RESUMEN
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.
Asunto(s)
Alelos , Diabetes Mellitus Tipo 1 , Frecuencia de los Genes , Haplotipos , Humanos , Brasil/epidemiología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/diagnóstico , Masculino , Femenino , Niño , Adolescente , Adulto , Preescolar , Adulto Joven , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Edad de Inicio , Lactante , Persona de Mediana EdadRESUMEN
We aimed to investigate the relationship between HLA alleles in patients with type 1 diabetes from an admixed population and the reported race/skin color of their relatives. This cross-sectional, multicenter study was conducted in public clinics in nine Brazilian cities and included 662 patients with type 1 diabetes and their relatives. Demographic data for patients and information on the race/skin color and birthplace of their relatives were obtained. Typing of the HLA-DRB1, -DQA1, and -DQB1 genes was performed. Most studied patients reported having a White relative (95.17%), and the most frequently observed allele among them was DRB1*03:01. Increased odds of presenting this allele were found only in those patients who reported having all White relatives. Considering that most of the patients reported having a White relative and that the most frequent observed allele was DRB1*03:01 (probably a European-derived allele), regardless of the race/skin color of their relatives, we conclude that the type 1 diabetes genotype comes probably from European, Caucasian ethnicity. However, future studies with other ancestry markers are needed to fill the knowledge gap regarding the genetic origin of the type 1 diabetes genotype in admixed populations such as the Brazilian.
Asunto(s)
Diabetes Mellitus Tipo 1 , Antígenos HLA-DQ , Brasil/epidemiología , Estudios Transversales , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Genotipo , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Humanos , Pigmentación de la Piel/genéticaRESUMEN
BACKGROUND: The genetic predisposition to multiple sclerosis (MS) is associated with HLA alleles, especially HLA-DRB1*15:01. OBJECTIVE: To identify associations between findings in magnetic resonance imaging (MRI) and genetic features in a Brazilian cohort of patients with MS. METHODS: We retrospectively studied data from 95 consecutive patients with MS. Two independent observers who were blinded to the clinical data identified black holes and enhanced lesions on T1 MRI sequences, and counted and measured contrast-enhanced lesions on T2 and Flair (fluid attenuation inversion recovery) sequences. Cases were classified according to lesion size, number, and volume. The HLA-DRB1, HLA-DQB1, and HLA-DQA1 alleles, and the rs4774, rs3087456, rs6897932, rs731236, and rs1033182 single nucleotide polymorphisms were identified by polymerase chain reaction amplification with sequence-specific primers using the One Lambda Inc. Kit, Canoga Park, CA, USA. RESULTS: Patients with the HLA-DQA1*04:01 allele had lesion load (adjusted for age, sex, and MS duration) above median compared with patients with other HLA-DQA1 alleles (p=0.02). There were no differences among all the other HLA alleles and single nucleotide polymorphisms and lesion load. CONCLUSIONS: The correlation of the HLA-DQA1*04:01 allele with a higher lesion load on T2/Flair MRI sequences suggests that the presence of this allele is associated with the risk of greater MS severity.
Asunto(s)
Cadenas alfa de HLA-DQ/genética , Esclerosis Múltiple , Alelos , Frecuencia de los Genes , Genes MHC Clase II , Predisposición Genética a la Enfermedad , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1/genética , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/genética , Estudios RetrospectivosRESUMEN
ABSTRACT Background: The genetic predisposition to multiple sclerosis (MS) is associated with HLA alleles, especially HLA-DRB1*15:01. Objective: To identify associations between findings in magnetic resonance imaging (MRI) and genetic features in a Brazilian cohort of patients with MS. Methods: We retrospectively studied data from 95 consecutive patients with MS. Two independent observers who were blinded to the clinical data identified black holes and enhanced lesions on T1 MRI sequences, and counted and measured contrast-enhanced lesions on T2 and Flair (fluid attenuation inversion recovery) sequences. Cases were classified according to lesion size, number, and volume. The HLA-DRB1, HLA-DQB1, and HLA-DQA1 alleles, and the rs4774, rs3087456, rs6897932, rs731236, and rs1033182 single nucleotide polymorphisms were identified by polymerase chain reaction amplification with sequence-specific primers using the One Lambda Inc. Kit, Canoga Park, CA, USA. Results: Patients with the HLA-DQA1*04:01 allele had lesion load (adjusted for age, sex, and MS duration) above median compared with patients with other HLA-DQA1 alleles (p=0.02). There were no differences among all the other HLA alleles and single nucleotide polymorphisms and lesion load. Conclusions: The correlation of the HLA-DQA1*04:01 allele with a higher lesion load on T2/Flair MRI sequences suggests that the presence of this allele is associated with the risk of greater MS severity.
