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1.
Cell Discov ; 8(1): 2, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35013182

RESUMO

Lepromatous leprosy (L-LEP), caused by the massive proliferation of Mycobacterium leprae primarily in macrophages, is an ideal disease model for investigating the molecular mechanism of intracellular bacteria evading or modulating host immune response. Here, we performed single-cell RNA sequencing of both skin biopsies and peripheral blood mononuclear cells (PBMCs) of L-LEP patients and healthy controls. In L-LEP lesions, we revealed remarkable upregulation of APOE expression that showed a negative correlation with the major histocompatibility complex II gene HLA-DQB2 and MIF, which encodes a pro-inflammatory and anti-microbial cytokine, in the subset of macrophages exhibiting a high expression level of LIPA. The exhaustion of CD8+ T cells featured by the high expression of TIGIT and LAG3 in L-LEP lesions was demonstrated. Moreover, remarkable enhancement of inhibitory immune receptors mediated crosstalk between skin immune cells was observed in L-LEP lesions. For PBMCs, a high expression level of APOE in the HLA-DRhighFBP1high monocyte subset and the expansion of regulatory T cells were found to be associated with L-LEP. These findings revealed the primary suppressive landscape in the L-LEP patients, providing potential targets for the intervention of intracellular bacteria caused persistent infections.

2.
Front Genet ; 12: 768259, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34976012

RESUMO

Background: Leprosy is a chronic infectious skin and neurological disease, and genetic background is considered to be one of the major factors of risk. The major histocompatibility complex (MHC) region not only affects susceptibility to leprosy but also its development and outcome. Given the complex traits of the MHC region, variants and the potential mechanism by which HLA influences leprosy development need to be further explored. Methods: We extracted previous genome-wide association study data from the Northern Han Chinese population to perform HLA fine-mapping. Using the 1,000 Genome Project Phase 3 dataset as the reference panel, single-nucleotide polymorphisms (SNP), insertion and deletion (INDEL) and copy number variant (CNV) imputation were carried out. HLA classical alleles and amino acids in the MHC region were imputed using the HAN-MHC database. Further stepwise regression analysis was conducted to analyze independent signals of variants related to leprosy. Results: We identified four independent variants: esv3608598, rs7754498, rs3130781 and rs144388449. Among them, esv3608598 is a CNV and the first HLA CNV associated with leprosy risk. SNP annotation using RegulomeDB, HaploReg, and rVarBase showed that three SNPs are likely to affect the pathogenesis of leprosy. Conclusion: In summary, this is the first study to assess the association between HLA CNV and leprosy susceptibility in a Northern Han Chinese population. By fine mapping of the MHC region in this population, our findings provide evidence for the contribution of HLA to leprosy susceptibility.

3.
PLoS Negl Trop Dis ; 14(10): e0008746, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33064728

RESUMO

Leprosy is a stigmatizing, chronic infection which degenerates the nervous system and often leads to incapacitation. Multi-drug therapy which consists of dapsone, rifampicin and clofazimine has been effective to combat this disease. In Indonesia, especially in Papua Island, leprosy is still a problem. Furthermore, there had been higher reports of Dapsone Hypersensitivity Syndrome (DHS) which also challenges leprosy elimination in certain aspects. Globally, DHS has a prevalence rate of 1.4% and a fatality rate up to 13%. The aim of this study is to validate HLA-B*13:01, a previously discovered biomarker for DHS in the Chinese population, as a biomarker for DHS in the Papua population.This is a case-control study of 34 leprosy patients who presented themselves with DHS (case subjects) and 52 leprosy patients without DHS (control subjects). Patients were recruited from 2 provinces: Papua and West Papua. DNA was extracted from 3 ml blood specimens. HLA-B alleles were typed using the gold-standard sequence based typing method. Results were then analysed using logistic regression and risk assessment was carried out. The results of HLA-typing showed that HLA-B*13:01 was the most significant allele associated with DHS, with odds ratio = 233.64 and P-value = 7.11×10-9, confirming the strong association of HLA-B*13:01 to DHS in the Papua population. The sensitivity of this biomarker is 91.2% and specificity is 96.2%, with an area under the curve of 0.95. HLA-B*13:01 is validated as a biomarker for DHS in leprosy patients in Papua, Indonesia, and can potentially be a good predictor of DHS to help prevent this condition in the future.


