RESUMEN
We report a novel HLA-DRB3*03 allele, now named DRB3*03:65, identified by next-generation sequencing.
Asunto(s)
Exones , Cadenas HLA-DRB3 , Prueba de Histocompatibilidad , Humanos , Alelos , Secuencia de Bases , Codón , Pueblos del Este de Asia , Secuenciación de Nucleótidos de Alto Rendimiento , Cadenas HLA-DRB3/genética , Análisis de Secuencia de ADN/métodosRESUMEN
HLA-DRB3*02:194 differs from HLA-DRB3*02:02:01:02 by one nucleotide substitution in codon 78 in exon 2.
Asunto(s)
Secuencia de Bases , Humanos , Cadenas HLA-DRB3/genética , Alelos , Prueba de Histocompatibilidad , Codón , Análisis de Secuencia de ADN , Cadenas HLA-DRB1RESUMEN
Full-length sequence of HLA-DRB3*03:46 covers the 5'-untranslated region (UTR), all introns and exons and the 3' UTR.
Asunto(s)
Genómica , Humanos , Secuencia de Bases , Cadenas HLA-DRB3/genética , Alelos , Prueba de HistocompatibilidadRESUMEN
HLA-DRB3*02:193 differs from DRB3*02:02:01:11 by one nucleotide substitution in exon 1, and intronic changes.
Asunto(s)
Secuencia de Bases , Humanos , Cadenas HLA-DRB3/genética , Alelos , Prueba de Histocompatibilidad , Exones/genética , Análisis de Secuencia de ADN , Cadenas HLA-DRB1RESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) is currently a global pandemic. The pathogenesis of severe COVID-19 has been widely investigated, but it is still unclear. Human leukocyte antigen (HLA) plays a central role in immune response, and its variants might be related to COVID-19 progression and severity. OBJECTIVE: To investigate the hypothesis that individual HLA variations could alter the course of COVID-19 and might be associated with the severity of COVID-19. METHODS: In this study, we conducted an HLA targeted capture enrichment and sequencing of severe COVID-19 patients matched to mild cases. A total of 16 COVID-19 patients, confirmed by SARS-CoV-2 viral RNA polymerase-chain-reaction (PCR) test and chest computed tomography (CT) scan, were enrolled in this study. The HLA targeted capture enrichment and sequencing were conducted. HLA typing was performed by comparing contigs with IPD-IMGT/HLA Database. RESULTS: In this study, 139 four-digit resolution HLA alleles were acquired. The results showed that HLA-DRB3*01:01 allele was significantly associated with the severity of COVID-19 (odds ratio [OR] = 27.64, 95% confidence interval [CI] = 1.35-560.50, P = 0.0064). And HLA-K*01:01 might be a potential risk factor for COVID-19 severity (OR = 0.11, 95% CI = 0.017-0.66, P = 0.019), but HLA-K*01:02 might be a protective factor (OR = 7.50, 95% CI = 1.48-37.92, P = 0.019). CONCLUSION: Three non-classical HLA alleles, including HLA-DRB3*01:01, HLA-K*01:01, HLA-K*01:02 were identified to be associated with the severity of COVID-19 by comparing mild and severe patients. The current findings would be helpful for exploring the influence of HLA gene polymorphisms on the development and severity of COVID-19.
Asunto(s)
COVID-19 , Humanos , COVID-19/genética , Cadenas HLA-DRB3/genética , SARS-CoV-2 , Antígenos de Histocompatibilidad Clase I/genética , Antígenos HLA/genéticaRESUMEN
Full-length sequence covers the 5'-untranslated region (UTR), all introns and exons and the 3' UTR.
