RESUMO
The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35-0.49, P = 3.71×10-8, for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45-0.55, P = 1.26×10-9). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations.
Assuntos
Cromossomos Humanos Par 10 , Resistência à Doença/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mycobacterium tuberculosis , Locos de Características Quantitativas , Tuberculose/genética , Tuberculose/microbiologia , Alelos , Biologia Computacional/métodos , França , Genótipo , Humanos , Metanálise como Assunto , Grupos Populacionais/genética , África do Sul , VietnãRESUMO
Leprosy is a chronic infectious disease of the skin and peripheral nerves with a strong genetic predisposition. Recent genome-wide approaches have identified numerous common variants associated with leprosy, almost all in the Chinese population. We conducted the first family-based genome-wide association study of leprosy in 622 affected offspring from Vietnam, followed by replication in an independent sample of 1181 leprosy cases and 668 controls of the same ethnic origin. The most significant results were observed within the HLA region, in which six SNPs displayed genome-wide significant associations, all of which were replicated in the independent case/control sample. We investigated the signal in the HLA region in more detail, by conducting a multivariate analysis on the case/control sample of 319 GWAS-suggestive HLA hits for which evidence for replication was obtained. We identified three independently associated SNPs, two located in the HLA class I region (rs1265048: OR = 0.69 [0.58-0.80], combined p-value = 5.53x10-11; and rs114598080: OR = 1.47 [1.46-1.48], combined p-value = 8.77x10-13), and one located in the HLA class II region (rs3187964 (OR = 1.67 [1.55-1.80], combined p-value = 8.35x10-16). We also validated two previously identified risk factors for leprosy: the missense variant rs3764147 in the LACC1 gene (OR = 1.52 [1.41-1.63], combined p-value = 5.06x10-14), and the intergenic variant rs6871626 located close to the IL12B gene (OR = 0.73 [0.61-0.84], combined p-value = 6.44x10-8). These results shed new light on the genetic control of leprosy, by dissecting the influence of HLA SNPs, and validating the independent role of two additional variants in a large Vietnamese sample.
Assuntos
Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Hanseníase/genética , Polimorfismo de Nucleotídeo Único , Feminino , Estudo de Associação Genômica Ampla , Humanos , Subunidade p40 da Interleucina-12/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Hanseníase/epidemiologia , MasculinoRESUMO
Leprosy is a chronic disease caused by Mycobacterium leprae. Worldwide, more than 200,000 new patients are affected by leprosy annually, making it the second most common mycobacterial disease after tuberculosis. The MHC/HLA region has been consistently identified as carrying major leprosy susceptibility variants in different populations at times with inconsistent results. To establish the unambiguous molecular identity of classical HLA class I and class II leprosy susceptibility factors, we applied next-generation sequencing to genotype with high-resolution 11 HLA class I and class II genes in 1,155 individuals from a Vietnamese leprosy case-control sample. HLA alleles belonging to an extended haplotype from HLA-A to HLA-DPB1 were associated with risk to leprosy. This susceptibility signal could be reduced to the HLA-DRB1*10:01~ HLA-DQA1*01:05 alleles which were in complete linkage disequilibrium (LD). In addition, haplotypes containing HLA-DRB3~ HLA-DRB1*12:02 and HLA-C*07:06~ HLA-B*44:03~ HLA-DRB1*07:01 alleles were found as two independent protective factors for leprosy. Moreover, we replicated the previously associated HLA-DRB1*15:01 as leprosy risk factor and HLA-DRB1*04:05~HLA-DQA1*03:03 as protective alleles. When we narrowed the analysis to the single amino acid level, we found that the associations of the HLA alleles were largely captured by four independent amino acids at HLA-DRß1 positions 57 (D) and 13 (F), HLA-B position 63 (E) and HLA-A position 19 (K). Hence, analyses at the amino acid level circumvented the ambiguity caused by strong LD of leprosy susceptibility HLA alleles and identified four distinct leprosy susceptibility factors.