Assuntos
Dapsona/efeitos adversos , Hipersensibilidade a Drogas/prevenção & controle , Antígeno HLA-B13/genética , Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Adolescente , Adulto , Alelos , Biomarcadores , Estudos de Casos e Controles , Clofazimina/administração & dosagem , Dapsona/administração & dosagem , Hipersensibilidade a Drogas/epidemiologia , Quimioterapia Combinada , Feminino , Humanos , Indonésia , Hansenostáticos/administração & dosagem , Modelos Logísticos , Masculino , Rifampina/administração & dosagem , Medição de Risco , Síndrome , Adulto Jovem
4.
Acta Derm Venereol ; 100(17): adv00299, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33047146

RESUMO

Filaggrin, encoded by the FLG gene, plays a crucial role in the barrier function of epidermis, but the association between FLG loss-of-function mutations and infectious skin diseases has not been systematically studied. FLG coding sequences from 945 patients with leprosy and 916 healthy controls were captured and enriched using an array-based high-throughput system, and subjected to next-generation sequencing. The loss-of-function mutations found were further validated by Sanger sequencing. A total of 21 loss-of-function mutations were found in 945 patients with leprosy, with a carrier rate of 17.53%, while the prevalence of these mutations in 916 healthy controls was 14.77%, which was significantly lower than in patients. Two individual FLG loss-of-function mutations (K4022X and Q1790X) were found to be significantly associated with leprosy. These results suggest a possible role for filaggrin in defending against leprosy pathogens.


Assuntos
Hanseníase , Proteínas S100/genética , Predisposição Genética para Doença , Genótipo , Humanos , Proteínas de Filamentos Intermediários/genética , Hanseníase/diagnóstico , Hanseníase/genética , Mutação , Proteínas S100/metabolismo
5.
PLoS Negl Trop Dis ; 14(8): e0008563, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797081

RESUMO

OBJECTIVE: Early diagnosis remains the primary goal for leprosy management programs. This study aims to determine whether active surveillance of patients with leprosy and their contact individuals increased identification of latent leprosy cases in the low-endemic areas. METHODS: This cross-sectional survey was carried out between October 2014 and August 2016 in 21 counties throughout Shandong Province. The survey was conducted among patients with leprosy released from treatment (RFT) and their contacts from both household and neighbors. RESULTS: A total of 2,210 RFT patients and 9,742 contacts comprising 7877 household contacts (HHCs), including 5,844 genetic related family members (GRFMs) and 2033 non-genetic related family members and 1,865 contacts living in neighboring houses (neighbor contacts, NCs), were recruited. Among identified individuals, one relapsed and 13 were newly diagnosed, giving a detection rate of 0.12%, corresponding to 120 times the passive case detection rate. Detection rates were similar for HHCs and NCs (0.114% vs. 0.214%, P = 0.287). Analysis of the family history of leprosy patients revealed clustering of newly diagnosed cases and association with residential coordinates of previously-diagnosed multibacillary leprosy cases. CONCLUSION: Active case-finding programs are feasible and contributes to early case detection by tracking HHCs and NCs in low-endemic areas.


Assuntos
Características da Família , Hanseníase/diagnóstico , Hanseníase/epidemiologia , Hanseníase/terapia , Características de Residência , Conduta Expectante , Adolescente , Adulto , Criança , Pré-Escolar , China/epidemiologia , Análise por Conglomerados , Estudos Transversais , Família , Feminino , Humanos , Lactente , Recém-Nascido , Hanseníase Multibacilar , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Front Immunol ; 11: 567, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32373110

RESUMO

Leprosy, a disease caused by the intracellular parasite Mycobacterium leprae or Mycobacterium lepromatosis, has affected humans for more than 4,000 years and is a stigmatized disease even now. Since clinical manifestations of leprosy patients present as an immune-related spectrum, leprosy is regarded as an ideal model for studying the interaction between host immune response and infection; in fact, the landscape of leprosy immune responses has been extensively investigated. Meanwhile, leprosy is to some extent a genetic disease because the genetic factors of hosts have long been considered major contributors to this disease. Many immune-related genes have been discovered to be associated with leprosy. However, immunological and genetic findings have rarely been studied and discussed together, and as a result, the effects of gene variants on leprosy immune responses and the molecular mechanisms of leprosy pathogenesis are largely unknown. In this context, we summarized advances in both the immunology and genetics of leprosy and discussed the perspective of the combination of immunological and genetic approaches in studying the molecular mechanism of leprosy pathogenesis. In our opinion, the integrating of immunological and genetic approaches in the future may be promising to elucidate the molecular mechanism of leprosy onset and how leprosy develops into different types of leprosy.


