Search

Made available in DSpace on 2021-06-25T10:15:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Despite intense efforts, the number of new cases of leprosy has remained significantly high over the past 20 years. Host genetic background is strongly linked to the pathogenesis of this disease, which is caused by Mycobacterium leprae (M. leprae), and there is a consensus that the most significant genetic association with leprosy is attributed to the major histocompatibility complex (MHC). Here, we investigated the association of human leukocyte antigen (HLA) class I and II genes with leprosy in a Brazilian population encompassing 826 individuals from a hyperendemic area of Brazil; HLA typing of class I (-A, -B, -C) and class II (-DRB1, -DQA1, -DQB1, -DPA1, and -DPB1) loci was conducted. Initially, the associations were tested using the chi-square test, with p-values adjusted using the false discovery rate (FDR) method. Next, statistically significant signals of the associations were submitted to logistic regression analyses to adjust for sex and molecular ancestry data. The results showed that HLA-C*08, -DPB1*04, and -DPB1*18 were associated with protective effects, while HLA-C*12 and -DPB1*105 were associated with susceptibility to leprosy. Thus, our findings reveal new associations between leprosy and the HLA-DPB1 locus and confirm previous associations between the HLA-C locus and leprosy. Lauro de Souza Lima Institute São Paulo State University (UNESP) Medical School Graduate Program in Health Sciences School of Medicine Pontifícia Universidade Católica do Paraná Leprosy Laboratory Oswaldo Cruz Institute-Fiocruz Laboratory of Immunogenetics Department of Basic Health Sciences Maringá State University (UEM) São Paulo State University (UNESP) Medical School

Vitiligo is an autoimmune disease of the skin that results in localized or disseminated white macules. One common feature of several existing classification protocols is the distribution of the disease into two main subtypes, non-segmental vitiligo (NSV) and segmental vitiligo (SV). SV is characterized by depigmentation spreading within one or more skin segments while NSV is widespread. Several clinical-epidemiological observations suggest that SV has distinct autoimmune pathophysiology compared to NSV. Furthermore, the clinical distribution pattern of SV lesions closely resembles other melanocyte mosaicism diseases. These observations led us to hypothesize that SV is caused by a localized autoimmune reaction targeting epidermal mosaicism melanocytes. Here, we proposed examples of experimental approaches to assess mosaicism in SV patients.

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 Colonia 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.

The aetiology of vitiligo has not been fully elucidated, and several hypotheses have been investigated; among them, the most explored assumes an autoimmune basis for the disease. Supporting this hypothesis is the frequent co-occurrence of autoimmune diseases with vitiligo. In addition, various genetic loci associated with vitiligo harbour key immune response genes. Our general hypothesis is that autoimmunity-associated genes participate in the control of vitiligo susceptibility. To investigate this hypothesis, we tested for association between vitiligo and genes CYP27B1, REL, TNFAIP3 and IL2/IL21, all previously related to autoimmune diseases associated with vitiligo. The study was performed using two independent population samples: a family-based discovery set (211 trios) and a replication set (131 cases/119 controls). Statistically significant association with vitiligo was detected between markers of the REL and IL2 gene in the family-based sample. Both association signals were concentrated among patients displaying autoimmune comorbidity and non-segmental vitiligo. Evidence for validation was detected for IL2 marker. Our findings suggest REL and IL2 as new vitiligo susceptibility genes and reinforce the hypothesis of a shared genetic mechanism controlling vitiligo and other autoimmune diseases.

Background: 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 in order to estimate the risk of a leprosy patient to develop LR. Here we present an artificial intelligence (AI)-based system able to estimate risk of LR 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 two 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 up to 87.7% accuracy, 85.7% sensitivity, and 89.4% specificity.Conclusion: We produced an easy-to-use, online, free-access system that allows the identification of leprosy patients at high risk of developing LR. Risk assessment of LR for individual patients may detect candidates close monitoring, with potential positive impact upon the prevention of permanent disabilities, the quality of life of the patients, as well as upon leprosy control programs.

