphism modulates the cytokine profile of Mycobacterium leprae HSP-reactive CD4+ T cells. Clin Immunol Immunopathol 1997; 82: 60–67.

    Article  CAS  Google Scholar 

  21. Moraes ME, Fernandez-Vina M, Stastny P . DNA typing for Class II HLA antigens with allele-specific or group-specific amplification. IV. Typing for alleles of HLA-DR2 group. Hum Immunol 1991; 31: 139–144.

    Article  CAS  Google Scholar 

  22. Makhatadze NJ, Franco MT, Layrisse Z . HLA class I and class II allele and haplotype distribution in the Venezuelan population. Hum Immunol 1997; 55: 53–58.

    Article  CAS  Google Scholar 

  23. Delgado JC, Baena A, Thim S, Goldfeld AE . Aspartic acid homozygosity at codon 57 of HLA-DQ beta is associated with susceptibility to pulmonary tuberculosis in Cambodia. J Immunol 2006; 176: 1090–1097.

    Article  CAS  Google Scholar 

  24. Malhotra D, Darvishi K, Sood S, Sharma S, Grover C, Relhan V et al. IL-10 promoter single nucleotide polymorphisms are significantly associated with resistance to leprosy. Hum Genet 2005; 118: 295–300.

    Article  CAS  Google Scholar 

  25. Fitness J, Floyd S, Warndorff DK, Sichali L, Waungulu LM, Crampin AC et al. Large-scale candidate gene study of leprosy susceptibility in the Karonga district of Northern Malawi. Am J Trop Med Hyg 2004; 71: 330–340.

    Article  CAS  Google Scholar 

  26. Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV . Association of vitamin D receptor genotype with leprosy type. J Infect Dis 1999; 179: 187–191.

    Article  CAS  Google Scholar 

  27. Mira MT, Alcaïs A, VanThuc N, Moraes MO, Di Flumeri C, Thai VH et al. Susceptibility to leprosy is associated with PARK2 e PACRG. Nature 2004; 427: 636–640.

    Article  CAS  Google Scholar 

  28. Olerup O, Zetterquist H . HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 h: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 1992; 39: 225–235.

    Article  CAS  Google Scholar 

  29. R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2005.

  30. Horvath S, Xu X, Laird NM . The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 2001; 9: 301–306.

    Article  CAS  Google Scholar 

  31. Lake SL, Blacker D, Laird NM . Family based tests of association in the presence of linkage. Am J Hum Genet 2000; 67: 1515–1525.

    Article  CAS  Google Scholar 

  32. Schaid DJ, Rowland C . Use of parents, sibs, and unrelated controls for detection of associations between genetic markers and disease. Am J Hum Genet 1998; 63: 1492–1506.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to Alexandre Alcaïs for critical reading and analysis of the paper to Valcemir F Silva-Filho for technical assistance and Denise Vieira for collection of Brazilian samples. These studies were supported in part by PAPES/FIOCRUZ, CNPq.

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Correspondence to M O Moraes.

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Vanderborght, P., Pacheco, A., Moraes, M. et al. HLA-DRB1*04 and DRB1*10 are associated with resistance and susceptibility, respectively, in Brazilian and Vietnamese leprosy patients. Genes Immun 8, 320–324 (2007). https://doi.org/10.1038/sj.gene.6364390

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