RESUMO
Eplet 52SK is unique in the HLA eplet registry as targeting the whole family of DQA1*01 alleles. It is proposed as an antibody-verified eplet but has not been validated enough to deserve this label. Especially, confusion can occur with reactivity targeting the 52PQ eplet which is present on the DQB1*05 and DQB1*06 alleles families, as DQ molecule stability imposes DQA1*01 to selectively associate with these DQ-ß families only. Using two Luminex single antigen (LSA) assays from two vendors, beads bearing DR-α/DQ6 heterodimers, a special build LSA panel of additional DQ beads, and an adsorption/elution strategy relying on cells from deceased donors or recombinant cells solely expressing one DQ antigen, we definitely established the antibody-verified status of eplet 52SK using patients' sera reacting only against the DQ5 and DQ6 beads of the One Lambda LSA panel in routine patients' follow up. We also show that reactivity against this eplet is not a rare event among anti-DQ1 immunisation. This study further strengthens the importance of considering the DQA1 locus in immunological studies of HLA and in organ allocation strategies.
Assuntos
Alelos , Cadeias alfa de HLA-DQ , Teste de Histocompatibilidade , Humanos , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Teste de Histocompatibilidade/métodos , Isoanticorpos/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologiaRESUMO
HLA-DQA1*01:02:24 differs from HLA-DQA1*01:02:01:03 by one nucleotide substitution in codon 167 in exon 3.
Assuntos
Alelos , Sequência de Bases , Éxons , Cadeias alfa de HLA-DQ , Teste de Histocompatibilidade , Análise de Sequência de DNA , Humanos , Cadeias alfa de HLA-DQ/genética , Análise de Sequência de DNA/métodos , Códon , Alinhamento de SequênciaRESUMO
Background and Objectives: The aim of the following cross-sectional study is to determine the association between human leukocyte antigen (HLA) alleles and outcomes in patients presenting to the emergency department (ED) with SARS-CoV-2 infection. Methods and Materials: Genotyping was made using the Axiom Human Genotyping SARS-CoV-2 Research Array. Statistical analysis was made with Fisher's exact test and multivariable logistic regression, adjusted for sex, age and clinical variables. Results: Of 190 patients, 11.1% were discharged from the ED; 57.9% were admitted to the COVID-19 ward, without intensive care unit (ICU) admission; 15.3% survived an ICU admission; and 15.8% died. After multivariable analysis, two HLA alleles protected against hospital admission (HLA-C*05:01, adjusted odds ratio [aOR] 0.2, 95% confidence interval [CI] 0.055-0.731; and HLA-DQB1*02:02, aOR 0.046, CI 0.002-0.871) and one was associated with higher risk for ICU admission or death (HLA-DQA1*05:01, aOR 2.517, CI 1.086-5.833). Conclusions: In this population, HLA-C*05:01 and HLA-DQB1*02:02 are associated with a protective effect against hospital admission and HLA-DQA1*05:01 is associated with higher risk of ICU admission or death in the multivariable analysis. This may help stratify risk in COVID-19 patients.
Assuntos
Alelos , COVID-19 , Humanos , COVID-19/mortalidade , COVID-19/imunologia , COVID-19/genética , Masculino , Feminino , Pessoa de Meia-Idade , Espanha/epidemiologia , Estudos Transversais , Idoso , SARS-CoV-2 , Adulto , Índice de Gravidade de Doença , Antígenos HLA/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Antígenos HLA-C/genética , Unidades de Terapia Intensiva , Serviço Hospitalar de Emergência/estatística & dados numéricos , GenótipoRESUMO
A single nucleotide substitution in the exon 3 gives rise to the novel HLA-DQA1*05:73 allele.
Assuntos
Alelos , Substituição de Aminoácidos , Cadeias alfa de HLA-DQ , Humanos , Sequência de Bases , Códon , Éxons/genética , Teste de Histocompatibilidade/métodos , Cadeias alfa de HLA-DQ/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodosRESUMO
A single nucleotide mismatch within exon 3 of HLA-DQA1 differentiates the novel allele DQA1*03:79 from DQA1*03:15.
Assuntos
Éxons , Cadeias alfa de HLA-DQ , Teste de Histocompatibilidade , Doadores de Tecidos , Humanos , Alelos , Sequência de Bases , Medula Óssea , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade/métodos , Cadeias alfa de HLA-DQ/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
HLA-DQA1*05:115 shows an alanine at position 59 not described previously.