Background Leprosy has been treated with multidrug therapy, which has been distributed for free across the globe and regarded as highly efficient. However, the impossibility of growing Mycobacterium leprae in axenic media has historically impaired assessments of M. leprae resistance, a parameter only recently detectable through molecular methods. Methods A systematic, population-based search for M. leprae resistance in suspected leprosy relapse cases and contacts was performed in Prata Village, an isolated, hyperendemic, former leprosy colony located in the Brazilian Amazon. Results led to an extended active search involving the entire Prata population. Confirmed leprosy cases were investigated for bacterial resistance using a combination of in vivo testing and direct sequencing of resistance genes folP1, rpoB, and gyrA. A molecular epidemiology analysis was performed using data from 17 variable number tandem repeats (VNTR). Results Mycobacterium leprae was obtained from biopsies of 37 leprosy cases (18 relapses and 19 new cases): 16 (43.24%) displayed drug-resistance variants. Multidrug resistance to rifampicin and dapsone was observed in 8 relapses and 4 new cases. Single resistance to rifampicin was detected in 1 new case. Resistance to dapsone was present in 2 relapses and 1 new case. Combined molecular resistance and VNTR data revealed evidence of intra-familial primary transmission of resistant M. leprae. Conclusions A comprehensive, population-based systematic approach to investigate M. leprae resistance in a unique population revealed an alarming scenario of the emergence and transmission of resistant strains. These findings may be used for the development of new strategies for surveillance of drug resistance in other populations., Our study, in a unique population, revealed the highest proportion of resistant Mycobacterium leprae isolates to single and multiple drugs ever reported and demonstrated intra-familial transmission of resistant M. leprae: immediate, strong attention to drug resistance in leprosy is suggested.

Host genetic susceptibility to leprosy has been intensively investigated over the last decades; however, there are no studies on the role of genetic variants in disease recurrence. A previous initiative identified three recurrent cases of leprosy for which none of the M. leprae strains, as obtained in the first and the second diagnosis, had any known genomic variants associated to resistance to Multidrug therapy; in addition, whole genome sequencing indicated that the same M. leprae was causing two out of the three recurrences. Thus, these individuals were suspected of being particularly susceptible to M. leprae infection, either as relapse or reinfection. To verify this hypothesis, 19 genetic markers distributed across 11 loci (14 genes) classically associated with leprosy were genotyped in the recurrent and in three matching non-recurrent leprosy cases. An enrichment of risk alleles was observed in the recurrent cases, suggesting the existence of a particularly high susceptibility genetic profile among leprosy patients predisposing to disease recurrence.

Background and Objective Interleukin-6 (IL-6) is a powerful stimulator of osteoclast differentiation and bone resorption. Production of IL-6 is modulated by polymorphisms, and higher levels of this cytokine are found locally in patients with chronic periodontitis. In this study we performed a modern approach – Complete physical mapping of the IL6 gene – to identify the polymorphisms associated with chronic periodontitis in a southern Brazilian population sample. Material and Methods One-hundred and nine individuals of both genders (mean age: 41.5 ± 8.5 years) were divided into a study group (56 participants with periodontitis) and a control group (53 individuals without periodontitis). After collection and purification of DNA, nine tag single nucleotide polymorphisms (SNPs; rs1524107, rs2069835, rs2069837, rs2069838, rs2069840, rs2069842, rs2069843, rs2069845 and rs2069849) covering the entire gene were selected according to the information available on the International HapMap Project website and evaluated using real-time PCR. Results Differences in the distribution of the following parameters were statistically significant between study and control groups: number of teeth (p = 0.030); probing depth (p < 0.001); clinical attachment level (p < 0.001); gingival index (p < 0.001); plaque index (p = 0.003); calculus index (p < 0.001); and dental mobility (p < 0.001). It was found that marker rs2069837 (located in intron 2 of IL6) under G dominant was associated with protection against chronic periodontitis in a Brazilian population in the presence of clinical variables, such as visible plaque, dentist visit frequency and dental floss use, and was suggested for the first time as a marker of susceptibility to chronic periodontitis. Conclusion Complete physical mapping of IL6 (using tag SNPs) was carried out for the first time, unveiling allele G of polymorphism rs2069837 (located in the second intron of IL6) as a suggestive marker of protection against chronic periodontitis in a Brazilian population.

