RESUMEN
Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.
Asunto(s)
Predisposición Genética a la Enfermedad , Lepra/genética , Linfotoxina-alfa/genética , Proyectos de Investigación , Adolescente , Adulto , Edad de Inicio , Alelos , Brasil/epidemiología , Estudios de Casos y Controles , Niño , Humanos , India/epidemiología , Lepra/epidemiología , Desequilibrio de Ligamiento , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Vietnam/epidemiologíaRESUMEN
This study reports our observations on the correlation between HLA-DR2 subtypes and their DR-DQ haplotypes in patients with tuberculoid (TT) leprosy and pulmonary tuberculosis (PTB). DRB1*1501 was significantly increased in patients with PTB (90%) as compared to controls (p < 0.05); whereas the prevalence of DRB1*1502 was significantly increased in patients with TT leprosy (p < 0.05), suggesting allele-specific binding of the pathogen to form disease-causing motifs to the T-cell receptor. Among DR2-DQ haplotypes, the deviation was noted in the distribution of unique and common haplotypes in patients with TT leprosy and PTB. A significant decrease of haplotype DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0502 in TT leprosy and a significant increase of DRB1*1501-DRB5*0101-DQA1*0103-DQB1*0601 in PTB patients were observed. The occurrence of specific DR2 subtypes and their haplotypes in the two disease groups suggests their involvement in disease pathogenesis