Assuntos
Hanseníase/genética , Hanseníase/imunologia , Humanos
7.
PLoS Negl Trop Dis ; 14(2): e0007891, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32078623

RESUMO

BACKGROUND: A few new leprosy cases still can be seen in Shandong province after elimination. In post-elimination era, government commitments dwindled and active case-finding activities were seldom done. Most of the cases were detected by passive modes and advanced cases with longer delay and visible disability were common. MATERIALS AND METHODS: Comprehensive measures including health promotion, personnel training, reward-offering, symptom surveillance and a powerful referral center were implemented in the past decade. The diagnosis of leprosy was mainly based on three cardinal clinical signs. Two-group classification system developed by the WHO was used and cases were classified into multibacillary (MB) type or paucibacillary (PB) type. Cases detected during period 2007-2017 were analyzed and associated factors of grade 2 disability (G2D) were explored. RESULTS: 231 new leprosy cases detected during 2007-2017 were analyzed. The mean age at diagnosis is 51.7±16.0 years and the number of males, peasants, illiterates, MB cases, G2D cases and immigrants were 130(56.3%), 221(95.7%), 73(31.6%), 184(79.7%), 92(39.8%) and 40(17.3%) respectively. 181(78.4%) cases were reported by skin clinics and 152 (65.8%) cases came from formerly high endemic counties/districts. The annual number of new cases showed a decreasing trend, from 42 cases in 2008 to 13 cases in 2017. 92 (39.8%) cases presented with G2D at diagnosis. The annual proportion of new cases with G2D declined from 50% in 2008 to 23% in 2017. PB type (OR = 2.76, 95% CI, 1.43-5.32), >12 months of patient delay (OR = 2.40, 95% CI, 1.38-4.19), >24 months of total delay (OR = 4.35, 95% CI, 2.33-8.11), detected by non skin-clinic (OR = 3.21, 95% CI, 1.68-6.14), known infectious source (OR = 1.77, 95% CI, 1.01-3.12) were associated with G2D. CONCLUSION: A few scattered cases still can be seen in post-elimination era and some kind of leprosy control program is still necessary. Government commitments including adequate financial security and strong policy support are vital. Comprehensive case-finding measures including health promotion, personnel training, reward-offering, with an emphasis on former high or middle endemic areas, are necessary to improve early presentation of suspected cases and to increase suspicion and encourage participation of all relevant medical staff. Symptom surveillance based on a powerful transfer center may play an important role in the early detection of new cases in post-elimination era.


Assuntos
Hanseníase/diagnóstico , Hanseníase/epidemiologia , Adulto , Idoso , China/epidemiologia , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
China CDC Wkly ; 2(4): 53-56, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-34594761
10.
PLoS Negl Trop Dis ; 13(3): e0007284, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30883558

RESUMO

BACKGROUND: The reduced amounts of Mycobacterium leprae (M. leprae) among paucibacillary (PB) patients reflect the need to further optimize methods for leprosy diagnosis. An increasing number of reports have shown that droplet digital polymerase chain reaction (ddPCR) is a promising tool for diagnosis of infectious disease among samples with low copy number. To date, no publications have investigated the utility of ddPCR in the detection of M. leprae. The aim of this study was to develop and evaluate a ddPCR assay for the diagnosis of PB leprosy. METHODOLOGY: The two most sensitive DNA targets for detection of M. leprae were selected from electronic databases for assessment of sensitivity and specificity by quantitative polymerase chain reaction (qPCR) and ddPCR. Control patients (n = 59) suffering from other dermatological diseases were used to define the cut-off of the duplex ddPCR assay. For comparative evaluation, qPCR and ddPCR assays were performed in 44 PB patients and 68 multibacillary (MB) patients. PRINCIPAL FINDINGS: M. leprae-specific repetitive element (RLEP) and groEL (encoding the 65 kDa molecular chaperone GroEL) were used to develop the ddPCR assay by systematically analyzing specificity and sensitivity. Based on the defined cut-off value, the ddPCR assay showed greater sensitivity in detecting M. leprae DNA in PB patients compared with qPCR (79.5% vs 36.4%), while both assays have a 100% sensitivity in MB patients. CONCLUSIONS/SIGNIFICANCE: We developed and evaluated a duplex ddPCR assay for leprosy diagnosis in skin biopsy samples from leprosy patients. While still costly, ddPCR might be a promising diagnostic tool for detection of PB leprosy.