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.

Background Between November 2013 and June 2014, 56 cases of bacteremia (15 deaths) associated with the use of Total Parenteral Nutrition (TPN) and/or calcium gluconate (CG) were reported in four Brazilian states. Methods We analyzed 73 bacterial isolates from four states: 45 from blood, 25 from TPN and three from CG, originally identified as Acinetobacter baumannii, Rhizobium radiobacter, Pantoea sp. or Enterobacteriaceae using molecular methods. Results The first two bacterial species were confirmed while the third group of species could not be identified using standard identification protocols. These isolates were subsequently identified by Multi-Locus Sequence Analysis as Phytobacter diazotrophicus, a species related to strains from similar outbreaks in the United States in the 1970’s. Within each species, TPN and blood isolates proved to be clonal, whereas the R. radiobacter isolates retrieved from CG were found to be unrelated. Conclusion This is the first report of a three-species outbreak caused by TPN contaminated with A. baumannii, R. radiobacter and P. diazotrophicus. The concomitant presence of clonal A. baumannii and P. diazotrophicus isolates in several TPN and blood samples, as well as the case of one patient, where all three different species were isolated simultaneously, suggest that the outbreak may be ascribed to a discrete contamination of TPN. In addition, this study highlights the clinical relevance of P. diazotrophicus, which has been involved in outbreaks in the past, but was often misidentified as P. agglomerans. Electronic supplementary material The online version of this article (10.1186/s12879-018-3287-2) contains supplementary material, which is available to authorized users.

Genetics plays a crucial role in controlling susceptibility to infectious diseases by modulating the interplay between humans and pathogens. This is particularly evident in leprosy, since the etiological agent, Mycobacterium leprae, displays semiclonal characteristics not compatible with the wide spectrum of disease phenotypes. Over the past decades, genetic studies have unraveled several gene variants as risk factors for leprosy per se, disease clinical forms and the occurrence of leprosy reactions. As expected, several of these genes are immune-related; yet, hypothesis-free approaches have led to genes not classically linked to immune response. The PARK2, originally described as a Parkinson's disease gene, illustrates the case: Parkin-the protein coded by PARK2-was defined as an important player regulating innate and adaptive immune responses only years after its description as a leprosy susceptibility gene. Interestingly, even with the use of powerful hypothesis-free study designs such as genome-wide association studies, most of the major gene effect controlling leprosy susceptibility remains elusive. One hypothesis to explain this "hidden heritability" is that rare variants not captured by classic association studies are of critical importance. To address this question, massively parallel sequencing of large segments of the human genome-even whole exomes/genomes-is an alternative to properly identify rare, disease-causing mutations. These mutations may then be investigated through sophisticated approaches such as cell reprogramming and genome editing applied to create in vitro models for functional leprosy studies.

Made available in DSpace on 2018-12-11T17:22:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-01-01 Despite high prevalence, the etiopathology of melasma is not fully understood. Nevertheless, many factors have been associated with the disease, including: sun exposure, sex steroids hormones, drugs, stress, and pregnancy. The high occurrence within familiars (40–60%) suggests a genetic predisposition to the disease. This study explored, through complex segregation analysis (CSA), the inheritance model that best fit the family segregation pattern of facial melasma when accounting for the main epidemiological risk factors. We evaluated 686 subjects from 67 families, and 260 (38%) of them had facial melasma. The CSA model, adjusted for age, skin phototype, sex, sun exposure at work, hormonal oral contraceptive, and pregnancy, evidenced a genetic component that was best fitted to a dominant pattern of segregation. Melasma results from an interaction between exposure factors (e.g. pregnancy, hormones, and sun exposure) over genetically predisposed individuals. Departamento de Dermatologia e Radioterapia SN FMB-Unesp, Campus de Rubião Jr. Programa de Pós-Graduação em Ciências da Saúde Escola de Medicina Pontifícia Universidade Católica do Paraná Programa de Pós-Graduação em Odontologia Escola de Ciências da Vida Pontifícia Universidade Católica do Paraná Departamento de Dermatologia e Radioterapia SN FMB-Unesp, Campus de Rubião Jr.