Asunto(s)
Genómica , Humanos , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Alelos , Secuencia de Bases , Cadenas HLA-DRB3/genética , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Influenza is a contagious disease that affects people of all ages and is linked to considerable mortality during epidemics and occasional outbreaks. Moreover, effective immunological biomarkers are needed for elucidating aetiology and preventing and treating severe influenza. Herein, we aimed to evaluate the key genes linked with the disease severity in influenza patients needing invasive mechanical ventilation (IMV). Three gene microarray data sets (GSE101702, GSE21802, and GSE111368) from blood samples of influenza patients were made available by the Gene Expression Omnibus (GEO) database. The GSE101702 and GSE21802 data sets were combined to create the training set. Hub indicators for IMV patients with severe influenza were determined using differential expression analysis and Weighted correlation network analysis (WGCNA) from the training set. The receiver operating characteristic curve (ROC) was also used to evaluate the hub genes from the test set's diagnostic accuracy. Different immune cells' infiltration levels in the expression profile and their correlation with hub gene markers were examined using single-sample gene set enrichment analysis (ssGSEA). RESULTS: In the present study, we evaluated a total of 447 differential genes. WGCNA identified eight co-expression modules, with the red module having the strongest correlation with IMV patients. Differential genes were combined to obtain 3 hub genes (HLA-DPA1, HLA-DRB3, and CECR1). The identified genes were investigated as potential indicators for patients with severe influenza who required IMV using the least absolute shrinkage and selection operator (LASSO) approach. The ROC showed the diagnostic value of the three hub genes in determining the severity of influenza. Using ssGSEA, it has been revealed that the expression of key genes was negatively correlated with neutrophil activation and positively associated with adaptive cellular immune response. CONCLUSION: We evaluated three novel hub genes that could be linked to the immunopathological mechanism of severe influenza patients who require IMV treatment and could be used as potential biomarkers for severe influenza prevention and treatment.
Asunto(s)
Redes Reguladoras de Genes , Gripe Humana , Biomarcadores , Perfilación de la Expresión Génica , Cadenas HLA-DRB3/genética , Humanos , Gripe Humana/genética , Respiración ArtificialRESUMEN
Multiple sclerosis (MS) is a chronic neurological disease believed to be caused by autoimmune pathogenesis. The aetiology is likely explained by a complex interplay between inherited and environmental factors. Genetic investigations into MS have been conducted for over 50 years, yielding >100 associations to date. Globally, the strongest linkage is with the human leukocyte antigen (HLA) HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype. Here, high-resolution sequencing of HLA was used to determine the alleles of DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 as well as their extended haplotypes and genotypes in 100 Swedish MS patients. Results were compared to 636 population controls. The heterogeneity in HLA associations with MS was demonstrated; among 100 patients, 69 extended HLA-DR-DQ genotypes were found. Three extended HLA-DR-DQ genotypes were found to be correlated to MS; HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype together with (A) HLA-DRB4*01:01:01//DRB4*01:01:01:01-DRB1*07:01:01-DQA1*02:01//02:01:01-DQB1*02:02:01, (B) HLA-DRBX*null-DRB1*08:01:01-DQA1*04:01:01-DQB1*04:02:01, and (C) HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01. At the allelic level, HLA-DRB3*01:01:02 was considered protective against MS. However, when combined with HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01, this extended haplotype was considered a predisposing risk factor. This highlights the limitations as included with investigations of single alleles relative to those of extended haplotypes/genotypes. In conclusion, with 69 genotypes presented among 100 patients, high-resolution sequencing was conducted to underscore the wide polymorphisms present among MS patients. Additional studies in larger cohorts will be of importance to define MS among the patient group not associated with HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01.
Asunto(s)
Esclerosis Múltiple , Antígenos HLA , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB3/genética , Cadenas HLA-DRB5/genética , Haplotipos , Humanos , Esclerosis Múltiple/genética , SueciaRESUMEN
HLA-DRB3*02:179N differs from DRB3*02:02:01:02 by one nucleotide substitution in codon 98 in exon 3.
Asunto(s)
Cadenas HLA-DRB3 , Humanos , Cadenas HLA-DRB3/genética , Alelos , Prueba de Histocompatibilidad , Secuencia de Bases , Análisis de Secuencia de ADNRESUMEN
Full-length sequence covers the 5'-untranslated region (UTR), all introns and exons, and the 3' UTR.