Assuntos
Hanseníase Paucibacilar/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium leprae/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Pele/microbiologia , Adolescente , Adulto , Idoso , Biópsia , Chaperonina 60/genética , Feminino , Humanos , Sequências Repetitivas Dispersas , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/genética , Sensibilidade e Especificidade , Adulto Jovem
11.
JAMA Dermatol ; 155(6): 666-672, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30916737

RESUMO

Importance: Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone. Objective: To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01-positive leprosy. Design, Setting, and Participants: A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events. Exposures: Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT. Main Outcomes and Measures: The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control. Results: Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01-negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10-5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status. Conclusions and Relevance: Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01-positive leprosy may significantly reduce the incidence of DHS in the Chinese population.


Assuntos
Dapsona/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/prevenção & controle , Antígeno HLA-B13/genética , Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Adulto , Alelos , China , Clofazimina/administração & dosagem , Estudos de Coortes , Dapsona/administração & dosagem , Síndrome de Hipersensibilidade a Medicamentos/epidemiologia , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Quimioterapia Combinada , Feminino , Humanos , Incidência , Hansenostáticos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rifampina/administração & dosagem
12.
Acta Dermatovenerol Croat ; 26(3): 273-275, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30390734

RESUMO

Dear Editor, Dermatitis herpetiformis (DH) is a chronic, polymorphic, pruritic autoimmune blistering skin disease characterized by subepidermal blisters, neutrophilic microabscesses, and granular IgA deposition within the dermal papillae. DH is classified as a cutaneous manifestation of coeliac disease, a type of gluten-sensitive enteropathy (1). The treatment of DH includes dapsone and a gluten-free diet (GFD). Other therapies should be considered in patients who are unable to tolerate dapsone, including sulfapyridine and glucocorticoids. Herein we present two cases of DH with good responses to tetracycline and niacinamide combination therapy. Case 1 was a 42-year-old man who was admitted to our hospital with a 3-year history of recurrent pruritic papules and bullous lesions involving the trunk and upper limbs. On examination, the patient showed disseminated erythematous papules on the upper limbs and back as well as vesicles. Nikolsky's sign for vesicles was negative (Figure 1, a-c). The results of routine blood examinations were within normal ranges. He did not have a history of chronic diarrhea. The histologic examination showed subepidermal blisters and accumulation of neutrophils at the papillary dermis of the involved ski. Direct immunofluorescence revealed fibrillar deposition of IgA on the dermal papillae (Figure 1. g, h). Case 2 was a 34-year-old woman who had a history of skin rash and pruritic lesions predominantly involving the arms and legs, which had been present for 10 months. She had been treated with prednisone (30 mg daily) with improvement; however, the lesions reappeared when the prednisone was discontinued. She had a history of constipation. On physical examination, the skin lesions manifested as erythematous papules, vesicles, and scabs on the limbs (Figure 2. a-c). She felt apparently pruritic. The histologic examination of the biopsy identified subepidermal blisters with a neutrophil infiltrate in the upper dermis. Direct immunofluorescence revealed granular deposition of IgA on the dermal papillae (Figure 2. e, f). The results of routine blood examinations were within normal ranges, with the exception of elevated IgE concentration (222.5 ku/L (normal range, 0-100 ku/L)). The clinical manifestations and histologic and immunofluorescence examinations of the two cases confirmed the diagnosis of DH. The two patients were subsequently started on a strict GFD. At that time, dapsone was not available in the hospital. The patients were treated with oral tetracycline (500 mg four times daily) and nicotinamide (500 mg three times daily). The rash affecting case 1 resolved entirely in 2 weeks. The patient discontinued the medications after 6 months, and occasionally presented with a few pruritic papules and vesicles, but the lesions resolved within 1 week. The lesions affecting case 2 completely healed within 1 month. The patient continued taking those medications and no recurrence of the skin lesions occurred during 2 years of follow-up. Dapsone is considered first-line therapy for patients with DH (2). Recent findings have shown dapsone and lower dosages of sulfasalazine combination therapy in DH are effective and well-tolerated (3). Alternative monotherapeutic agents in mild autoimmune bullous diseases such as DH include a tetracycline group of antibiotics with niacinamide or its derivatives as well as sulfasalazine. Because dapsone is difficult to obtain in China except for patients with leprosy, we treated the patients with tetracycline and nicotinamide. To our knowledge, only a few cases of DH have been successfully treated with oral tetracycline and niacinamide (2,4). One of the patients was also prescribed heparin (4). Tetracycline has anti-inflammatory properties due to the inhibition of metalloproteinase activity and mast cell activation (5). Nicotinamide is a potent modulator of several pro-inflammatory cytokines. Nicotinamide can inhibit cytokine release (IL-1, IL-6, IL-8, and TNF-α) from immune cells, inhibit chemotaxis and degranulation of immune cells, inhibit lymphocyte blast transformation, and suppress T-cell activity (6). The non-antibiotic properties of tetracycline in combination with nicotinamide may participate in inhibition of antibody formation, modulation of pro-inflammatory cytokines, inflammatory cell accumulation, lymphocyte transformation, and T-cell activation. In summary, we reported two typical cases of DH that were successfully treated with oral tetracycline and niacinamide, which completely healed the rash and relieved the symptoms within 1 month. The combination of tetracycline and nicotinamide can be recommended as a useful therapy for patients where dapsone is not available or for patients who do not tolerate dapsone.