The species Phytobacter diazotrophicus and the associated genus Phytobacter were originally described by Zhanget al. [Arch Microbiol189 (2008), 431-439] on the basis of few endophytic nitrogen-fixing bacteria isolated from wild rice (Oryza rufipogon) in China. In this study, we demonstrate that a number of clinical isolates that were either described in the literature, preserved in culture collections, or obtained during a 2013 multi-state sepsis outbreak in Brazil also belong to the same genus. 16S rRNA gene sequencing, multilocus sequence analysis based on gyrB, rpoB, atpD and infB genes, as well as digital DNA-DNA hybridization support the existence of a second species within the genus Phytobacter. All isolates from the recent Brazilian outbreak, along with some older American clinical strains, were found to belong to the already described species Phytobacterdiazotrophicus, whereas three clinical strains retrieved in the USA over a time span of almost four decades, could be assigned to a new Phytobacter species. Implementation of an extended set of biochemical tests showed that the two Phytobacter species could phenotypically be discriminated from each other by the ability to utilize l-sorbose and d-serine. This feature was limited to the strains of the novel species described herein, for which the name Phytobacter ursingii sp. nov. is proposed, with ATCC 27989T (=CNCTC 5729T) as the designated type strain. An emended description of the species Phytobacter diazotrophicus and of the genus Phytobacter is also provided.

A solid body of evidence produced over decades of intense research supports the hypothesis that leprosy phenotypes are largely dependent on the genetic characteristics of the host. The early evidence of a major gene effect controlling susceptibility to leprosy came from studies of familial aggregation, twins, and Complex Segregation Analysis. Later, linkage and association analysis, first applied to the investigation of candidate genes and chromosomal regions and more recently, to genome-wide scans, have revealed several leukocyte antigen complex and nonleukocyte antigen complex gene variants as risk factors for leprosy phenotypes such as disease per se, its clinical forms and leprosy reactions. In addition, powerful, hypothesis-free strategies such as Genome-Wide Association Studies have led to an exciting, unexpected development: Leprosy susceptibility genes seem to be shared with Crohn's and Parkinson's diseases. Today, a major challenge is to find the exact variants causing the biological effect underlying the genetic associations. New technologies, such as Next Generation Sequencing that allows, for the first time, the cost and time-effective sequencing of a complete human genome, hold the promise to reveal such variants. Strategies can be developed to study the functional effect of these variants in the context of infection, hopefully leading to the development of new targets for leprosy treatment and prevention.

Dental caries is a common multifactorial disease, resulting from the interaction of biofilm, cariogenic diet and host response over time. Lactotransferrin (LTF) is a main salivary glycoprotein, which modulates the host immune-inflammatory and antibacterial response. Although a genetic component for caries outcome has been identified, little is known over the genetic aspects underlying its susceptibility. Thus, the aim of this study was to investigate the association between LTF polymorphisms and caries susceptibility. Six hundred seventy seven 12-year-old students were selected: 346 with (DMFT ≥ 1) and 331 without caries experience (DMFT = 0). Also, individuals concentrating higher levels of disease (polarization group, DMFT ≥ 2, n = 253) were tested against those with DMFT ≤ 1 (n = 424). Along with clinical parameters, three representative LTF tag SNPs (rs6441989, rs2073495, rs11716497) were genotyped and the results were evaluated using univariate and multivariate analyses. Allele A for tag SNP rs6441989 was found to be significantly less frequent in the polarization group, conferring a protective effect against caries experience [AA + AG × GG (OR: 0.710, 95% CI: 0.514-0.980, p = 0.045)], and remained significantly associated with caries protection in the presence of gingivitis (p = 0.020) and plaque (p = 0.035). These results might contribute to the understanding of the genetic control of caries susceptibility in humans.

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.

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.

