RESUMO
Leprosy Type-1 Reactions (T1Rs) are pathological inflammatory responses that afflict a sub-group of leprosy patients and result in peripheral nerve damage. Here, we employed a family-based GWAS in 221 families with 229 T1R-affect offspring with stepwise replication to identify risk factors for T1R. We discovered, replicated and validated T1R-specific associations with SNPs located in chromosome region 10p21.2. Combined analysis across the three independent samples resulted in strong evidence of association of rs1875147 with T1R (p = 4.5x10-8; OR = 1.54, 95% CI = 1.32-1.80). The T1R-risk locus was restricted to a lncRNA-encoding genomic interval with rs1875147 being an eQTL for the lncRNA. Since a genetic overlap between leprosy and inflammatory bowel disease (IBD) has been detected, we evaluated if the shared genetic control could be traced to the T1R endophenotype. Employing the results of a recent IBD GWAS meta-analysis we found that 10.6% of IBD SNPs available in our dataset shared a common risk-allele with T1R (p = 2.4x10-4). This finding points to a substantial overlap in the genetic control of clinically diverse inflammatory disorders.
Assuntos
Humanos , Masculino , Feminino , Estudo de Associação Genômica Ampla , Hanseníase/genética , Hanseníase/patologia , Predisposição Genética para Doença , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R. METHODS: We performed a high-resolution association scan of the TNFSF15 locus to evaluate the association with T1R in 2 geographically and ethnically distinct populations: a family-based sample from Vietnam and a case-control sample from Brazil, comprising a total of 1768 subjects. RESULTS: In the Vietnamese sample, 47 single-nucleotide polymorphisms (SNPs) overlapping TNFSF15 and the adjacent TNFSF8 gene were associated with T1R but not with leprosy. Of the 47 SNPs, 39 were cis-expression quantitative trait loci (cis-eQTL) for TNFSF8 including SNPs located within the TNFSF15 gene. In the Brazilian sample, 18 of these cis-eQTL SNPs overlapping the TNFSF8 gene were validated for association with T1R. CONCLUSIONS: Taken together, these results indicate TNFSF8 and not TNFSF15 as an important T1R susceptibility gene. Our data support the need for infection genetics to go beyond genes for pathogen control to explore genes involved in a commensurate host response.
Assuntos
Humanos , Mapeamento Cromossômico , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Ligante CD30/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Estudos de Associação Genética , Hanseníase/genética , Hanseníase/imunologiaRESUMO
Type-1 (T1R) and Type-2 (T2R) leprosy reactions (LR), which affect up to 50% of leprosy patients, are aggressive inflammatory episodes of sudden onset and highly variable incidence across populations. LR are often diagnosed concurrently with leprosy, but more frequently occur several months after treatment onset. It is not uncommon for leprosy patients to develop recurring reactional episodes; however, they rarely undergo both types of LR. Today, LR are the main cause of permanent disabilities associated with leprosy and represent a major challenge in the clinical management of leprosy patients. Although progress has been made in understanding the immunopathology of LR, the factors that cause a leprosy patient to suffer from LR are largely unknown. Given the impact that ethnic background has on the risk of developing LR, host genetic factors have long been suspected of contributing to LR. Indeed, polymorphisms in seven genes [Toll-like receptors (TLR)1, TLR2, nucleotide-binding oligomerisation domain containing 2, vitamin D receptor, natural resistance-associated macrophage protein 1, C4B and interleukin-6] have been found to be associated with one or more LR outcomes. The identification of host genetic markers with predictive value for LR would have a major impact on nerve damage control in leprosy. In this review, we present the recent advances achieved through genetic studies of LR.
Assuntos
Humanos , Biomarcadores , Hanseníase , Hanseníase/genética , Hanseníase/imunologia , Hanseníase/patologiaRESUMO
A variety of host immunogenetic factors appear to influence both an individual's susceptibility to infection with Mycobacterium leprae and the pathologic course of the disease. Animal models can contribute to a better understanding of the role of immunogenetics in leprosy through comparative studies helping to confirm the significance of various identified traits and in deciphering the underlying mechanisms that may be involved in expression of different disease related phenotypes. Genetically engineered mice, with specific immune or biochemical pathway defects, are particularly useful for investigating granuloma formation and resistance to infection and are shedding new light on borderline areas of the leprosy spectrum which are clinically unstable and have a tendency toward immunological complications. Though armadillos are less developed in this regard, these animals are the only other natural hosts of M. leprae and they present a unique opportunity for comparative study of genetic markers and mechanisms associable with disease susceptibility or resistance, especially the neurological aspects of leprosy. In this paper, we review the recent contributions of genetically engineered mice and armadillos toward our understanding of the immunogenetics of leprosy.