Assuntos
Antibacterianos/uso terapêutico , Dermatite Herpetiforme/tratamento farmacológico , Niacinamida/uso terapêutico , Tetraciclina/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Adulto , Dermatite Herpetiforme/patologia , Feminino , Humanos , Masculino
13.
PLoS Negl Trop Dis ; 12(9): e0006789, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30231057

RESUMO

Genome wide association studies (GWASs) have revealed multiple genetic variants associated with leprosy in the Chinese population. The aim of our study was to utilize the genetic variants to construct a risk prediction model through a weighted genetic risk score (GRS) in a Chinese set and to further assess the performance of the model in identifying higher-risk contact individuals in an independent set. The highest prediction accuracy, with an area under the curve (AUC) of 0.743 (95% confidence interval (CI): 0.729-0.757), was achieved with a GRS encompassing 25 GWAS variants in a discovery set that included 2,144 people affected by leprosy and 2,671 controls. Individuals in the high-risk group, based on genetic factors (GRS > 28.06), have a 24.65 higher odds ratio (OR) for developing leprosy relative to those in the low-risk group (GRS≤18.17). The model was then applied to a validation set consisting of 1,385 people affected by leprosy and 7,541 individuals in contact with leprosy, which yielded a discriminatory ability with an AUC of 0.707 (95% CI: 0.691-0.723). When a GRS cut-off value of 22.38 was selected with the optimal sensitivity and specificity, it was found that 39.31% of high risk contact individuals should be screened in order to detect leprosy in 64.9% of those people affected by leprosy. In summary, we developed and validated a risk model for the prediction of leprosy that showed good discrimination capabilities, which may help physicians in the identification of patients coming into contact with leprosy and are at a higher-risk of developing this condition.


Assuntos
Predisposição Genética para Doença , Testes Genéticos/métodos , Hanseníase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Medição de Risco , Adulto Jovem
14.
Exp Dermatol ; 27(3): 245-250, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29283461

RESUMO

The nuclear transcription factor-κB (NF-κB) plays a pivotal role in controlling both innate and adaptive immunity and regulates the expressions of many immunological mediators. Abundant evidences have showed the importance of NF-κB pathway in the host immune responses against Mycobacterium leprae in the development of leprosy. However, no particular association study between leprosy and NF-κB pathway-related gene polymorphisms was reported. Here, we performed a large-scale and two-stage candidate association study to investigate the association between 94 NF-κB pathway-related genes and leprosy. Our results showed that rs58744688 was significantly associated with leprosy (P = 7.57 × 10-7 , OR = 1.12) by combining the previous genomewide association data sets and four independent validation sample series, consisting of a total of 4631 leprosy cases and 6413 healthy controls. This founding implicated that MAP3K14 and FMNL1 were susceptibility genes for leprosy, which suggested the involvement of macrophage targeting and NF-κB pathway in the development of leprosy.