Vitiligo is a depigmenting disorder characterized by loss of functional melanocytes from the epidermis. Experimental data suggest that defective melanocyte adhesion may underlie the pathogenesis of the disease. In particular, association between vitiligo and genetic variants of the DDR1 gene involved in melanocyte adhesion has been recently published. A subsequent, independent study revealed lower expression of DDR1 in vitiligo lesions. Here, we expand this investigation by testing for association between vitiligo and polymorphisms of CDH1, IL1B and NOV (formerly CCN3), genes belonging to the DDR1 adhesion pathway, in two population samples of distinct design. Our results reveal that alleles of marker rs10431924 of the CDH1 gene are associated with vitiligo, especially in the presence of autoimmune comorbidities.

Type-1 (T1R) and Type-2 (T2R) leprosy reactions (LR), which affect up to 50% of leprosy patients, are aggressive inflammatory episodes of sudden onset and highly variable incidence across populations. LR are often diagnosed concurrently with leprosy, but more frequently occur several months after treatment onset. It is not uncommon for leprosy patients to develop recurring reactional episodes; however, they rarely undergo both types of LR. Today, LR are the main cause of permanent disabilities associated with leprosy and represent a major challenge in the clinical management of leprosy patients. Although progress has been made in understanding the immunopathology of LR, the factors that cause a leprosy patient to suffer from LR are largely unknown. Given the impact that ethnic background has on the risk of developing LR, host genetic factors have long been suspected of contributing to LR. Indeed, polymorphisms in seven genes [Toll-like receptors (TLR)1, TLR2, nucleotide-binding oligomerisation domain containing 2, vitamin D receptor, natural resistance-associated macrophage protein 1, C4B and interleukin-6] have been found to be associated with one or more LR outcomes. The identification of host genetic markers with predictive value for LR would have a major impact on nerve damage control in leprosy. In this review, we present the recent advances achieved through genetic studies of LR.

Risk stratification and treatment intensification, based on minimal residual disease (MRD) mensurement, changed the prognosis of pediatric patients with acute lymphocytic leukemia (ALL). The main aim of this study was to investigate whether peripheral blood (PB) MRD measurement at day 8 (D8) could predict the risk stratification category determined by bone marrow (BM) MRD at day 15 (D15). The study was performed prospectively, in a cohort of 40 children with B-lineage ALL, adopting the protocol of the Brazilian Cooperative Group of the Treatment Childhood Leukemia (GBTLI-2009). MRD was detected by flow cytometry (FC) using a simplifed panel that can reliably identify MRD at early phases of induction therapy. Upon diagnosis, the proportion of low and high-risk patients, was 24:16 (60%:40%). The main result of our study demonstrated the potential of D8 MRD in anticipating of week the risk stratification of high-risk patients as determined by D15 BM MRD. In these patients D8 MRD level of 1% was able to segregate high risk fast responders from high risk slow responders (p = 0.0097). This result could represent an opportunity for early treatment intensification, as already performed in some protocols.

PURPOSE: Mycobacterium leprae exploits complement activation and opsonophagocytosis to infect phagocytes. M-ficolin is encoded by the FCN1 gene and initiates the lectin pathway on monocyte surfaces. We investigated FCN1 promoter polymorphisms that could be responsible for the high interindividual variability of M-ficolin levels and for modulating leprosy susceptibility.METHODS: We genotyped rs2989727 (-1981 G > A), rs28909068 (-791 G > A), rs10120023 (-542 G > A), rs17039495 (-399 G > A), rs28909976 (-271IndelT), rs10117466 (-144C > A) and rs10858293 (+33 T > G) in 400 controls and 315 leprosy patients from Southern Brazil, and in 296 Danish healthy individuals with known M-ficolin levels.RESULTS: Ten haplotypes were identified with sequence-specific PCR and/or haplotype-specific sequencing. We found evidence for a protective codominant additive effect of FCN1*-542A-144C with leprosy in Euro-Brazilians (P=0.003, PBf =0.021, OR=0.243 [CI95% =0.083-0.71]), which was independent of age, ethnic group and gender effects (P=0.029). There was a trend for a positive association of the -399A variant in Afro-Brazilians (P=0.022, PBf =0.154, OR=4.151 [CI95% =1.115-15.454], as well as for a negative association of the FCN1*3A haplotype with lepromatous leprosy, compared with less severe forms of the disease (P=0.016, PBf =0.112, OR=0.324 [CI95% =0.123-0.858]). Danish individuals with this haplotype presented M-ficolin levels higher than the population average of circa 1,000 ng/ml, and -542A-144C, which is able to modify the recognition of transcription factors in silico, occurred in individuals with levels under the 25 percentil (P=0.031).CONCLUSIONS: Our data provide the first evidence that FCN1 polymorphisms are associated with leprosy. M-ficolin may represent a novel key to understand the immunopathogenesis of M. leprae infection.

