Prediction of the occurrence of leprosy reactions based on Bayesian networks.

Introduction: Leprosy reactions (LR) are severe episodes of intense activation of the host inflammatory response of uncertain etiology, today the leading cause of permanent nerve damage in leprosy patients. Several genetic and non-genetic risk factors for LR have been described; however, there are limited attempts to combine this information to estimate the risk of a leprosy patient developing LR. Here we present an artificial intelligence (AI)-based system that can assess LR risk using clinical, demographic, and genetic data. Methods: The study includes four datasets from different regions of Brazil, totalizing 1,450 leprosy patients followed prospectively for at least 2 years to assess the occurrence of LR. Data mining using WEKA software was performed following a two-step protocol to select the variables included in the AI system, based on Bayesian Networks, and developed using the NETICA software. Results: Analysis of the complete database resulted in a system able to estimate LR risk with 82.7% accuracy, 79.3% sensitivity, and 86.2% specificity. When using only databases for which host genetic information associated with LR was included, the performance increased to 87.7% accuracy, 85.7% sensitivity, and 89.4% specificity. Conclusion: We produced an easy-to-use, online, free-access system that identifies leprosy patients at risk of developing LR. Risk assessment of LR for individual patients may detect candidates for close monitoring, with a potentially positive impact on the prevention of permanent disabilities, the quality of life of the patients, and upon leprosy control programs.

Update on the pathogenesis of vitiligo

Abstract Vitiligo is a complex disease whose pathogenesis results from the interaction of genetic components, metabolic factors linked to cellular oxidative stress, melanocyte adhesion to the epithelium, and immunity (innate and adaptive), which culminate in aggression against melanocytes. In vitiligo, melanocytes are more sensitive to oxidative damage, leading to the increased expression of proinflammatory proteins such as HSP70. The lower expression of epithelial adhesion molecules, such as DDR1 and E-cadherin, facilitates damage to melanocytes and exposure of antigens that favor autoimmunity. Activation of the type 1-IFN pathway perpetuates the direct action of CD8+ cells against melanocytes, facilitated by regulatory T-cell dysfunction. The identification of several genes involved in these processes sets the stage for disease development and maintenance. However, the relationship of vitiligo with environmental factors, psychological stress, comorbidities, and the elements that define individual susceptibility to the disease are a challenge to the integration of theories related to its pathogenesis.

Update on the pathogenesis of vitiligo.

Vitiligo is a complex disease whose pathogenesis results from the interaction of genetic components, metabolic factors linked to cellular oxidative stress, melanocyte adhesion to the epithelium, and immunity (innate and adaptive), which culminate in aggression against melanocytes. In vitiligo, melanocytes are more sensitive to oxidative damage, leading to the increased expression of proinflammatory proteins such as HSP70. The lower expression of epithelial adhesion molecules, such as DDR1 and E-cadherin, facilitates damage to melanocytes and exposure of antigens that favor autoimmunity. Activation of the type 1-IFN pathway perpetuates the direct action of CD8+ cells against melanocytes, facilitated by regulatory T-cell dysfunction. The identification of several genes involved in these processes sets the stage for disease development and maintenance. However, the relationship of vitiligo with environmental factors, psychological stress, comorbidities, and the elements that define individual susceptibility to the disease are a challenge to the integration of theories related to its pathogenesis.

Association of MICA and HLA-B alleles with leprosy in two endemic populations in Brazil.

Leprosy is a prevalent disease in Brazil, which ranks as the country with the second highest number of cases in the world. The disease manifests in a spectrum of forms, and genetic differences in the host can help to elucidate the immunopathogenesis. For a better understanding of MICA association with leprosy, we performed a case-control and a family-based study in two endemic populations in Brazil. MICA and HLA-B alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCR-SSOP-Luminex-based technology. In the familial study, analysis of 46 families was completed by direct sequencing of all exons and 3'/5'untranslated regions, using the Ilumina MiSeq platform. All data were collected between 2006 and 2009. Statistical analysis was performed using the Chi-square or Fisher's exact test together with a multivariate analysis. Family-based association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002-HLA-B*35 with leprosy in both the per se and the multibacillary (MB) forms when compared to healthy contacts. The MICA allele *008 was associated with the clinical forms of paucibacillary (PB). Additionally, MICA*029 was associated with the clinical forms of MB. The association of MICA*029 allele (MICA-A4 variant) with the susceptibility to the MB form suggests this variant for the transmembrane domain of the MICA molecule may be a risk factor for leprosy. Two MICA and nine HLA-B variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLA-B markers rs2596498 and rs2507992, and high LD (R2  = .92) between these and the marker rs2442718. This familial study demonstrates that MICA association signals are not independent from those observed for HLA-B. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele.