Assuntos
Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Hanseníase/genética , Transdução de Sinais/genética , Idoso , Estudos de Casos e Controles , Feminino , Forminas , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Polimorfismo de Nucleotídeo Único
15.
J Invest Dermatol ; 138(5): 1101-1106, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29233746

RESUMO

Dapsone hypersensitivity syndrome is a rare yet severe adverse drug reaction caused by dapsone, a principal drug in multidrug therapy for leprosy. HLA-B*13:01 has been identified as a strong risk factor of dapsone hypersensitivity syndrome; however, its low positive predictive value indicated that additional genetic variants may be involved in the disease development. To discover contributing genetic variants within HLA loci in addition to HLA-B*13:01, we performed a high-coverage next-generation sequencing (NGS)-based HLA typing analysis in 103 dapsone-hypersensitive and 857 dapsone-tolerant HLA-B*13:01-positive leprosy patients in a Chinese population. Five amino acid variants in high linkage disequilibrium of HLA-DRB1 were significantly associated with dapsone hypersensitivity syndrome (positions 133, 142, -17, 11, and 13). DRB1*16:02 and DRB1*15:01 tagged by these risk-conferring amino acid residues were associated at a nominal significance level. This study identifies five amino acid variants within HLA-DRB1 that are in high linkage disequilibrium and significantly associated with dapsone hypersensitivity syndrome in a Chinese population.


Assuntos
Dapsona/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Indian J Dermatol Venereol Leprol ; 84(4): 431-436, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28485307

RESUMO

Background: Treatments for autoimmune blistering disease carry significant risks of medical complications and can affect the patient's quality of life. Recently, the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire was developed in Australia. Objective: The objective of this study was to evaluate the reliability and validity of the Chinese version of the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire in Chinese patients with autoimmune blistering diseases. Methods: The Chinese version of the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire was produced by forward-backward translation and cross-cultural adaptation of the original English version. Autoimmune blistering disease patients recruited in the study self-administered the Chinese Treatment of Autoimmune Bullous Disease Quality of Life questionnaire, the Dermatology Life Quality Index and the 36-item Short-Form Health Survey. Reliability of the Chinese Treatment of Autoimmune Bullous Disease Quality of Life was evaluated using internal consistency and test-retest (days 0 and 7) methods. Validity was analyzed by face, content, construct, convergent and discriminant validity measures. Results: A total of 86 autoimmune blistering disease patients were recruited for the study. Cronbach's alpha coefficient was 0.883 and the intraclass correlation coefficient was 0.871. Face and content validities were satisfactory. Convergent validity testing revealed correlation coefficients of 0.664 for the Treatment of Autoimmune Bullous Disease Quality of Life and Dermatology Life Quality Index and -0.577 for the Treatment of Autoimmune Bullous Disease Quality of Life and 36-item Short-Form Health Survey. With respect to discriminant validity, no significant differences were observed in the Treatment of Autoimmune Bullous Disease Quality of Life scores of men and women (t = 0.251, P = 0.802), inpatients and outpatients (t = 0.447, P = 0.656), patients on steroids and steroid-sparing medications (t = 0.672, P = 0.503) and patients with different autoimmune blistering disease subtypes (F = 0.030, P = 0.971). Limitations: Illiterate patients were excluded from the study. The patients were from a single hospital and most of their conditions were in a relatively stable status. Conclusion: The Chinese version of the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire is a reliable and valid instrument to measure treatment burden and to serve as an end point in clinical trials in Chinese autoimmune blistering disease patients.


Assuntos
Doenças Autoimunes/diagnóstico , Comparação Transcultural , Qualidade de Vida , Dermatopatias Vesiculobolhosas/diagnóstico , Inquéritos e Questionários/normas , Tradução , Adolescente , Adulto , Idoso , Doenças Autoimunes/etnologia , Doenças Autoimunes/psicologia , China/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Qualidade de Vida/psicologia , Reprodutibilidade dos Testes , Autorrelato/normas , Dermatopatias Vesiculobolhosas/etnologia , Dermatopatias Vesiculobolhosas/psicologia , Adulto Jovem
17.
J Invest Dermatol ; 137(12): 2544-2551, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28842327