Assuntos
Aminoácidos/genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Hanseníase/patologia , Mutação , Adolescente , Adulto , Feminino , Haplótipos , Humanos , Hanseníase/genética , Masculino , Adulto JovemRESUMO
Type-1 reactions (T1R) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the genewise enrichment of rare protein-altering variants in 7 genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Genewise enrichment of nonsynonymous variants was tested with both kernel-based (sequence kernel association test [SKAT]) and burden methods. Of the 7 genes tested 2 showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (PSKAT-O = 1.6 × 10-4). This genewise association was driven almost entirely by the gain-of-function variant R1628P (P = 0.004; odds ratio = 0.29). The second genewise association was found for the Parkin coding gene PRKN (formerly PARK2) where 7 rare variants were enriched in T1R-affected cases (PSKAT-O = 7.4 × 10-5). Mutations in both PRKN and LRRK2 are known causes of Parkinson's disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that amino acids in Parkin targeted by nonsynonymous T1R-risk mutations were also enriched for mutations implicated in PD (P = 1.5 × 10-4). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity.
Assuntos
Hanseníase , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Mutação , Doença de Parkinson , Ubiquitina-Proteína Ligases , Feminino , Humanos , Hanseníase/genética , Hanseníase/metabolismo , Hanseníase/patologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Masculino , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy susceptibility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for expression quantitative trait loci (eQTL) that are associated with transcript variation before and after stimulation with M. leprae sonicate in whole blood cells. We show that M. leprae antigen stimulation mainly triggered the upregulation of immune related genes and that a substantial proportion of the differential gene expression is genetically controlled. Indeed, using stringent criteria, we identified 318 genes displaying cis-eQTL at an FDR of 0.01, including 66 genes displaying response-eQTL (reQTL), i.e. cis-eQTL that showed significant evidence for interaction with the M. leprae stimulus. Such reQTL correspond to regulatory variations that affect the interaction between human whole blood cells and M. leprae sonicate and, thus, likely between the human host and M. leprae bacilli. We found that reQTL were significantly enriched among binding sites of transcription factors that are activated in response to infection, and that they were enriched among single nucleotide polymorphisms (SNPs) associated with susceptibility to leprosy per se and Type-I Reaction, and seven of them have been targeted by recent positive selection. Our study suggested that natural selection shaped our genomic diversity to face pathogen exposure including M. leprae infection.
Assuntos
Antígenos de Bactérias/imunologia , Hanseníase/genética , Locos de Características Quantitativas , Regulação para Baixo , Estudos de Associação Genética , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno/genética , Humanos , Hanseníase/imunologia , Mycobacterium leprae , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , RNA Bacteriano/isolamento & purificação , Regulação para CimaRESUMO
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
Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Hanseníase/genética , RNA Longo não Codificante/genética , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/patologia , Hanseníase/complicações , Hanseníase/patologia , Masculino , Degeneração Neural/complicações , Degeneração Neural/genética , Degeneração Neural/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , RNA Longo não Codificante/biossíntese , Fatores de Risco , VietnãRESUMO
Leprosy reversal reactions type 1 (T1R) are acute immune episodes that affect a subset of leprosy patients and remain a major cause of nerve damage. Little is known about the relative importance of innate versus environmental factors in the pathogenesis of T1R. In a retrospective design, we evaluated innate differences in response to Mycobacterium leprae between healthy individuals and former leprosy patients affected or free of T1R by analyzing the transcriptome response of whole blood to M. leprae sonicate. Validation of results was conducted in a subsequent prospective study. We observed the differential expression of 581 genes upon exposure of whole blood to M. leprae sonicate in the retrospective study. We defined a 44 T1R gene set signature of differentially regulated genes. The majority of the T1R set genes were represented by three functional groups: i) pro-inflammatory regulators; ii) arachidonic acid metabolism mediators; and iii) regulators of anti-inflammation. The validity of the T1R gene set signature was replicated in the prospective arm of the study. The T1R genetic signature encompasses genes encoding pro- and anti-inflammatory mediators of innate immunity. This suggests an innate defect in the regulation of the inflammatory response to M. leprae antigens. The identified T1R gene set represents a critical first step towards a genetic profile of leprosy patients who are at increased risk of T1R and concomitant nerve damage.