Assuntos
Alanina , Alelos , Cadeias alfa de HLA-DQ , Humanos , Cadeias alfa de HLA-DQ/genética , Alanina/genética , Éxons , Teste de Histocompatibilidade , Substituição de Aminoácidos , Domínios ProteicosRESUMO
BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune disease and the most common chronic rheumatological disease affecting children under the age of 16. The etiology of JIA remains poorly understood, but evidence suggests a significant genetic predisposition. METHODS: We analyzed a Swedish cohort of 329 JIA patients and 728 healthy adult controls using the Illumina OmniExpress array for genotyping. HLA alleles were imputed from GWAS data using the SNP2HLA algorithm. RESULTS: Case-control analysis yielded 12 SNPs with genome-wide significant association to JIA, all located on chromosome 6 within the MHC class II gene region. Notably, the top SNP (rs28421666) was located adjacent to HLA-DQA1 and HLA-DRB1. HLA-DRB1*08:01, HLA-DQA1*04:01, and HLA-DQB1*04:02 were the haplotypes most strongly associated with an increased risk of JIA in the overall cohort. When analyzing disease specific subtypes, these alleles were associated with oligoarthritis and RF-negative polyarthritis. Within the complex linkage disequilibrium of the HLA-DRB1-DQA1-DQB1 haplotype, our analysis suggests that HLA-DRB1*08 might be the primary allele linked to JIA susceptibility. The HLA-DRB1*11 allele group was also independently associated with JIA and specifically enriched in the oligoarthritis patient group. Additionally, our study revealed a significant correlation between antinuclear antibody (ANA) positivity and specific HLA alleles. The ANA-positive JIA group showed stronger associations with the HLA-DRB1-DQA1-DQB1 haplotype, HLA-DRB1*11, and HLA-DPB1*02, suggesting a potential connection between genetic factors and ANA production in JIA. Furthermore, logistic regression analysis reaffirmed the effects of HLA alleles, female sex, and lower age at onset on ANA positivity. CONCLUSIONS: This study identified distinct genetic associations between HLA alleles and JIA subtypes, particularly in ANA-positive patients. These findings contribute to a better understanding of the genetic basis of JIA and provide insights into the genetic control of autoantibody production in ANA-positive JIA patients. This may inform future classification and personalized treatment approaches for JIA, ultimately improving patient outcomes and management of this disease.
Assuntos
Anticorpos Antinucleares , Artrite Juvenil , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Humanos , Artrite Juvenil/genética , Artrite Juvenil/imunologia , Suécia , Masculino , Feminino , Anticorpos Antinucleares/sangue , Adolescente , Criança , Estudos de Casos e Controles , Estudos de Coortes , Alelos , Haplótipos , Adulto , Estudo de Associação Genômica Ampla , Genótipo , Cadeias alfa de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Pré-Escolar , Desequilíbrio de LigaçãoRESUMO
BACKGROUND: Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug-induced liver injury (DILI) due to AZ. METHODS: The clinical characteristics of individuals with definite, highly likely, or probable AZ-DILI enrolled in the US Drug-Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ-DILI cases was compared to population controls, other DILI cases, and other antibiotic-associated DILI cases. RESULTS: Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ-DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA-DQA1*03:01 was significantly more common in AZ-DILI versus population controls and amoxicillin-clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). CONCLUSION: Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA-DQA1*03:01 was significantly more common in AZ cases compared to controls.
