Genetic susceptibility in leprosy: molecular analysis of HLA classroom II and classroom III.
Several studies demonstrated the influence of human genetic variability on the capacity to respond against M. leprae, etiologic agent of leprosy disease. Through different techniques the modern genetics has contributed for the determination of important regions associated with this illness, such as the 6p21 chromosome, mainly pointing to the HLA/TNF region. In leprosy, studies involving SNPs of the TNFamp;#61537; gene have shown different associations depending on the studied population. Simultaneously, there are evidences that HLA-DRB1 alleles play an important role in the development of the illness. Therefore, considering the possibility of genetic pre-disposition to be one of the responsible factors for the development of leprosy, the present study has as objective to analyze the role of the HLA/TNF region using different approaches. First, for the analyses of the HLA-DR locus a case-control study was carried out involving 1269 Brazilian citizens. For the posterior confirmation of the obtained results, a replication study was carried out, using the TDT methodology with 194 Vietnamese families. For the analyses of the TNF region a case-control study was carried out with 1170 individuals belonging to the Brazilian population, analyzing SNPs at position +252 of the LTA gene and -863, -308 and -238 of the TNFamp;#61537; gene. Screening tests and haplotipic analyses were applied on the respective SNPs. Results found for the HLA-DR locus confirmed previous studies which demonstrated association of the HLA-DRB1*15 allele with susceptibility for leprosy in the Brazilian population. Additionally, due to the high power of the sample size used in this study as well as in the replication study, it was possible to observe the association of the HLA-DRB1*10 and HLA-DRB1*04 alleles with susceptibility and resistance for disease, respectively. In the TNF region, the results suggest that the haplotypes -863C/-308A; -308A/-238G and +252G/-308A are associated with resistance to leprosy, showing the recurrence of the ?A? allele at position -308 between the 3 significant haplotypes, suggesting that it can be used as a tagSNP in further studies. Therefore, based on the results obtained in the present study it?s possible to show the importance of the HLA-DRB1*10, HLA-DRB1*04 and TNF-308A alleles as genetic markers for leprosy.
Advisor:Milton Ozório Moraes; Euzenir Nunes Sarno
School:Faculdades Oswaldo Cruz
Source Type:Master's Thesis
Keywords:Mycobacterium leprae Leprosy Genes MHC Class II Polymorphism Genetic Lymphotoxin-alpha
Date of Publication:02/14/2007