RESUMO
To investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6-<11 years, ≥11-<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self-reported colour-race and identified a familiar history of T1D in first-degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub-Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA-DQB1*03:02g, -DQA1*03:01g, -02:01g, DRB1*04:05g and -04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, -13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self-reported colour-race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high-risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well-known genomic risk or protection factors for T1D.
Assuntos
Alelos , Diabetes Mellitus Tipo 1 , Frequência do Gene , Haplótipos , Humanos , Brasil/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/diagnóstico , Masculino , Feminino , Criança , Adolescente , Adulto , Pré-Escolar , Adulto Jovem , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Idade de Início , Lactente , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Anti-desmoglein (Dsg)1 is produced in pemphigus foliaceus (PF), affecting exclusively the skin. Pemphigus vulgaris (PV) shows the production of anti-Dsg3 in the mucosal form, and anti-Dsg1 and 3 in the mucocutaneous form. Anti-Dsg3 autoantibodies have been rarely reported in PF. OBJECTIVES: To determine the factors associated with the production and pathogenicity of anti-Dsg3 in PF. METHODS: Comparative analytical study of three patients groups: 16 PF-anti-Dsg3+, and 42 PF-anti-Dsg3(-) and 22 PV treatment-naïve cases. Serum was used in the anti-Dsg1 and 3 ELISA, and in immunoblotting (IB) with human epidermis extract. The expression of Dsg1 and 3 in paraffin sections was analyzed by immunohistochemistry (IHC). HLA-DRB1 alleles were compiled from a database. RESULTS: In the PF-anti-Dsg3+ group: age range similar to that of the PV group (pâ¯>â¯0.9999); predominance of the generalized form of PF (pâ¯=â¯0.002); anti-Dsg3 titers lower than those of PV (pâ¯<â¯0.0001); IB confirmed Dsg3 identification in one (8.33%) of 12 patients; IHC showed exclusive cytoplasmic internalization of Dsg1; HLA-DRB1 alleles of susceptibility to PF, with the absence of alleles associated with PV, in the five typed patients. STUDY LIMITATIONS: Most of the patients in the PF-anti-Dsg3+ group were undergoing treatment. CONCLUSION: The presence of anti-Dsg3 antibodies in PF was related to older age (comparable to that of PV) and the generalized form of PF. The non-pathogenicity of anti-Dsg3 antibodies in PF can be attributed to the low serum anti-Dsg3 titers, the lack of Dsg3 internalization as detected by IHC, and the absence of PV-associated HLA-DRB1 alleles.
Assuntos
Autoanticorpos , Desmogleína 1 , Desmogleína 3 , Imuno-Histoquímica , Pênfigo , Humanos , Pênfigo/imunologia , Desmogleína 3/imunologia , Autoanticorpos/imunologia , Autoanticorpos/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Desmogleína 1/imunologia , Ensaio de Imunoadsorção Enzimática , Adulto Jovem , Immunoblotting , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Idoso de 80 Anos ou mais , AdolescenteRESUMO
The novel HLA-DRB1*03:215 allele, first described in a potential bone marrow donor from Brazil.
Assuntos
Alelos , Cadeias HLA-DRB1 , Teste de Histocompatibilidade , Humanos , Cadeias HLA-DRB1/genética , Teste de Histocompatibilidade/métodos , Éxons , Análise de Sequência de DNA/métodos , Doadores de Tecidos , Brasil , Sequenciamento de Nucleotídeos em Larga Escala/métodosRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disorder that impacts connective tissue and can affect various organs and systems within the body. One important aspect of this disease is the role of the human leukocyte antigen (HLA) system, a protein complex that plays a role in the immune response. Specifically, the HLA-DRB1 and HLA-DQB1 genes have been implicated in the development of SLE. In order to better understand this relationship in the Guatemalan population, a study was conducted with the objective of characterizing the allelic and haplotype profiles of the HLA-DQB1 and HLA-DRB1 loci in 50 patients diagnosed with SLE who were receiving treatment at a hospital in Guatemala. Allele and haplotype frequencies were determined and compared to 127 healthy Guatemalan subjects as a control group. The results of the analysis showed a reduction in the frequencies of HLA-DQB1*03 and HLA-DRB1*14 in SLE patients, which could suggest a protective effect on the development of the disease. In contrast, a risk association was found between HLA-DRB1*07, HLA-DRB1*08, HLA-DQB1*02 and HLA-DQB1*06 in SLE patients. Finally, we observed an additional protective associated of haplotype HLA-DRB1*04â¼DQB1*03 with SLE patients, while haplotypes HLA-DRB1*07â¼DQB1*02 and DRB1*08-DQB1*06 showed a risk association.
