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.
Single-nucleotide polymorphisms within the genes coding for tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 have been associated with several infectious diseases. To determine whether such polymorphisms are associated with leprosy, genotyping was performed at the -308 and -238 positions of the promoter of the TNF-alpha gene in 210 and 191 patients with multibacillary (MB) leprosy, respectively; 90 and 79 patients with paucibacillary (PB) leprosy; and 92 control subjects. For the -592 and -819 positions within the promoter of the IL-10 gene, 143 patients with MB leprosy, 79 patients with PB leprosy, and 62 control subjects were included in the analysis. TNF2 allele frequency was significantly higher among control subjects than among all patients with leprosy or in the MB group (P<.05 and P<.01). For the IL-10 gene, the frequency of the homozygous -819TT genotype was significantly higher among patients than among control subjects. These data indicate that a relationship exists between TNF-alpha and IL-10 promoter polymorphisms and the development of PB leprosy.
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 ¼ 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.
We have determined IL-10 promoter genotypes of five single-nucleotide polymorphisms (SNPs): TÀ3575A, AÀ2849G, CÀ2763A, -AÀ1082G and CÀ819T. The haplotype frequencies were defined in healthy subjects compared to leprosy patients, and analyzed for their occurrence in multi-(MB) vs paucibacillary (PB) as severe and mild forms of leprosy, respectively. Haplotypes defined by three SNP positions (À3575, À2849 and À2763) captured significant differences between controls and patients (P ¼ 0.04). The haplotype carrying À3575A, À2849G and À2763C was associated with resistance to leprosy and to the development of severe forms of the disease using either a binomial (controls vs cases, P ¼ 0.005, OR ¼ 0.35, CI ¼ 0.13-0.91) or ordinal (controls vs PB vs MB, P ¼ 0.006, OR ¼ 0.32, CI ¼ 0.12-0.83) model. By contrast, the IL-10 haplotype À3575T/ À2849A/À2763C was found to be associated with susceptibility to leprosy per se (P ¼ 0.027, OR ¼ 2.37, CI ¼ 1.04-5.39), but not leprosy type. The data suggest that the IL-10 locus contributes to the outcome of leprosy.
Leprosy is an infectious disease caused by Mycobacterium leprae. Tumor necrosis factor (TNF) plays a key role in the host response. Some association studies have implicated the single nucleotide polymorphism TNF -308G>A in leprosy susceptibility, but these results are still controversial. We first conducted 4 association studies (2639 individuals) that showed a protective effect of the -308A allele (odds ratio [OR] = 0.77; P = .005). Next, results of a meta-analysis reinforced this association after inclusion of our new data (OR = 0.74; P = .04). Furthermore, a subgroup analysis including only Brazilian studies suggested that the association is specific to this population (OR = 0.63; P = .005). Finally, functional analyses using whole blood cultures showed that patients carrying the -308A allele produced higher TNF levels after lipopolysaccharide (LPS) (6 hours) and M. leprae (3 hours) stimulation. These results reinforce the association between TNF and leprosy and suggest the -308A allele as a marker of disease resistance, especially among Brazilians.
With the objective to evaluate PCR-mediated detection of Mycobacterium tuberculosis DNA as a diagnostic procedure for diagnosis of tuberculosis in individuals attending ambulatory services in Primary Health Units of the City Tuberculosis Program in Rio de Janeiro, Brazil, their In 1995, 94,870 new cases of tuberculosis (TB) were reported in Brazil, being 76,840 pulmonary TB; the incidence of the disease was 58.2/100.000 (Ruffino Netto 1999). The situation is more severe in big cities like São Paulo and Rio de Janeiro, where co-infection with HIV and multi-drug resistant strains of Mycobacterium tuberculosis complicates efficient use of general control programs. Rapid diagnosis and adequate treatment of TB is the most efficient way to avoid spread of TB. During the last couple of years, several studies were performed to compare recently developed commercial and "in house" PCR systems with conventional diagnostic procedures such as detection of acid-fast bacilli by microscopy, culture and X-ray (Eing et al. 1998, Tortoli et al. 1999 speed, sensitivity and specificity, nucleic acid amplification systems are promising diagnostic tools; however, double blind studies have shown that the use of "in house" PCR as a routine procedure for diagnosis of TB is still controversial (Noordhoek et al. 1994, Suffys et al. 2000. More studies are needed to evaluate the sensitivity of the methods on paucibacillary material and for evaluation of feasibility and cost-effectiveness when used as a routine procedure in TB control programs, especially in developing countries (Roos et al. 1998).One of the bottle necks of PCR for diagnostic purpose is the extraction of parasite DNA from clinical samples (Noordhoek et al. 1994). During the last decade, several methods have been published, including a very promising procedure using guanidiniumthiocyanate (GuSCN) for isolation of different types of nucleic acids from cell-rich sources and pathogenic bacteria (Boom et al. 1990). For evaluation of PCR as a diagnostic procedure of pulmonary TB in individuals attended at 14 ambulatory services in Rio de Janeiro, sputum samples were collected locally, stored at 4°C for a maximum of 4 days and further processed at the State Reference Laboratoroy (Central Laboratory Noel Nutels- Lacen, RJ). The laboratory methods for processing cultures and smears as well as for the identification of mycobacteria were standard procedures (Kent & Kubica 1985). Briefly, an aliquot of 8-10 ml of sputum was processed using using NaOH-Nacetyl-L-cysteine, resuspended in 2.5 ml phosphatebuffered saline and a fraction was processed according to Boom et al. (1990), slightly modified. Briefly, 0.2 ml of the sample was added to 0.2 ml of 0.1 mm glass beads (Biospec products, Bartlesville, OK, USA) and 0.9 ml of L6 lysis buffer (Boom et al. 1990), vortexed during 10 min, submitted to two cycles of heat shock (5 min 65°C and 5 min -170°C) after which 40 µl of celite were added and the solution mixed gently at room temperature during 30 min. Supernatant was discarded and the pell...
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