Assuntos
Antígenos de Bactérias/sangue , Perfilação da Expressão Gênica , Hanseníase/genética , Mycobacterium leprae/genética , Degeneração Neural/genética , Adolescente , Adulto , Antígenos de Bactérias/isolamento & purificação , Criança , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata/genética , Interferon gama/sangue , Hanseníase/microbiologia , Hanseníase/fisiopatologia , Masculino , Mycobacterium leprae/patogenicidade , Degeneração Neural/microbiologia , Degeneração Neural/fisiopatologia , Estudos RetrospectivosRESUMO
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
Ligante CD30/genética , Hanseníase/genética , Mapeamento Cromossômico , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hanseníase/imunologia , Polimorfismo de Nucleotídeo Único , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
Leprosy is caused by infection with Mycobacterium leprae and is classified clinically into paucibacillary (PB) or multibacillary (MB) subtypes based on the number of skin lesions and the bacillary index detected in skin smears. We previously identified a major PB susceptibility locus on chromosome region 10p13 in Vietnamese families by linkage analysis. In the current study, we conducted high-density association mapping of the 9.5 Mb linkage peak on chromosome region 10p13 covering 39 genes. Using leprosy per se and leprosy subtypes as phenotypes, we employed 294 nuclear families (303 leprosy cases, 63 % MB, 37 % PB) as a discovery sample and 192 nuclear families (192 cases, 55 % MB, 45 % PB) as a replication sample. Replicated significant association signals were revealed in the genes for cubilin (CUBN) and nebulette (NEBL). In the combined sample, the C allele (frequency 0.26) at CUBN SNP rs10904831 showed association [p = 1 × 10(-5); OR 0.52 (0.38-0.7)] with MB leprosy only. Likewise, allele T (frequency 0.42) at NEBL SNP rs11012461 showed association [p = 4.2 × 10(-5); OR 2.51 (1.6-4)] with MB leprosy only. These associations remained valid for the CUBN signal when taking into account the effective number of tests performed (type I error significance threshold = 2.4 × 10(-5)). We used the results of our analyses to propose a new model for the genetic control of polarization of clinical leprosy.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 10/genética , Proteínas do Citoesqueleto/genética , Ligação Genética , Predisposição Genética para Doença , Proteínas com Domínio LIM/genética , Hanseníase Multibacilar/genética , Receptores de Superfície Celular/genética , Alelos , Povo Asiático/genética , Mapeamento Cromossômico , Feminino , Frequência do Gene , Genética Populacional , Genótipo , Humanos , Masculino , Mycobacterium leprae , Polimorfismo de Nucleotídeo Único , VietnãRESUMO
One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2/PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2/PACRG. For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence (P = 1.1 × 10(-5)) for association among Vietnamese patients. Next, we enrolled a case-control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture >80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy (P < 10(-8)). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced.
Assuntos
Etnicidade/genética , Hanseníase/genética , Chaperonas Moleculares/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idade de Início , Povo Asiático/genética , Estudos de Casos e Controles , Criança , Feminino , Estudos de Associação Genética , Humanos , Índia , Íntrons , Hanseníase/diagnóstico , Desequilíbrio de Ligação , Masculino , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Vietnã , População Branca/genética , Adulto JovemRESUMO
Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,000 persons each year. Clinically, leprosy can be categorized as paucibacillary or multibacillary disease. These clinical forms develop in persons that are intrinsically susceptible to leprosy per se, that is, leprosy independent of its specific clinical manifestation. We report here on a genome-wide search for loci controlling susceptibility to leprosy per se in a panel of 86 families including 205 siblings affected with leprosy from Southern Vietnam. Using model-free linkage analysis, we found significant evidence for a susceptibility gene on chromosome region 6q25 (maximum likelihood binomial (MLB) lod score 4.31; P = 5 x 10(-6)). We confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers (D6S1035 and D6S305) showed strong evidence for association with leprosy (P = 6.7 x 10(-4) and P = 5.9 x 10(-5), respectively).
Assuntos
Cromossomos Humanos Par 6/genética , Hanseníase/genética , Alelos , Cromossomos Humanos Par 10/genética , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , VietnãRESUMO
A genomewide association study in Chinese patients with leprosy detected association signals in 16 single-nucleotide polymorphisms (SNPs) belonging to 6 loci, of which 4 are related to the NOD2 signaling pathway and are Crohn's disease susceptibility loci. Here, we studied these 16 SNPs as potential leprosy susceptibility factors in 474 Vietnamese leprosy simplex families. We replicated SNPs at HLA-DR-DQ, RIPK2, CCDC122-LACC1, and NOD2 as leprosy susceptibility factors in Vietnam. These results validated the striking overlap in the genetic control of Crohn's disease and leprosy.