Assuntos
Frequência do Gene , Predisposição Genética para Doença , Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Haplótipos , Lúpus Eritematoso Sistêmico , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Alelos , Estudos de Casos e Controles , Estudos de Associação Genética , Genótipo , Guatemala , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/diagnósticoRESUMO
Identification of four new HLA alleles (B*27:265, B*35:569, DRB1*08:117, and DPB1*1435:01) in Brazilian bone marrow donors.
Assuntos
Antígenos HLA-B , Humanos , Frequência do Gene , Alelos , Cadeias beta de HLA-DP/genética , Cadeias HLA-DRB1/genética , Antígenos HLA-B/genéticaRESUMO
BACKGROUND: Brazil ranks second in the absolute number of transplants. However, the supply remains insufficient to meet the demands, resulting in a lengthy waitlist. This study aimed to analyze whether the frequency of human leukocyte antigen (HLA) and the value of calculated panel reactive antibody (cPRA) would influence the waiting time for kidney transplantation. METHODS: The HLA-A, B, and -DRB1 frequencies and the cPRA value were analyzed in 11,186 kidney transplant candidates included in the waitlist from 2006 to 2016. RESULTS: The most frequent alleles were HLA-A*02, HLA-B*35, and HLA-DRB1*13. The overall mean length of stay on the list was 986 ± 1001 days. The mean waiting time for the three most frequent alleles of the HLA-A and B loci showed no significant difference when compared with the least frequent alleles; however, for the HLA-DRB1 locus, the most frequent alleles showed a shorter waiting time. In the association between HLA and PRA, the average length of stay on the list increased according to the candidate's degree of sensitization, regardless of the analyzed HLA frequency. CONCLUSION: The length of stay on the waitlist is influenced by the frequency of the HLA alleles of the DRB1 locus and the degree of sensitization.
Assuntos
Transplante de Rim , Humanos , Cadeias HLA-DRB1/genética , Brasil , Listas de Espera , Antígenos HLA-A/genética , Antígenos HLA , Alelos , Anticorpos , Frequência do GeneRESUMO
Multiple sclerosis (MS) is a chronic and demyelinating disease with an autoimmune origin, which leads to neurodegeneration and progressive disability. Approximately 30 to 50% of patients do not respond optimally to disease-modifying therapies (DMTs), and therapeutic response may be influenced by genetic factors such as genetic variants. Therefore, our study aimed to investigate the association of the HLA-DRB1*0403 genetic variant and therapeutic response to DMTs in MS. We included 105 patients with MS diagnosis. No evidence of disease activity based on the absence of clinical relapse, disability progression or radiological activity (NEDA-3) was used to classify the therapeutic response. Patients were classified as follows: (a) controls: patients who achieved NEDA-3; (b) cases: patients who did not achieve NEDA-3. DNA was extracted from peripheral blood leukocytes. HLA-DRB1*0403 genetic variant was analyzed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. NEDA-3 was achieved in 86.7% of MS patients treated with DMTs. Genotype frequencies were GG 50.5%, GA 34.3%, and AA 15.2%. No differences were observed in the genetic variant AA between patients who achieved NEDA-3 versus patients who did not achieve NEDA-3 (48.7% vs. 43.1%, p = 0.6). We concluded that in Mexican patients with MS, HLA-DRB1*0403 was not associated with the therapeutic response to DMTs.
Assuntos
Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Cadeias HLA-DRB1/genética , Predisposição Genética para Doença , Estudos de Casos e Controles , GenótipoRESUMO
The coronavirus disease 2019 (COVID-19) mortality rates varied among the states of Brazil during the course of the pandemics. The human leukocyte antigen (HLA) is a critical component of the antigen presentation pathway. Individuals with different HLA genotypes may trigger different immune responses against pathogens, which could culminate in different COVID-19 responses. HLA genotypes are variable, especially in the highly admixed Brazilian population. In this ecological study, we aimed to investigate the correlation between HLA haplotypes and the different regional distribution of COVID-19 mortality in Brazil. HLA data was obtained from 4,148,713 individuals registered in The Brazilian Voluntary Bone Marrow Donors Registry. COVID-19 data was retrieved from epidemiological bulletins issued by State Health Secretariats via Brazil's Ministry of Health from February/2020 to July/2022. We found a positive significant correlation between the HLA-A*01~B*08~DRB1*03 haplotype and COVID-19 mortality rates when we analyzed data from 26 states and the Federal District. This result indicates that the HLA-A*01~B*08~DRB1*03 haplotype may represent an additional risk factor for dying due to COVID-19. This haplotype should be further studied in other populations for a better understanding of the variation in COVID-19 outcomes across the world.