Assuntos
Antibacterianos , Azitromicina , Doença Hepática Induzida por Substâncias e Drogas , Humanos , Feminino , Masculino , Doença Hepática Induzida por Substâncias e Drogas/genética , Pessoa de Meia-Idade , Azitromicina/efeitos adversos , Adulto , Antibacterianos/efeitos adversos , Idoso , Adulto Jovem , Antígenos HLA/genética , Adolescente , Frequência do Gene , Cadeias alfa de HLA-DQRESUMO
The clinical spectrum of COVID-19 includes a wide range of manifestations, from mild symptoms to severe pneumonia. HLA system plays a pivotal role in immune responses to infectious diseases. The purpose of our study was to investigate the association between HLA and COVID-19 severity in a Japanese population. The study included 209 Japanese COVID-19 patients aged ≥20 years. Saliva samples were collected and used to determine the HLA genotype by HLA imputation through genome-wide association analyses. The association between HLA genotype and COVID-19 severity was then evaluated. The allele frequency was compared between patients with respiratory failure (severe group: 91 cases) and those without respiratory failure (non-severe group: 118 cases), categorising the data into three time periods: pre-Omicron epidemic period, Omicron epidemic period, and total period of this study (from January 2021 to May 2023). In comparing the severe and non-severe groups, the frequencies of the HLA-DQA1*01:03 (35.1% vs. 10.5%, odds ratio [OR] = 4.57, corrected p [pc] = 0.041) and -DQB1*06:01 (32.4% vs. 7.9%, OR = 5.54, pc = 0.030) alleles were significantly higher in the severe group during the pre-Omicron epidemic period. During the Omicron epidemic period, HLA-DQB1*06 (32.4% vs. 7.9%, OR = 5.54, pc = 0.030) was significantly higher in the severe group. During total period of this study, HLA-DQA1*01:03 (30.2% vs. 14.4%, OR = 2.57, corrected pc = 0.0013) and -DQB1*06:01 (44.5% vs. 26.7%, OR = 2.20, pc = 0.013) alleles were significantly higher in the severe group. HLA-DQB1*06:01 and -DQA1*01:03 were in strong linkage disequilibrium with each other (r2 = 0.91) during total period of this study, indicating that these two alleles form a haplotype. The frequency of the HLA-DQA1*01:03-DQB1*06:01 in the severe group was significantly higher than in the non-severe group during pre-Omicron epidemic period (32.4% vs. 7.9%, OR = 5.59, pc = 0.00072), and total period of this study (28.6% vs. 13.1%, OR = 2.63, pc = 0.0013). During Omicron epidemic period, the haplotype did not demonstrate statistical significance, although the odds ratio indicated a value greater 1. Frequencies of the HLA-DQA1*01:03 and -DQB1*06:01 alleles were significantly higher in severe COVID-19 patients, suggesting that these alleles are risk factors for severe COVID-19 pneumonia in the Japanese population.
Assuntos
COVID-19 , Frequência do Gene , Predisposição Genética para Doença , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , SARS-CoV-2 , Índice de Gravidade de Doença , Humanos , Cadeias alfa de HLA-DQ/genética , COVID-19/genética , COVID-19/imunologia , COVID-19/epidemiologia , Cadeias beta de HLA-DQ/genética , Masculino , SARS-CoV-2/imunologia , Feminino , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Alelos , Japão/epidemiologia , Adulto , Genótipo , Haplótipos , Idoso de 80 Anos ou maisRESUMO
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
HLA-DQA1*03:75 differs from HLA-DQA1*03:02:01:01 by a single non-synonymous nucleotide substitution in exon 2.
Assuntos
Alelos , Éxons , Cadeias alfa de HLA-DQ , Teste de Histocompatibilidade , Transplante de Rim , Doadores de Tecidos , Humanos , Cadeias alfa de HLA-DQ/genética , República da Coreia , Povo Asiático/genética , Análise de Sequência de DNA/métodos , Sequência de BasesRESUMO
HLA-DQA1*05:03:03, a novel HLA class II allele detected by next-generation sequencing.
Assuntos
Alelos , Éxons , Cadeias alfa de HLA-DQ , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Cadeias alfa de HLA-DQ/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Códon , Sequência de Bases , Análise de Sequência de DNA/métodosRESUMO
BACKGROUND: Gestational diabetes mellitus (GDM) is associated with DNA methylation and lifestyle. The effects of DNA methylation on GDM, and the interaction between DNA methylation and lifestyle factors are not well elucidated. The objective of this study was to explore the association between GDM, DNA methylation and lifestyle factors. METHODS: A nest case-control design was performed. Sociodemographic data, dietary intake and daily physical activity information of pregnant women were collected. Bisulfate pyrosequencing was used to detect the DNA methylation level of PPARGC1A, HLA-DQA1, and ADCY3 genes. The differences of DNA methylation levels between the GDM group and the control group were compared. The correlation between clinical characteristics, dietary, physical activity and DNA methylation level was analyzed. RESULTS: A total of 253 pregnant women were enrolled, of which, 60 participants (GDM: 30; control: 30) were included in the final analysis. There were no significant differences in DNA methylation levels of six methylated sites between the two groups in this study (P > 0.05). Daily intake of potato and poultry were associated with DNA methylation level of the CpG 1 site of the ADCY3 gene in all participants and the control group (P < 0.05). Duration of folic acid intake before pregnancy was correlated with the methylation level of the CpG 1 site of the ADCY3 gene in all participants (r = 0.341, P = 0.04) and the control group (r = 0.431, P = 0.025). Daily oil intake was correlated with the methylation level of CpG 2 (r = 0.627, P = 0.016) and CpG 3 (r = 0.563, P = 0.036) of PPARGC1A in the GDM group. CONCLUSION: The association between the DNA methylation levels and GDM wasn't validated. There were associations between dietary and DNA methylation in pregnant women. A large-sample-sized and longitudinal study is warranted to further investigate the impacts of lifestyle on DNA methylation.