RESUMO

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 × 10-9, odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 × 10-8, OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 × 10-10, OR = 1.36), rs146466242 in FLG (P = 3.39 × 10-12, OR = 1.45), and rs55882956 in TYK2 (P = 1.04 × 10-6, OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 × 10-9, OR = 1.14) and rs181206 in IL27 (P = 1.08 × 10-7, OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hanseníase/genética , Polimorfismo de Nucleotídeo Único , Alelos , Autofagia , Proteínas Adaptadoras de Sinalização CARD/genética , Estudos de Casos e Controles , China , Estudos de Coortes , Endocitose , Exoma , Feminino , Frequência do Gene , Variação Genética , Genótipo , Humanos , Hanseníase/etnologia , Masculino , Fagocitose , Reprodutibilidade dos Testes , Pele/metabolismo
18.
Am J Trop Med Hyg ; 96(5): 1014-1018, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28167593

RESUMO

AbstractDapsone is a bactericidal and bacteriostatic against Mycobacterium leprae, a causative agent of leprosy. Dapsone is also applied in a range of medical fields because of its anti-inflammatory and immunomodulatory effects. Dapsone hypersensitivity syndrome (DHS) is a rare yet serious adverse drug reaction (ADR) caused by dapsone involving multiple organs. We performed a systematic review of published articles describing dapsone-induced hypersensitivity syndrome, including all Chinese articles and the latest literature available in online databases published between October 2009 and October 2015. We determined the prevalence, clinical characteristics, and mortality rate of DHS. Importantly, we also summarized the recent advances in genetic testing allowing prediction of ADRs. In an initial systematic electronic search, we retrieved 191 articles. Subsequently, these articles were further filtered and ultimately 84 articles (60 Chinese case reports, 21 non-Chinese articles, and three epidemiological studies) were selected, which included 877 patients. The prevalence of DHS among Chinese patients was 1.5% with a fatality rate of 9.6%. Early withdrawal of dapsone and appropriate treatment reduced the fatality rate. Most importantly, genetic screening for the HLA-B*13:01 allele among high-risk populations showed a significant utility as a useful genetic marker to DHS. In conclusion, this review discusses the epidemiological and clinical characteristics of DHS among Chinese patients, which may help physicians to understand this syndrome.


Assuntos
Dapsona/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/prevenção & controle , Testes Genéticos/métodos , Antígeno HLA-B13/genética , Hansenostáticos/efeitos adversos , Adolescente , Adulto , Idoso , Alelos , Criança , China/epidemiologia , Dapsona/administração & dosagem , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/mortalidade , Substituição de Medicamentos/estatística & dados numéricos , Feminino , Antígeno HLA-B13/imunologia , Humanos , Hansenostáticos/administração & dosagem , Hanseníase/tratamento farmacológico , Hanseníase/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/efeitos dos fármacos , Prevalência , Prevenção Primária/métodos , Análise de Sobrevida , Síndrome
19.
Nat Commun ; 7: 13760, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27976721

RESUMO

Leprosy, a chronic infectious disease, results from the uncultivable pathogen Mycobacterium leprae (M. leprae), and usually progresses to peripheral neuropathy and permanent progressive deformity if not treated. Previously published genetic studies have identified 18 gene/loci significantly associated with leprosy at the genome-wide significant level. However as a complex disease, only a small proportion of leprosy risk could be explained by those gene/loci. To further identify more susceptibility gene/loci, we hereby performed a three-stage GWAS comprising 8,156 leprosy patients and 15,610 controls of Chinese ancestry. Four novel loci were identified including rs6807915 on 3p25.2 (P=1.94 × 10-8, OR=0.89), rs4720118 on 7p14.3 (P=3.85 × 10-10, OR=1.16), rs55894533 on 8p23.1 (P=5.07 × 10-11, OR=1.15) and rs10100465 on 8q24.11 (P=2.85 × 10-11, OR=0.85). Altogether, these findings have provided new insight and significantly expanded our understanding of the genetic basis of leprosy.


Assuntos
/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Hanseníase/genética , Adulto , Idoso , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes
20.
Sci Rep ; 6: 31429, 2016 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-27507062

RESUMO

Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn's disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r(2) = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC.


Assuntos
Doença de Crohn/genética , Hanseníase/genética , Cirrose Hepática Biliar/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Doença de Crohn/metabolismo , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Humanos , Hanseníase/metabolismo , Cirrose Hepática Biliar/metabolismo , Masculino , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
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