Asunto(s)
Genómica , Tecnología , Regiones no Traducidas 3' , Alelos , Secuencia de Bases , Cadenas HLA-DRB3/genética , Prueba de Histocompatibilidad , Humanos , Análisis de Secuencia de ADNRESUMEN
HLA-DRB3*02:174 differs from DRB3*02:02:01 by one nucleotide substitution in codon 95 in exon 3.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Exones/genética , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB3/genética , Prueba de Histocompatibilidad , HumanosRESUMEN
BACKGROUND: Nonimmediate (delayed)-allergic reactions to penicillins are common and some of them can be life-threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci. METHODS: Using next-generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls. RESULTS: The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37-23.32; p < .0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA-DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06-1.92; p = .001), but not immediate hypersensitivity. CONCLUSION: We showed that the HLA-DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA-DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins.
Asunto(s)
Hipersensibilidad a las Drogas , Hipersensibilidad Tardía , Hipersensibilidad Inmediata , Alelos , Hipersensibilidad a las Drogas/epidemiología , Genotipo , Cadenas HLA-DRB3/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/genética , Hipersensibilidad Inmediata/complicaciones , Penicilinas/efectos adversosRESUMEN
The HLA-DRB3*02:02:19 allele differs from DRB3*02:02:01:02 by a single nucleotide change in exon 2.
Asunto(s)
Nucleótidos , Alelos , Exones/genética , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB3/genética , Prueba de Histocompatibilidad , HumanosRESUMEN
Allele frequencies and haplotype frequencies of HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1, and -DPB1 have been rarely reported in South Koreans using unambiguous, phase-resolved next generation DNA sequencing. In this study, HLA typing of 11 loci in 173 healthy South Koreans were performed using next generation DNA sequencing with long-range PCR, TruSight® HLA v2 kit, Illumina MiSeqDx platform system, and Assign™ for TruSight™ HLA software. Haplotype frequencies were calculated using the PyPop software. Direct counting methods were used to investigate the association with DRB1 for samples with only one copy of a particular secondary DRB locus. We compared these allele types with the ambiguous allele combinations of the IPD-IMGT/HLA database. We identified 20, 40, 26, 31, 19, 16, 4, and 16 alleles of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1, respectively. The number of HLA-DRB3/4/5 alleles was 4, 5, and 3, respectively. The haplotype frequencies of most common haplotypes were as follows: A*33:03:01-B*44:03:01-C*14:03-DRB1*13:02:01-DQB1*06:04:01-DPB1*04:01:01 (2.89%), A*33:03:01-B*44:03:01-C*14:03 (4.91%), DRB1*08:03:02-DQA1*01:03:01-DQB1*06:01:01-DPA1*02:02:02-DPB1*05:01:01 (5.41%), DRB1*04:05:01-DRB4*01:03:01 (12.72%), DQA1*01:03:01-DQB1*06:01:01 (13.01%), and DPA1*02:02:02-DPB1*05:01:01 (30.83%). In samples with only one copy of a specific secondary DRB locus, we examined its association with DRB1. We, thus, resolved 10 allele ambiguities in HLA-B, -C (each exon 2+3), -DRB1, -DQB1, -DQA1, and -DPB1 (each exon 2) of the IPD-IMGT/HLA database. Korean population was geographically close to Japanese and Han Chinese populations in the genetic distances by multidimensional scaling (MDS) plots. The information obtained by HLA typing of the 11 extended loci by next generation sequencing may be useful for more exact diagnostic tests on various transplantations and the genetic population relationship studies in South Koreans.