Assuntos
Metilação de DNA , Diabetes Gestacional , Dieta , Exercício Físico , Cadeias alfa de HLA-DQ , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Humanos , Feminino , Gravidez , Diabetes Gestacional/genética , Adulto , Estudos de Casos e Controles , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Cadeias alfa de HLA-DQ/genética , Catalase/genética , Estilo de Vida , Polipeptídeo Hipofisário Ativador de Adenilato CiclaseRESUMO
HLA-DQA1*05:112 differs from HLA-DQA1*05:05:01:01 by one nucleotide substitution in codon -7 in exon 1.
Assuntos
Alelos , Sequência de Bases , Éxons , Cadeias alfa de HLA-DQ , Teste de Histocompatibilidade , Análise de Sequência de DNA , Humanos , Cadeias alfa de HLA-DQ/genética , Teste de Histocompatibilidade/métodos , Análise de Sequência de DNA/métodos , Códon , Alinhamento de SequênciaRESUMO
HLA-DQA1*04:14N differs from HLA-DQA1*04:01:01:03 by a single nucleotide deletion in codon 113 in exon 3.
Assuntos
Alelos , Éxons , Cadeias alfa de HLA-DQ , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Cadeias alfa de HLA-DQ/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Códon , Sequência de Bases , Análise de Sequência de DNA/métodos , Deleção de SequênciaRESUMO
OBJECTIVE: To identify new genetic variants associated with SLE in Taiwan and establish polygenic risk score (PRS) models to improve the early diagnostic accuracy of SLE. METHODS: The study enrolled 2429 patients with SLE and 48 580 controls from China Medical University Hospital in Taiwan. A genome-wide association study (GWAS) and PRS analyses of SLE and other three SLE markers, namely ANA, anti-double-stranded DNA antibody (dsDNA) and anti-Smith antibody (Sm), were conducted. RESULTS: Genetic variants associated with SLE were identified through GWAS. Some novel genes, which have been previously reported, such as RCC1L and EGLN3, were revealed to be associated with SLE in Taiwan. Multiple PRS models were established, and optimal cut-off points for each PRS were determined using the Youden Index. Combining the PRSs for SLE, ANA, dsDNA and Sm yielded an area under the curve of 0.64 for the optimal cut-off points. An analysis of human leucocyte antigen (HLA) haplotypes in SLE indicated that individuals with HLA-DQA1*01:01 and HLA-DQB1*05:01 were at a higher risk of being classified into the SLE group. CONCLUSIONS: The use of PRSs to predict SLE enables the identification of high-risk patients before abnormal laboratory data were obtained or symptoms were manifested. Our findings underscore the potential of using PRSs and GWAS in identifying SLE markers, offering promise for early diagnosis and prediction of SLE.
Assuntos
Estratificação de Risco Genético , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Antinucleares/sangue , Estudos de Casos e Controles , Haplótipos , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Polimorfismo de Nucleotídeo Único , Taiwan/epidemiologiaRESUMO
Characterisation of HLA-DQA1*01:02:01:30, HLA-DQA1*01:03:01:14, HLA-DQA1*03:03:01:20, HLA-DQA1*04:01:01:13, HLA-DQA1*05:05:01:40 alleles in Spanish individuals.
Assuntos
Alelos , Cadeias alfa de HLA-DQ , Humanos , Cadeias alfa de HLA-DQ/genética , Teste de Histocompatibilidade , Espanha , Análise de Sequência de DNA/métodos , Éxons , Sequência de BasesRESUMO
HLA-DQA1*02:32 differs from DQA1*02:01:01 by one nucleotide substitution in codon 210 in exon 4.
Assuntos
Alelos , Éxons , Cadeias alfa de HLA-DQ , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Cadeias alfa de HLA-DQ/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Sequência de Bases , Códon , Análise de Sequência de DNA/métodosRESUMO
Full length sequence characterisation of the novel HLA-DQA1*05:107 allele from whole genome sequencing data.
Assuntos
Alelos , Cadeias alfa de HLA-DQ , Humanos , Sequência de Bases , Cadeias alfa de HLA-DQ/genética , Sequenciamento Completo do GenomaRESUMO
HLA-DQA1*05:05:17:03 differs from HLA-DQA1*05:05:01:02 by a single base substitution in exon 1 and HLA-DQA1*05:05:17:01 within introns 1 and 2.