Association of MICA and HLA­B alleles with leprosy in two endemic populations in Brazil

Leprosy is a prevalent disease in Brazil, which ranks as the country with the second highest number of cases in the world. The disease manifests in a spectrum of forms, and genetic differences in the host can help to elucidate the immunopathogenesis. For a better understanding of MICA association with leprosy, we performed a case­control and a family­based study in two endemic populations in Brazil. MICA and HLA­B alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCR­SSOP­Luminex­based technology. In the familial study, analysis of 46 families was completed by direct sequencing of all exons and 3'/5'untranslated regions, using the Ilumina MiSeq platform. All data were collected between 2006 and 2009. Statistical analysis was performed using the Chi­square or Fisher's exact test together with a multivariate analysis. Family­based association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002­HLA­B*35 with leprosy in both the per se and the multibacillary (MB) forms when compared to healthy contacts. The MICA allele *008 was associated with the clinical forms of paucibacillary (PB). Additionally, MICA*029 was associated with the clinical forms of MB. The association of MICA*029 allele (MICA­A4 variant) with the susceptibility to the MB form suggests this variant for the transmembrane domain of the MICA molecule may be a risk factor for leprosy. Two MICA and nine HLA­B variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLA­B markers rs2596498 and rs2507992, and high LD (R2 = .92) between these and the marker rs2442718. This familial study demonstrates that MICA association signals are not independent from those observed for HLA­B. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele(AU).

Association Analysis Suggests SOD2 as a Newly Identified Candidate Gene Associated With Leprosy Susceptibility.

Genetic studies have identified several genes and genomic regions contributing to the control of host susceptibility to leprosy. Here, we test variants of the positional and functional candidate gene SOD2 for association with leprosy in 2 independent population samples. Family-based analysis revealed an association between leprosy and allele G of marker rs295340 (P = .042) and borderline evidence of an association between leprosy and alleles C and A of markers rs4880 (P = .077) and rs5746136 (P = .071), respectively. Findings were validated in an independent case-control sample for markers rs295340 (P = .049) and rs4880 (P = .038). These results suggest SOD2 as a newly identified gene conferring susceptibility to leprosy.

NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians.

Leprosy is a complex disease with phenotypes strongly influenced by genetic variation. A Chinese genome-wide association study (GWAS) depicted novel genes and pathways associated with leprosy susceptibility, only partially replicated by independent studies in different ethnicities. Here, we describe the results of a validation and replication study of the Chinese GWAS in Brazilians, using a stepwise strategy that involved two family-based and three independent case-control samples, resulting in 3,614 individuals enrolled. First, we genotyped a family-based sample for 36 tag single-nucleotide polymorphisms (SNPs) of five genes located in four different candidate loci: CCDC122-LACC1, NOD2, TNFSF15 and RIPK2. Association between leprosy and tag SNPs at NOD2 (rs8057431) and CCDC122-LACC1 (rs4942254) was then replicated in three additional, independent samples (combined OR(AA) = 0.49, P = 1.39e-06; OR(CC) = 0.72, P = 0.003, respectively). These results clearly implicate the NOD2 pathway in the regulation of leprosy susceptibility across diverse populations.

Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonópolis, Southern Brazil.

BACKGROUND: The objective of this study was to investigate the association between KIR genes and the immunopathogenesis of leprosy. METHODS: The types of KIR and HLA genes were evaluated by PCR-SSOP-Luminex in 408 patients with leprosy and 413 healthy individuals. Statistical analysis was performed using the Chi-square or Fisher's exact test and stepwise multivariate analysis. RESULTS: There was a higher frequency of activating KIR genes (KIR2DS1, 2DS2 and 3DS1) together with their HLA ligands in the tuberculoid (TT) group as compared to the lepromatous leprosy (LL) group. KIR2DL2/2DL2-C1 was more frequent in the patient, TT and LL groups than in the control group. Borderline patients presented a higher frequency of inhibitory pairs when compared to the control group, and a higher frequency of activating pairs as compared to the LL group. Multivariate analysis confirmed the associations and demonstrated that being a female is a protective factor against the development of the disease per se and the more severe clinical form. CONCLUSIONS: This study showed that activating and inhibitory KIR genes may influence the development of leprosy - in particular, activating genes may protect against the more aggressive form of the disease - thereby demonstrating the role of NK cells in the immunopathology of the disease.

Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonópolis, Southern Brazil

BACKGROUND: The objective of this study was to investigate the association between KIR genes and the immunopathogenesis of leprosy. METHODS: The types of KIR and HLA genes were evaluated by PCR-SSOP-Luminex in 408 patients with leprosy and 413 healthy individuals. Statistical analysis was performed using the Chi-square or Fisher's exact test and stepwise multivariate analysis. RESULTS: There was a higher frequency of activating KIR genes (KIR2DS1, 2DS2 and 3DS1) together with their HLA ligands in the tuberculoid (TT) group as compared to the lepromatous leprosy (LL) group. KIR2DL2/2DL2-C1 was more frequent in the patient, TT and LL groups than in the control group. Borderline patients presented a higher frequency of inhibitory pairs when compared to the control group, and a higher frequency of activating pairs as compared to the LL group. Multivariate analysis confirmed the associations and demonstrated that being a female is a protective factor against the development of the disease per se and the more severe clinical form. CONCLUSIONS: This study showed that activating and inhibitory KIR genes may influence the development of leprosy - in particular, activating genes may protect against the more aggressive form of the disease - thereby demonstrating the role of NK cells in the immunopathology of the disease.

NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians

Leprosy is a complex disease with phenotypes strongly influenced by genetic variation. A Chinese genome-wide association study (GWAS) depicted novel genes and pathways associated with leprosy susceptibility, only partially replicated by independent studies in different ethnicities. Here, we describe the results of a validation and replication study of the Chinese GWAS in Brazilians, using a stepwise strategy that involved two family-based and three independent case-control samples, resulting in 3,614 individuals enrolled. First, we genotyped a family-based sample for 36 tag single-nucleotide polymorphisms (SNPs) of five genes located in four different candidate loci: CCDC122-LACC1, NOD2, TNFSF15 and RIPK2. Association between leprosy and tag SNPs at NOD2 (rs8057431) and CCDC122-LACC1 (rs4942254) was then replicated in three additional, independent samples (combined OR(AA) = 0.49, P = 1.39e-06; OR(CC) = 0.72, P = 0.003, respectively). These results clearly implicate the NOD2 pathway in the regulation of leprosy susceptibility across diverse populations.

Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy.

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.

Genetic risk factors for human susceptibility to infections of relevance in dermatology.

BACKGROUND: In the pre-microbiological era, it was widely accepted that diseases, today known to be infectious, were hereditary. With the discovery of microorganisms and their role in the pathogenesis of several diseases, it was suggested that exposure to the pathogen was enough to explain infection. Nowadays, it is clear that infection is the result of a complex interplay between pathogen and host, therefore dependant on the genetic make-up of the two organisms. Dermatology offers several examples of infectious diseases in different stages of understanding of their molecular basis. In this review, we summarize the main advances towards dissecting the genetic component controlling human susceptibility to infectious diseases of interest in dermatology. Widely investigated diseases such as leprosy and leishmaniasis are discussed from the genetic perspective of both host and pathogen. Others, such as rare mycobacterioses, fungal infections and syphilis, are presented as good opportunities for research in the field of genetics of infection.

Genetic risk factors for human susceptibility to infections of relevance in dermatology / Fatores de risco genético para a suscetibilidade humana à infecções de relevância em dermatologia

BACKGROUND: In the pre-microbiological era, it was widely accepted that diseases, today known to be infectious, were hereditary. With the discovery of microorganisms and their role in the pathogenesis of several diseases, it was suggested that exposure to the pathogen was enough to explain infection. Nowadays, it is clear that infection is the result of a complex interplay between pathogen and host, therefore dependant on the genetic make-up of the two organisms. Dermatology offers several examples of infectious diseases in different stages of understanding of their molecular basis. In this review, we summarize the main advances towards dissecting the genetic component controlling human susceptibility to infectious diseases of interest in dermatology. Widely investigated diseases such as leprosy and leishmaniasis are discussed from the genetic perspective of both host and pathogen. Others, such as rare mycobacterioses, fungal infections and syphilis, are presented as good opportunities for research in the field of genetics of infection.

INTRODUÇÃO: Durante a era pré-microbiológica, era comum a visão de que doenças, hoje sabidamente infecciosas, eram hereditárias. Com a descoberta dos microorganismos e seu papel na patogênese de diversas patologias, chegou-se a propor que a exposição ao patógeno era condição suficiente para explicar infecção. Hoje, está claro que infecção é o resultado de uma complexa interação entre patógeno e hospedeiro, dependendo portanto, em última análise, do make-up genético de ambos os organismos. A dermatologia oferece diversos exemplos de doenças infecciosas em diferentes graus de entendimento de suas bases moleculares. Nesta revisão, resumimos os principais avanços na direção da dissecção do componente genético controlando suscetibilidade do ser humano a doenças infecciosas de importância na dermatologia. Doenças amplamente estudadas, como a hanseníase e a leishmaniose, são discutidas sob o ponto de vista da genética tanto do hospedeiro quanto do patógeno. Outras, como micobacterioses raras, micoses e sífilis, são apresentadas como boas oportunidades para pesquisa na área de genética de infecção.