ABSTRACT
This paper presents the first evaluation of the molecular epidemiology of Mycobacterium tuberculosis in Peru. We characterised 323 isolates using spoligotyping and mycobacterial interspersed repetitive units variable number tandem repeats (MIRU-VNTR) typing. We aimed to determine the levels of genetic diversity and genetic differentiation among and within Peruvian isolates and the epidemiological factors which may be driving patterns of population structure and evolution of M. tuberculosis in Peru. Our results compared to the fourth international spoligotyping database (SpolDB4) and MIRU-VNTRplus, show that the main M. tuberculosis families present are Latin American-Mediterranean, Haarlem, T, and Beijing. Bayesian clustering recovered 15 groups in the Peruvian M. tuberculosis isolates, among which two were composed mainly of orphans, implying the presence of native "Peruvian" strains not previously reported. Variable levels of association with drug resistance were observed, with Beijing genotypes not showing any association with multidrug resistance, while in other groups MIRU-VNTR loci 2, 23, 31, and 40 were found to be associated with the multidrug-resistant tuberculosis (MDR-TB) phenotype, suggesting that a linkage disequibrium between these MIRU and drug resistance loci may be present. Genetic differentiation was present among drug resistant and sensitive strains. Ethambutol appeared to be the main driver of differentiation, suggesting that strong selection pressure could have been exerted by drug treatment in Peru over recent years.
Subject(s)
Bacterial Typing Techniques/methods , Drug Resistance, Multiple, Bacterial , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/genetics , Adolescent , Adult , Alleles , Bayes Theorem , Databases, Genetic , Ethambutol/pharmacology , Female , Genetic Variation , Genotype , Humans , Linkage Disequilibrium , Male , Microbial Sensitivity Tests , Middle Aged , Minisatellite Repeats , Molecular Typing/methods , Mycobacterium tuberculosis/isolation & purification , Mycobacterium tuberculosis/pathogenicity , Peru/epidemiology , Phylogeny , Selection, Genetic , Sputum/microbiology , Tuberculosis/epidemiology , Tuberculosis/microbiology , Young AdultABSTRACT
Racial variation, twin studies, segregation analyses, linkage and association studies all suggest that genetic factors play an important role in predisposition to tuberculosis. Many previous studies have been performed with pulmonary TB patients, as the most prevalent form of clinical TB (nearly 95%), and very few of them have considered extrapulmonary TB. The present study evaluates the effects of variation in eight candidate genes (LTA, TNF, IL1B, IL1RN, IL10, TGFB1, TIRAP and P2X7) with pulmonary, pleural, miliary and other extrapulmonary forms of TB in a Peruvian population from the North of Lima. 626 TB cases and 513 healthy controls were enrolled in this study. LTA(+368) and IL10(-592) were associated with different clinical forms of TB (P<0.05). LTA(+368) genotype A/A was protective for pleural TB, LTA(+368) G/A was correlated with susceptibility to miliary TB. Genotypes A/A and G/A were associated with protection and susceptibility respectively when considering all extrapulmonary TB forms versus either healthy controls or pulmonary TB patients. Carriers of IL10(-592)*C were under-represented among those with pulmonary TB and all TB forms (P<0.001). IL10(-1082)-IL10(-592) haplotypes showed different distributions among patients with pulmonary TB and all TB forms (P<0.01) when compared to healthy controls. In addition, IL10(-1082)-IL10(-592) haplotypes showed differences between pleural, miliary and all forms of extrapulmonary TB when compared with pulmonary TB (P<0.05). All findings are consistent with an under-representation of the IL10(-1082)*A-IL10(-592)*A haplotype in pulmonary TB patients. These results suggest that the polymorphisms LTA(+368) and IL10(-592), or variants in strong linkage disequilibrium, variably affect susceptibility to the differing clinical forms of TB in Peruvians.
Subject(s)
Tuberculosis/genetics , Adolescent , Adult , Case-Control Studies , Chi-Square Distribution , Cytokines/genetics , Female , Gene Frequency , Genetic Predisposition to Disease , Genome, Human , Haplotypes , Humans , Linkage Disequilibrium , Male , Peru/epidemiology , Polymerase Chain Reaction , Tuberculosis/epidemiologyABSTRACT
Polymorphism in SLC11A1 has been implicated in host susceptibility to tuberculosis. We have studied associations between INT4, D543N, and 3'UTR polymorphisms of SLC11A1 and different clinical forms of TB. Analysis used 507 patients with pulmonary TB, 123 with extra pulmonary TB and 513 controls. INT4 and D543N showed allelic association with pulmonary TB (P=0.02 and 0.03 respectively). INT4-D543N-3'UTR haplotypes showed an association with pulmonary TB (P=0.03). No association of SLC11A1 with miliary TB was observed, and a possible association of D543N to the pleural form (P=0.08) was suggested. These results support association between SLC11A1 and TB, particularly to the common pulmonary form.