RESUMO Antecedentes: A predisposição genética para a esclerose múltipla (EM) está associada a alelos HLA, principalmente o HLA-DRB1*15:01. Objetivo: Identificar associações entre lesões na ressonância magnética e características genéticas em uma coorte brasileira de pacientes com EM. Métodos: Estudamos retrospectivamente os dados de 95 pacientes consecutivos com EM. Dois observadores independentes que desconheciam os dados clínicos identificaram "black holes" e lesões realçadas pelo contraste nas sequências de ressonância magnética T1 e contaram e mediram as lesões nas sequências T2 e FLAIR (fluid attenuated inversion recovery). Os casos foram classificados de acordo com tamanho, número e volume da lesão. Os alelos HLA-DRB1, HLA-DQB1 e HLA-DQA1 e os polimorfismos de nucleotídeo único rs4774, rs3087456, rs6897932, rs731236 e rs1033182 foram identificados por amplificação de reação em cadeia da polimerase com iniciadores específicos de sequência usando o kit One Lambda Inc., Canoga Park, CA, EUA. Resultados: Os pacientes com alelo HLA-DQA1*04:01 apresentaram carga de lesão (ajustada para idade, sexo e duração da EM) acima da mediana em comparação com outros pacientes com demais alelos HLA-DQA1 (p=0,02). Não houve diferenças entre todos os outros alelos HLA e polimorfismos de nucleotídeo único e carga lesional. Conclusões: A correlação do alelo HLA-DQA1*04:01 com maior carga de lesão nas sequências de RM em T2 sugere que a presença desse alelo pode estar associada ao risco de maior gravidade da EM.
Asunto(s)
Humanos , Cadenas alfa de HLA-DQ/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/diagnóstico por imagen , Imagen por Resonancia Magnética , Estudios Retrospectivos , Genes MHC Clase II , Predisposición Genética a la Enfermedad , Alelos , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1/genética , Frecuencia de los GenesRESUMEN
The novel HLA-DQA1*03:03:05 allele, first described in a potential bone marrow donor from Brazil.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Alelos , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Characterization of three novel HLA-DQA1 alleles: HLA-DQA1*01:02:01:15, -DQA1*03:03:01:15, and -DQA1*05:05:01:26.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Alelos , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Characterization of two novel HLA-DQA1*03:03:01 variants, HLA-DQA1*03:03:01:13 and -DQA1*03:03:01:14.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Alelos , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Characterization of five novel HLA-DQA1*01 variants, HLA-DQA1*01:01:01:08, -DQA1*01:02:01:14, -DQA1*01:02:02:05, -DQA1*01:03:01:10 and -DQA1*01:05:01:03.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Alelos , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Identification of the first HLA-DQA1*01:01:02 variant, called HLA-DQA1*01:01:02:02.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Alelos , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Characterization of two novel HLA-DQA1*05:05:01 variants, HLA-DQA1*05:05:01:22 and -DQA1*05:05:01:23.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Alelos , Trasplante de Médula Ósea , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Characterization and confirmation of an HLA-DQA1*04:01:01 variant, HLA-DQA1*04:01:01:09.
Asunto(s)
Cadenas alfa de HLA-DQ , Alelos , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Characterization of two novel HLA-DQA1*05:05:01 variants, HLA-DQA1*05:05:01:24 and -DQA1*05:05:01:25.
Asunto(s)
Cadenas alfa de HLA-DQ , Alelos , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Identification of the novel HLA-DQA1*02:11 allele that differs from HLA-DQA1*02:01:01:01 in exon 2.
Asunto(s)
Médula Ósea , Cadenas alfa de HLA-DQ , Alelos , Trasplante de Médula Ósea , Brasil , Cadenas alfa de HLA-DQ/genética , Humanos , Donantes de TejidosRESUMEN
Characterization of two novel HLA-DQA1*03:03:01 variants, HLA-DQA1*03:03:01:11 and -DQA1*03:03:01:12.
Asunto(s)
Cadenas alfa de HLA-DQ , Polimorfismo de Nucleótido Simple , Alelos , Brasil , Cadenas alfa de HLA-DQ/genética , HumanosRESUMEN
Sixty hundred and forty-one Brazilian individuals from the north and northwestern state of Paraná, southern Brazil, were selected for the study. The HLA-A, -B, -DRB1, -DQA1, and -DQB1 genotyping were performed using rSSO and Micro SSP analysis. These genotype data are available in the Allele Frequencies Net Database under the population name "Brazil Paraná Caucasian" number "AFND3618".