Assuntos
Povo Asiático/genética , Doença de Crohn/genética , Hanseníase/genética , Família , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Hanseníase/epidemiologia , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Vietnã/epidemiologiaRESUMO
Experimental evidence suggested the existence of unidentified leprosy susceptibility loci in the human leukocyte antigen (HLA) complex. To identify such genetic risk factors, a high-density association scan of a 1.9-mega-base (Mb) region in the HLA complex was performed. Among 682 single-nucleotide polymorphisms (SNPs), 59 were associated with leprosy (P <.01) in 198 Vietnamese single-case leprosy families. Genotyping of these SNPs in an independent sample of 292 Vietnamese single-case leprosy families replicated the association of 12 SNPs (P <.01). Multivariate analysis of these 12 SNPs showed that the association information could be captured by 2 intergenic HLA class I region SNPs (P = 9.4 × 10â»9)-rs2394885 and rs2922997 (marginal multivariate P = 2.1 × 10â»7 and P = .0016, respectively). SNP rs2394885 tagged the HLA-C*15:05 allele in the Vietnamese population. The identical associations were validated in a third sample of 364 patients with leprosy and 371 control subjects from North India. These results implicated class I alleles in leprosy pathogenesis.
Assuntos
Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Hanseníase/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Frequência do Gene , Genótipo , Humanos , Índia , Lactente , Hanseníase/imunologia , Pessoa de Meia-Idade , Vietnã , Adulto JovemRESUMO
This study investigates the moderating role of strategic interaction on the relationship between bank lending and macroeconomic factors, using panel data on Vietnamese commercial banks over 2008-2018. We find that the effect of macroeconomic and monetary policy shocks on bank lending behaviour is less pronounced when banks engage in a less competitively aggressive environment. The study contributes to the literature of bank lending by incorporating macroeconomic environment and micro (strategic interaction)-level to analyze the lending behaviour of an individual bank. Since the analysis of macroeconomic factors alone is insufficient to explain the aggregate relationships in the model of banking, understanding the nature of strategic interaction is essential to predetermine how bank lending behaviour relates to the transmission mechanism of monetary policy.
RESUMO
Leprosy is the second most prevalent mycobacterial disease globally. Despite the existence of an effective therapy, leprosy incidence has consistently remained above 200,000 cases per year since 2010. Numerous host genetic factors have been identified for leprosy that contribute to the persistently high case numbers. In the past decade, genetic epidemiology approaches, including genome-wide association studies (GWAS), identified more than 30 loci contributing to leprosy susceptibility. However, GWAS loci commonly encompass multiple genes, which poses a challenge to define causal candidates for each locus. To address this problem, we hypothesized that genes contributing to leprosy susceptibility differ in their frequencies of rare protein-altering variants between cases and controls. Using deep resequencing we assessed protein-coding variants for 34 genes located in GWAS or linkage loci in 555 Vietnamese leprosy cases and 500 healthy controls. We observed 234 nonsynonymous mutations in the targeted genes. A significant depletion of protein-altering variants was detected for the IL18R1 and BCL10 genes in leprosy cases. The IL18R1 gene is clustered with IL18RAP and IL1RL1 in the leprosy GWAS locus on chromosome 2q12.1. Moreover, in a recent GWAS we identified an HLA-independent signal of association with leprosy on chromosome 6p21. Here, we report amino acid changes in the CDSN and PSORS1C2 genes depleted in leprosy cases, indicating them as candidate genes in the chromosome 6p21 locus. Our results show that deep resequencing can identify leprosy candidate susceptibility genes that had been missed by classic linkage and association approaches.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hanseníase/genética , Adolescente , Adulto , Proteína 10 de Linfoma CCL de Células B/genética , Feminino , Ligação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Subunidade alfa de Receptor de Interleucina-18/genética , Subunidade beta de Receptor de Interleucina-18/genética , Masculino , Adulto JovemRESUMO
The chromosomal region 10p13 has been linked to paucibacillary leprosy in two independent studies. The MRC1 gene, encoding the human mannose receptor (MR), is located in the 10p13 region and non-synonymous SNPs in exon 7 of the gene have been suggested as leprosy susceptibility factors. We determined that G396S is the only non-synonymous exon 7-encoded polymorphism in 396 unrelated Vietnamese subjects. This SNP was genotyped in 490 simplex and 90 multiplex leprosy families comprising 704 patients (47% paucibacillary; 53% multibacillary). We observed significant under-transmission of the serine allele of the G396S polymorphism with leprosy per se (P = 0.036) and multibacillary leprosy (P = 0.034). In a sample of 384 Brazilian leprosy cases (51% paucibacillary; 49% multibacillary) and 399 healthy controls, we observed significant association of the glycine allele of the G396S polymorphism with leprosy per se (P = 0.016) and multibacillary leprosy (P = 0.023). In addition, we observed a significant association of exon 7 encoded amino acid haplotypes with leprosy per se (P = 0.012) and multibacillary leprosy (P = 0.004). Next, we tested HEK293 cells over-expressing MR constructs (293-MR) with three exon 7 haplotypes of MRC1 for their ability to bind and internalize ovalbumin and zymosan, two classical MR ligands. No difference in uptake was measured between the variants. In addition, 293-MR failed to bind and internalize viable Mycobacterium leprae and BCG. We propose that the MR-M. leprae interaction is modulated by an accessory host molecule of unknown identity.