Assuntos
Medula Óssea , COVID-19 , Humanos , Haplótipos , Brasil/epidemiologia , Frequência do Gene , Antígenos HLA-B/genética , COVID-19/genética , Cadeias HLA-DRB1/genética , Alelos , Antígenos HLA/genética , Antígenos HLA-A/genéticaRESUMO
BACKGROUND: Immigrants represented 21.8% of cases in a Spanish cohort of hospitalised patients with COVID-19, a proportion exceeding the percentage of immigrants in that area's total population. Among the ethnic-related genetic risk factors for COVID-19, human leukocyte antigen (HLA) genotypes in diverse populations might bias the response to SARS-CoV-2 infection and/or progression. Similarly, genetic differences in natural killer-activating and inhibitory receptors could play a role in the immune system's response to the viral infection. METHODS: We characterised HLA alleles and KIR genes in 52 Ecuadorian patients hospitalised for moderate and severe COVID-19 and 87 Ecuadorian controls from the general population living in the same area. RESULTS: There was a significantly increased frequency of the HLA-B*39 antigen and the activating KIR2DS4 receptor in the presence of its HLA-C*04 ligand in the COVID-19 group when compared with the control group. In contrast, there was a significant reduction in the frequency of carriers of KIR2DL1 and of the KIR3DL1/Bw4 receptor/ligand combination among COVID-19 group. On the other hand, HLA-A*24:02 and HLA-DRB1*09:01 alleles showed significantly lower frequencies specifically in the severe COVID-19 group. CONCLUSION: HLA-B*39 alleles might be genetic risk factors for developing COVID-19 in Ecuadorian individuals. In the presence of its ligand C*04, the natural killer-activating receptor KIR2DS4 might also increase the risk of developing COVID-19, while, in the presence of HLA-Bw4 alleles, the inhibitory receptor KIR3DL1 might play a protective role. Patients with COVID-19 who carry HLA-A*24:02 and HLA-DRB1*09:01 alleles might be protected against more severe forms of COVID-19.
Assuntos
COVID-19 , Receptores KIR , Humanos , Cadeias HLA-DRB1/genética , Ligantes , Fatores de Proteção , Equador/epidemiologia , Receptores KIR/genética , COVID-19/genética , SARS-CoV-2 , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos HLA-B/genética , Genótipo , Antígenos HLA-A/genéticaRESUMO
Single nucleotide polymorphisms (SNPs) have been reported to play an important role in the etiology of dental caries. The aim of this research was, through a systematic review, to identify SNPs recently associated with dental caries in pediatric populations. We included studies performed in humans up to 18 years of age that evaluated the relationship between SNPs and dental caries from 2017 to 2022. Articles that covered other study variables were excluded. PubMed, ScienceDirect and Web of Science were used to search for information and the included articles were evaluated with one of the Joanna Briggs Institute's tools. Twenty-five articles were selected, 60% of which were given high methodological quality. A total of 10,743 research subjects, ranging in age from 20 months to 17 years, participated in the study. The SNPs considered risk factors were identified in the genes miRNA202, VDR, AMELX, TUFT1, KLK4, MBL2, ENAM, DEFB1, HLA-DRB1, TAS1R1, DSPP, RUNX2 and MMP13; those considered protective factors were identified in the genes MMP20, AMBN, MMP9, TIMP2, TNF-α, VDR, IL1B, ENAM and HLA-DRB1. This systematic review presents the genetic polymorphisms that are associated with the etiology of caries in children and adolescents, some of which act as risk factors and others as protective factors against the disease.
Se ha reportado que los polimorfismos de nucleótido único (SNPs) juegan un papel importante en la etiología de la caries dental. El objetivo de esta investigación fue, a través de una revisión sistemática, identificar los SNPs asociados recientemente a la caries dental en poblaciones pediátricas. Se incluyeron estudios realizados en humanos de hasta 18 años de edad que evaluaron la relación entre los SNPs y la caries dental, publicados desde el 2017 hasta el 2022. Se excluyeron los artículos que abarcaron otras variables de estudio. PubMed, ScienceDirect y Web of Science se utilizaron para la búsqueda de información y los artículos incluidos fueron evaluados con una de las herramientas del Instituto Joanna Briggs. Fueron seleccionados 25 artículos, al 60% de ellos se le otorgó calidad metodológica alta. En total participaron 10,743 sujetos de invetigación, cuyas edades variaron de 20 meses a 17 años. Los SNPs considerados factores de riesgo fueron identificados en los genes miRNA202, VDR, AMELX, TUFT1, KLK4, MBL2, ENAM, DEFB1, HLA-DRB1, TAS1R1, DSPP, RUNX2 y MMP13, los considerados factores de protección se identificaron en los genes MMP20, AMBN, MMP9, TIMP2, TNF-α, VDR, IL1B, ENAM y HLA-DRB1. Esta revisión sistemática expone los polimorfismos genéticos que se encuentran asociados a la etiología de la caries en niños y adolescentes, algunos de los cuales actúan como factores de riesgo y otros como factores de protección ante la enfermedad.