Assuntos
Animais , Camundongos , Animais Geneticamente Modificados , Tatus/genética , Modelos Animais de Doenças , Fenômenos Imunogenéticos/imunologia , Hanseníase/genética , Hanseníase/imunologia , Mycobacterium leprae , Camundongos/genética , Tatus/microbiologia , Mycobacterium leprae/genética , Mycobacterium leprae/imunologiaRESUMO
The tuberculin skin test (TST) measures the intensity of antimycobacterial acquired immunity and is used to diagnose latent infection with Mycobacterium tuberculosis. We report evidence for a codominant gene explaining â¼65% of the TST variability. Disregarding the host genetic background may lead to misclassifications of TST-based diagnosis of latent M. tuberculosis infection.
Assuntos
Variação Genética , Tuberculose Latente/diagnóstico , Tuberculose Latente/genética , Mycobacterium tuberculosis/imunologia , Teste Tuberculínico/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Colômbia , Características da Família , Feminino , Humanos , Lactente , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Type-1 (T1R) and Type-2 (T2R) leprosy reactions (LR), which affect up to 50% of leprosy patients, are aggressive inflammatory episodes of sudden onset and highly variable incidence across populations. LR are often diagnosed concurrently with leprosy, but more frequently occur several months after treatment onset. It is not uncommon for leprosy patients to develop recurring reactional episodes; however, they rarely undergo both types of LR. Today, LR are the main cause of permanent disabilities associated with leprosy and represent a major challenge in the clinical management of leprosy patients. Although progress has been made in understanding the immunopathology of LR, the factors that cause a leprosy patient to suffer from LR are largely unknown. Given the impact that ethnic background has on the risk of developing LR, host genetic factors have long been suspected of contributing to LR. Indeed, polymorphisms in seven genes [Toll-like receptors (TLR)1, TLR2, nucleotide-binding oligomerisation domain containing 2, vitamin D receptor, natural resistance-associated macrophage protein 1, C4B and interleukin-6] have been found to be associated with one or more LR outcomes. The identification of host genetic markers with predictive value for LR would have a major impact on nerve damage control in leprosy. In this review, we present the recent advances achieved through genetic studies of LR.
Assuntos
Biomarcadores , Hanseníase , Humanos , Hanseníase/genética , Hanseníase/imunologia , Hanseníase/patologiaRESUMO
A variety of host immunogenetic factors appear to influence both an individual's susceptibility to infection with Mycobacterium leprae and the pathologic course of the disease. Animal models can contribute to a better understanding of the role of immunogenetics in leprosy through comparative studies helping to confirm the significance of various identified traits and in deciphering the underlying mechanisms that may be involved in expression of different disease related phenotypes. Genetically engineered mice, with specific immune or biochemical pathway defects, are particularly useful for investigating granuloma formation and resistance to infection and are shedding new light on borderline areas of the leprosy spectrum which are clinically unstable and have a tendency toward immunological complications. Though armadillos are less developed in this regard, these animals are the only other natural hosts of M. leprae and they present a unique opportunity for comparative study of genetic markers and mechanisms associable with disease susceptibility or resistance, especially the neurological aspects of leprosy. In this paper, we review the recent contributions of genetically engineered mice and armadillos toward our understanding of the immunogenetics of leprosy.
Assuntos
Animais Geneticamente Modificados , Tatus/genética , Modelos Animais de Doenças , Fenômenos Imunogenéticos/imunologia , Hanseníase/genética , Hanseníase/imunologia , Camundongos/genética , Mycobacterium leprae , Animais , Tatus/microbiologia , Camundongos/imunologia , Mycobacterium leprae/genética , Mycobacterium leprae/imunologiaRESUMO
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.
Assuntos
Hanseníase/genética , Mycobacterium leprae/isolamento & purificação , Fator de Necrose Tumoral alfa/genética , Adulto , Brasil/epidemiologia , Estudos de Casos e Controles , DNA/química , DNA/genética , Feminino , Variação Genética , Genótipo , Humanos , Hanseníase/epidemiologia , Hanseníase/microbiologia , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
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.
Assuntos
Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Variação Genética , Brasil/epidemiologia , DNA , Estudos de Casos e Controles , Reação em Cadeia da Polimerase , Fator de Necrose Tumoral alfa/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Hanseníase/genética , Hanseníase/microbiologia , Hanseníase/epidemiologia , Mycobacterium leprae/isolamento & purificaçãoRESUMO
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.