Assuntos
Éxons , Lectinas Tipo C/genética , Hanseníase/genética , Lectinas de Ligação a Manose/genética , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Estudos de Casos e Controles , Células Cultivadas , Clonagem Molecular , Predisposição Genética para Doença , Humanos , Lectinas Tipo C/metabolismo , Lectinas Tipo C/fisiologia , Desequilíbrio de Ligação , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Lectinas de Ligação a Manose/fisiologia , Proteínas Mutantes/genética , Mycobacterium bovis/metabolismo , Mycobacterium leprae/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Ligação Proteica , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/fisiologia , TransfecçãoRESUMO
After sustained exposure to Mycobacterium leprae, only a subset of exposed individuals develops clinical leprosy. Moreover, leprosy patients show a wide spectrum of clinical manifestations that extend from the paucibacillary (PB) to the multibacillary (MB) form of the disease. This "polarization" of leprosy has long been a major focus of investigation for immunologists because of the different immune response in these two forms. But while leprosy per se has been shown to be under tight human genetic control, few epidemiological or genetic studies have focused on leprosy subtypes. Using PubMed, we collected available data in English on the epidemiology of leprosy polarization and the possible role of human genetics in its pathophysiology until September 2015. At the genetic level, we assembled a list of 28 genes from the literature that are associated with leprosy subtypes or implicated in the polarization process. Our bibliographical search revealed that improved study designs are needed to identify genes associated with leprosy polarization. Future investigations should not be restricted to a subanalysis of leprosy per se studies but should instead contrast MB to PB individuals. We show the latter approach to be the most powerful design for the identification of genetic polarization determinants. Finally, we bring to light the important resource represented by the nine-banded armadillo model, a unique animal model for leprosy.
Assuntos
Tatus , Hanseníase Multibacilar/genética , Hanseníase Paucibacilar/genética , Doenças Negligenciadas/genética , Alelos , Animais , Tatus/microbiologia , Modelos Animais de Doenças , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Hanseníase Multibacilar/epidemiologia , Hanseníase Multibacilar/microbiologia , Hanseníase Multibacilar/fisiopatologia , Hanseníase Paucibacilar/epidemiologia , Hanseníase Paucibacilar/microbiologia , Hanseníase Paucibacilar/fisiopatologia , Masculino , Mycobacterium leprae/fisiologia , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/microbiologiaRESUMO
BACKGROUND: Depending on the epidemiological setting, a variable proportion of leprosy patients will suffer from excessive pro-inflammatory responses, termed type-1 reactions (T1R). The LRRK2 gene encodes a multi-functional protein that has been shown to modulate pro-inflammatory responses. Variants near the LRRK2 gene have been associated with leprosy in some but not in other studies. We hypothesized that LRRK2 was a T1R susceptibility gene and that inconsistent association results might reflect different proportions of patients with T1R in the different sample settings. Hence, we evaluated the association of LRRK2 variants with T1R susceptibility. METHODOLOGY: An association scan of the LRRK2 locus was performed using 156 single-nucleotide polymorphisms (SNPs). Evidence of association was evaluated in two family-based samples: A set of T1R-affected and a second set of T1R-free families. Only SNPs significant for T1R-affected families with significant evidence of heterogeneity relative to T1R-free families were considered T1R-specific. An expression quantitative trait locus (eQTL) analysis was applied to evaluate the impact of T1R-specific SNPs on LRRK2 gene transcriptional levels. PRINCIPAL FINDINGS: A total of 18 T1R-specific variants organized in four bins were detected. The core SNP capturing the T1R association was the LRRK2 missense variant M2397T (rs3761863) that affects LRRK2 protein turnover. Additionally, a bin of nine SNPs associated with T1R were eQTLs for LRRK2 in unstimulated whole blood cells but not after exposure to Mycobacterium leprae antigen. SIGNIFICANCE: The results support a preferential association of LRRK2 variants with T1R. LRRK2 involvement in T1R is likely due to a pathological pro-inflammatory loop modulated by LRRK2 availability. Interestingly, the M2397T variant was reported in association with Crohn's disease with the same risk allele as in T1R suggesting common inflammatory mechanism in these two distinct diseases.