In leprosy, type 1 reaction (T1R) and type 2 reaction (T2R) are major causes of nerve injury and permanent disabilities. A previous study on plasma levels of 27 cytokines in patients with T1R or T2R and controls with nonreactional leprosy identified the gene for interleukin 6 (IL-6) as a candidate for genetic analysis. Two nested case-control studies were built from a cohort of 409 patients with leprosy from central Brazil, monitored for T1R and T2R. There was evidence for association between T2R and IL-6 tag single-nucleotide polymorphisms rs2069832 (P = .002), rs2069840 (P = .03), and rs2069845 (P = .04), with information on the entire IL-6 locus, as well as functional IL-6 variant rs1800795 (P = .005). Moreover, IL-6 plasma levels in patients with T2R correlated with IL-6 genotypes (P = .04). No association was found between IL-6 variants and T1R. Identifying genetic predictive factors for leprosy reactions may have a major impact on preventive strategies.

Vitiligo classification systems are often based exclusively on the number and distribution of the white patches. To what extend these classification protocols reflect possible different pathophysiological basis for vitiligo or carry any prognostic value is currently unknown.To investigate patterns of association between type of vitiligo and common disease-related variables, in order to advance on the understanding of the exact nature of different clinical forms of disease, as well as to identify features with prognostic value for clinical progression of early diagnosed vitiligo.This is a cross-sectional study of a population sample from south of Brazil composed of 586 independent vitiligo-affected individuals. Different strategies of case-control analysis were employed to test for association between the three most common vitiligo clinical types and age of onset, family history of vitiligo, occurrence of Köebner phenomenon (KP) and presence of autoimmune co-morbidity.Individuals affected by segmental vitiligo showed lower average age of onset (16 years) when compared with vulgaris (23.9 years) and acrofacial cases (29 years) (p0.001). The distribution of occurrence of KP, family history of vitiligo and co-occurrence of autoimmune disease followed a gradient pattern, with high, intermediate and low chance of occurrence of all three variables observed for vulgaris, acrofacial and segmental vitiligo, respectively (p0.001 for overall distribution).Results indicate a uniform pattern of association between vitiligo clinical forms and KP, positive vitiligo family history and occurrence of co-morbidity autoimmune. The impact of the observed pattern of association over disease prognosis and classification is discussed.

Dental decay is a complex, chronic disease and one of the most common illnesses in dentistry today. Several dental decay risk factors have been identified during the last years; however, these variables alone may not entirely explain the disease development. Genetic research applied to dental decay began in the 1930s with experimental reports in animals and human observational research. Only recently, have some studies begun to search for genetic polymorphisms in humans and apply linkage analysis. However, due to the complex characteristics of the disease, the strong influence from several biological and environmental factors, and the small number of genetic studies related to dental caries, the genetic basis still requires further study. Therefore, the aim of this review is to provide a brief description of the current methodology for genetic analysis of complex traits, followed by a comprehensive evaluation of the literature related to genetic susceptibility/resistance to dental decay and a discussion of different aspects of the applied methodology. Advances towards the elucidation of the dental decay genetic basis may contribute to the understanding of the disease etiopathogenesis and to the identification of high risk groups, thus providing potential targets for effective screening, prevention and treatment.