Asunto(s)
Genotipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Brasil , Femenino , Técnicas de Genotipaje , Humanos , MasculinoRESUMEN
Characterization of three novel HLA-DQA1*03:03:01 variants, HLA-DQA1*03:03:01:08, -DQA1*03:03:01:09, and -DQA1*03:03:01:10.
Asunto(s)
Cadenas alfa de HLA-DQ/genética , Polimorfismo de Nucleótido Simple , Obtención de Tejidos y Órganos , Alelos , Trasplante de Médula Ósea , Brasil , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia de ADNRESUMEN
Characterization of the first HLA-DQA1*01:05:01 variant, called HLA-DQA1*01:05:01:02.
Asunto(s)
Cadenas alfa de HLA-DQ/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Alelos , Brasil , HumanosRESUMEN
The aim of this study was to determine the allele and haplotype frequencies of HLA-A, -B, -DRB1, and -DQB1 in a self-declared White population from the north and northwestern state of Paraná, southern Brazil, and compare the data with populations worldwide. The genotyping was performed with a group of 641 individuals, based on PCR-SSO and -SSP methods, and allele and haplotype frequencies were estimated. Comparisons with European, African, Asian, and Amerindian populations were performed. The most frequent allelic groups, alleles and haplotypes were: HLA-A*02, HLA-B*35, HLA-DRB1*07:01, HLA-DQB1*03:01, and HLA-A*01/B*08/DRB1*03:01. The results reinforced a predominance of a European composition in the self-declared White population from the north and northwestern Paraná.
Asunto(s)
Genética de Población , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Haplotipos , Adulto , Alelos , Brasil , Femenino , Frecuencia de los Genes , Voluntarios Sanos , Humanos , Masculino , Polimorfismo GenéticoRESUMEN
ABSTRACT Objective To evaluate the frequency of DQ2.5 and DQ8 alleles using the Tag-single-nucleotide polymorphism (Tag-SNP) technique in individuals with type 1 diabetes mellitus (T1DM) and celiac disease (CD) in southern Brazil. Materials and methods In a prospective design, we performed the search for DQA1*0501 and DQB1*0201 alleles for DQ2.5 and DQB1*0302 for DQ8 through Real-Time Polymerase Chain Reaction (RT-PCR) technique, using TaqMan Genotyping Assays (Applied Biosystems, USA). The diagnosis of CD was established by duodenal biopsy and genotypic determination performed by StepOne Software v2.3. Allelic and genotypic frequencies were compared between groups using Chi-square and Fisher's exact tests and the multiple comparisons using Finner's adjustment. Results Three hundred and sixty two patients with a median age of 14 years were divided into 3 groups: T1DM without CD (264); T1DM with CD (32) and CD without T1DM (66). In 97% of individuals with T1DM and CD and 76% of individuals with CD without T1DM, respectively, the alleles DQ2.5 and/or DQ8 were identified (p < 0.001). DQ2.5 was more common in individuals with CD (p = 0.004) and DQ8 was more common in individuals with type 1 diabetes (p = 0.008). Conclusions The evaluation of the alleles for DQ2.5 and DQ8 by Tag-SNP technique showed a high negative predictive value among those with T1DM, similar to that described by the conventional technique. The high frequency of DQ8 alleles in individuals with T1DM did not allow differentiating those at higher risk of developing T1DM.
Asunto(s)
Humanos , Masculino , Femenino , Enfermedad Celíaca/genética , Predisposición Genética a la Enfermedad/genética , Diabetes Mellitus Tipo 1/genética , Frecuencia de los Genes/genética , Enfermedad Celíaca/complicaciones , Estudios Prospectivos , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Diabetes Mellitus Tipo 1/complicaciones , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , GenotipoRESUMEN
The aim of this study was to analyze the HLA class II alleles in neuromyelitis optica (NMO) and MS patients from Rio de Janeiro to clarify whether the pattern of genetic predisposition in NMO is different from the one seen in MS or whether it is possible to determine specific alleles of susceptibility or resistance. The DR3 haplotype was over represented in NMO while the DR15 was over represented in MS. The HLA-DRB1*03:01 allele was associated with NMO regardless the NMO-IgG status but did not influence the long term disability. The comparison of the allele and haplotype frequencies significantly discriminated patients with NMO vs. MS.