Assuntos
Suscetibilidade a Doenças , Inflamação/genética , Inflamação/patologia , Hanseníase/genética , Hanseníase/patologia , Mutação de Sentido Incorreto , Proteínas Serina-Treonina Quinases/genética , Adulto , Feminino , Estudos de Associação Genética , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: International consensus statements on the management of scalp psoriasis are available, but no such recommendations exist for Asia. METHODS: The Asia Scalp Psoriasis Study Group (ASPSG) met in May 2011 to review the epidemiologic pattern of scalp psoriasis in Southeast Asia and to develop Asia-specific recommendations for its management. RESULTS: The overall prevalence of psoriasis in Asia is <0.3%, but 75-90% have scalp involvement, whether isolated or with lesions elsewhere, which can negatively impact quality of life (QoL). Treatment decisions should be based primarily on objective disease severity, but should also take account of patient QoL. Psychosocial support and more aggressive treatment should be offered to all patients with moderate to severe QoL impairment. Topical therapy is indicated first-line in all patients, with combination therapy (corticosteroid + calcipotriol), more occlusive formulations, keratolytics, and very potent corticosteroids for patients needing greater or faster efficacy. Systemic therapies, light or laser treatments should be reserved for patients with severe and recalcitrant disease. CONCLUSIONS: The ASPSG recommends a patient-centered approach to scalp psoriasis management, consistent with the international consensus statements. Asian physicians should also consider patient QoL, prior treatment response, formulation preferences, likely adherence, cost, time available for self-management, and potential adverse events.
Assuntos
Fármacos Dermatológicos/administração & dosagem , Assistência Centrada no Paciente/métodos , Fototerapia/métodos , Psoríase/terapia , Dermatoses do Couro Cabeludo/terapia , Administração Cutânea , Corticosteroides/administração & dosagem , Adulto , Idade de Início , Ásia , Consenso , Feminino , Humanos , Malassezia/isolamento & purificação , Masculino , Psoríase/etnologia , Psoríase/microbiologia , Psoríase/patologia , Qualidade de Vida , Dermatoses do Couro Cabeludo/etnologia , Dermatoses do Couro Cabeludo/microbiologia , Dermatoses do Couro Cabeludo/patologia , Índice de Gravidade de DoençaRESUMO
Leprosy is a persistent infectious disease caused by Mycobacterium leprae that still affects over 200,000 new patients annually. The host genetic background is an important risk factor for leprosy susceptibility and the PARK2 gene is a replicated leprosy susceptibility candidate gene. The protein product of PARK2, Parkin, is an E3 ubiquitin ligase that is involved in the development of various forms of Parkinsonism. The human macrophage is both a natural host cell of M. leprae as well as a primary mediator of natural immune defenses, in part by secreting important pro-inflammatory cytokines and chemokines. Here, we report that down-regulation of Parkin in THP-1 macrophages, human monocyte-derived macrophages and human Schwann cells resulted in a consistent and specific decrease in interleukin-6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1/CCL2) production in response to mycobacteria or LPS. Interestingly, production of IL-6 at 6 hours by THP-1 cells stimulated with live M. leprae and M. bovis BCG was dependent on pretreatment with 1,25-dihydroxyvitamin D(3) (VD). Parkin knockdown in VD-treated cells blocked IL-6 induction by mycobacteria. However, IκB-α phosphorylation and levels of IκB-ξ, a nuclear protein required for IL-6 expression, were not affected by Parkin silencing. Phosphorylation of MAPK ERK1/2 and p38 was unaffected by Parkin silencing while JNK activation was promoted but did not explain the altered cytokine production. In a final set of experiments we found that genetic risk factors of leprosy located in the PARK2 promoter region were significantly correlated with M. leprae sonicate triggered CCL2 and IL6 transcript levels in whole blood assays. These results associated genetically controlled changes in the production of MCP-1/CCL2 and IL-6 with known leprosy susceptibility factors.