Vitiligo is a chronic disease characterized by macules devoid of melanin and identifiable melanocytes. Adhesion of melanocytes to the basement membrane by integrin CCN3 is mediated through collagen IV receptor DDR1. We hypothesize that genetic variants of the DDR1 gene are associated with the occurrence of vitiligo. To test this hypothesis, we genotyped 10 DDR1 tag single-nucleotide polymorphisms (SNPs) in 212 trios composed of an affected child and both parents. Associated markers were then genotyped in 134 independent, unrelated individuals with vitiligo and 134 unrelated controls. Allele T of tag SNP rs4618569 was associated with an increased risk for vitiligo in the family trios (P=0.002, odds ratio (OR)=5.27; 95% confidence interval (CI)=1.59-17.40), whereas allele C of tag SNP rs2267641 was associated with an increased risk for vitiligo in both family-based and case-control populations (P=0.01, OR=3.47; 95% CI=1.22-9.17; P=0.04, OR=6.00; 95% CI=1.73-52.33, respectively). The best evidence for association in the trios was obtained for a haplotype composed of risk alleles of markers rs4618569 and rs2267641 (P=0.0006). There was an age-dependent enrichment of rs4618569 T allele and rs2267641 C allele in early-onset affected individuals. In conclusion, we propose DDR1 as a susceptibility gene for vitiligo, possibly implicating a defective cell adhesion in vitiligo pathogenesis.

Summary Objectives The aim of the present work was to standardise a PCR-Restriction Fragment Length Polymorphism analysis (PRA) as a tool to detect the mycobacteriologic composition of lepromas from leprosy patients used in the production of lepromin to improve the quality of the Mitsuda test. Design PCR-Restriction Fragment Length Polymorphism analysis using hsp65 and rpoB genes were applied to 11 reference strains of mycobacteria, including M. leprae, and the obtained PRA profiles were compared to mycobacteria in clinical specimens. Results Out of the biopsies studied, 52·2% had DNA fragment amplified for both genes (hsp65 and rpoB) for M. leprae. However, other Mycobacterium species were observed in samples of lepromatous leprosy patients. Here we discussed the importance of mycobacteria identification in the antigen of Mitsuda production to be used in the evaluation of leprosy. Conclusions Our results suggest that the use of the molecular approach for sample selection can contribute to an improvement in the quality of produced lepromin.

The Mitsuda reaction, a delayed granulomatous skin reaction elicited by the intradermal injection of heat-killed Mycobacterium leprae, is an in vivo test reflecting the ability to generate an immune granuloma after sensitization by diverse mycobacterial infections. Accumulating evidence for the genetic control of the Mitsuda reaction has been reported. We performed a genomewide linkage scan for the quantitative Mitsuda reaction in 19 large families from Vietnam with a history of leprosy (114 offspring). Suggestive linkage was found at chromosomal regions 2q35 (P = 9 x 10(-4) at the SLC11A1 locus) and 17q21-25 (P = 8 x 10(-4)). Interestingly, these 2 regions have been previously linked to mycobacterial infection and other granulomatous diseases.

A hanseníase é doença infecciosa milenar que, apesar da existência de terapêutica eficaz, ainda persiste como problema de saúde pública em seis países, entre eles o Brasil, líder mundial em prevalência da doença. Ao longo das últimas décadas, a hanseníase vem sendo estudada por perspectiva talvez inesperada para uma doença infecciosa: modernos métodos de análise experimental têm sido empregados para evidenciar a importância do componente genético no controle da susceptibilidade do hospedeiro à hanseníase e seus fenótipos. Esses estudos indicam que constituição genética favorável do hospedeiro, somada a fatores propícios, ambientais e relativos ao agente patogênico, tem alto impacto na definição da susceptibilidade tanto à infecção propriamente dita quanto à evolução clínica da doença. Hoje, diversos genes e regiões genômicas já foram relacionados ao controle da susceptibilidade à hanseníase. Outros estudos estão em andamento, visando ao avanço no entendimento das bases moleculares de controle da susceptibilidade do hospedeiro à doença. O conjunto de resultados desses estudos pode levar a formas mais eficazes de diagnóstico, tratamento e prevenção da hanseníase e outras doenças infecciosas. Leprosy is an ancient chronic infectious disease that, despite the existence of efficient therapy, still persists as a public health problem in six countries, including Brazil, the world leader in leprosy prevalence. During the past decades, leprosy has been studied from a somewhat unusual perspective for an infectious disease: modern methods for experimental analysis have been applied to demonstrate the existence of an important genetic effect controlling host susceptibility to leprosy and its phenotypes. These studies indicate that a favorable host genetic make-up, combined with environmental and pathogen-related variables, has a high impact on the definition of susceptibility to both infection and clinical manifestation of leprosy. To date, several genes and genomic regions have been implicated in the control of leprosy susceptibility. Additional ongoing studies aim at advancing further in the elucidation of the molecular basis of host susceptibility to the disease. This body of evidence may lead to new strategies for diagnosis, treatment and prevention of leprosy and other infectious diseases.

Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.

Leprosy is a chronic infectious disease that affects 600,000 new individuals worldwide every year. This article summarizes some of the advances achieved over the past decades towards the description of the exact number, location and nature of the genetic variants responsible for the well established genetic component controlling leprosy susceptibility in humans.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated 700,000 new individuals each year. A strong contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability observed between individuals exposed to M. leprae. As there is no relevant animal model for human leprosy, forward genetics is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy.

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.

The Amazon is responsible for approximately 40% of the American tegumentary leishmaniasis (ATL) in Brazil. Herein the sustained presence of ATL in Manaus, the largest settlement in the Amazon, was investigated. Records of notification of historic cases, and data from cases prospectively enrolled in the Tropical Medicine Foundation of the Amazonas State were used. Geographic coordinates of prospective patients' living sites were used to detect inner-city clusters of ATL. Infecting Leishmania species was determined by polymerase chain reaction. Among prospectively enrolled subjects, 94.8% were infected with Leishmania (Viannia) guyanensis, 76.7% were male, 30.2% were 0-20 years old, and 69.8% had an urban residence. Historic cases showed a profile similar to that of prospectively enrolled subjects. Several clusters of ATL, widely distributed within the city of Manaus, could be detected. In conclusion, there was a high frequency of disease in young age groups and cases clustered in urban neighborhoods. It cannot be determined from these data whether transmission of these cases occurred within or outside the city of Manaus.

In an unprecedented effort in the field of vitiligo, a global consensus resulted on a suggested new classification protocol for the disease. The main histopathological finding in vitiligo is the total absence of functioning melanocytes in the lesions, while the inflammatory cells most commonly found on the edges of the lesions are CD4+ and CD8+ T lymphocytes. Physical and pharmacological treatment strategies aim to control the autoimmune damage and stimulate melanocyte migration from the unaffected edges of lesions and the outer hair follicle root sheath to the affected skin; moreover, surgical treatments can be combined with topical and physical treatments.

Conflicting findings about the association between leprosy and TLR1 variants N248S and I602S have been reported. Here, we performed case-control and family based studies, followed by replication in 2 case-control populations from Brazil, involving 3162 individuals. Results indicated an association between TLR1 248S and leprosy in the case-control study (SS genotype odds ratio [OR], 1.81; P = .004) and the family based study (z = 2.02; P = .05). This association was consistently replicated in other populations (combined OR, 1.51; P < .001), corroborating the finding that 248S is a susceptibility factor for leprosy. Additionally, we demonstrated that peripheral blood mononuclear cells (PBMCs) carrying 248S produce a lower tumor necrosis factor/interleukin-10 ratio when stimulated with Mycobacterium leprae but not with lipopolysaccharide or PAM3cysK4. The same effect was observed after infection of PBMCs with the Moreau strain of bacillus Calmette-Guerin but not after infection with other strains. Finally, molecular dynamics simulations indicated that the Toll-like receptor 1 structure containing 248S amino acid is different from the structure containing 248N. Our results suggest that TLR1 248S is associated with an increased risk for leprosy, consistent with its hypoimmune regulatory function.