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Frecuencia de los Genes , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadenas alfa de HLA-DP/genética , Cadenas beta de HLA-DP/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB3/genética , Cadenas HLA-DRB4/genética , Cadenas HLA-DRB5/genética , Haplotipos , Pueblo Asiatico/genética , Frecuencia de los Genes/genética , Sitios Genéticos/genética , Haplotipos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , República de CoreaRESUMEN
BACKGROUND AND OBJECTIVES: Associations between HLA alleles and susceptibility to M-type phospholipase A2 receptor (PLA2R)-related membranous nephropathy have been well defined previously in Chinese patients. However, the relationships between HLA alleles and kidney outcome remain unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Five HLA genes (DRB1, DQA1, DQB1, DRB3, and DRB5) were genotyped in a prospective cohort of 392 patients with PLA2R-related membranous nephropathy. The associations between HLA alleles and kidney outcomes were studied. RESULTS: A total of 79 HLA alleles were identified in this study. Four HLA alleles, DRB1*13:01 (n=12; hazard ratio, 3.7; 95% confidence interval, 1.8 to 7.8; P<0.001), DQB1*06:03 (n=12; hazard ratio, 3.7; 95% confidence interval, 1.8 to 7.8; P<0.001), DRB1*04:05 (n=12; hazard ratio, 3.8; 95% confidence interval, 1.5 to 9.5; P=0.004), and DQB1*03:02 (n=21; hazard ratio, 3.1; 95% confidence interval, 1.4 to 6.7; P=0.005), were associated with a ≥40% eGFR decline during follow-up. DRB1*13:01 and DQB1*06:03 were tightly linked with each other. Forty-four of the 392 patients (11%) carried at least one of the four identified risk HLA alleles in this study. Compared with patients who were negative for all risk HLA alleles, those carrying at least one risk HLA allele had a significant risk of a ≥40% eGFR decline during follow-up (hazard ratio, 3.9; 95% confidence interval, 2.3 to 6.7; P<0.001). After adjusting for age, sex, proteinuria, albumin, eGFR, and anti-PLA2R antibody levels, multivariable Cox analysis showed that patients carrying any of the four risk HLA alleles remained associated with a higher risk of a ≥40% decline in eGFR (hazard ratio, 4.1; 95% confidence interval, 2.3 to 7.1; P<0.001). CONCLUSIONS: Carrying any of the HLA alleles, DRB1*13:01/DQB1*06:03, DRB1*04:05, and DQB1*03:02, was independently associated with poor prognosis in Chinese patients with PLA2R-related membranous nephropathy.
Asunto(s)
Glomerulonefritis Membranosa/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas beta de HLA-DR/genética , Receptores de Fosfolipasa A2/genética , Adulto , Alelos , Pueblo Asiatico/genética , China , Progresión de la Enfermedad , Femenino , Genotipo , Tasa de Filtración Glomerular , Glomerulonefritis Membranosa/fisiopatología , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB3/genética , Cadenas HLA-DRB5/genética , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
Two new HLA-DRB3 alleles were characterized, DRB3*02:151 and DRB3*03:48.
Asunto(s)
Antígenos HLA-DR , Alelos , Secuencia de Bases , Antígenos HLA-DR/genética , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB3/genética , HumanosRESUMEN
HLA-DRB3*03:49 differs from DRB3*03:01:01:01 by one nucleotide substitution in codon 191 in exon 4.
Asunto(s)
Cadenas HLA-DRB3 , Alelos , Codón , Exones/genética , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB3/genética , Prueba de Histocompatibilidad , Humanos , Análisis de Secuencia de ADNRESUMEN
HLA-DRB3*01:86 differs from HLA-DRB3*01:01:02:01 by one nucleotide substitution in codon 225 in exon 4.
Asunto(s)
Cadenas HLA-DRB3 , Alelos , Secuencia de Bases , Exones/genética , Cadenas HLA-DRB1 , Cadenas HLA-DRB3/genética , Prueba de Histocompatibilidad , HumanosRESUMEN
HLA-DRB3*02:02:25 differs from HLA-DRB3*02:02:01:02 by one nucleotide substitution in codon 116 in exon 3.
Asunto(s)
Mutación Missense , Alelos , Codón , Exones/genética , Cadenas HLA-DRB1 , Cadenas HLA-DRB3/genética , Prueba de Histocompatibilidad , HumanosRESUMEN
Alloimmunization against human platelet antigen (HPA)-1a during pregnancy can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) and severe bleeding in the foetus or newborn and likely depends on several factors. HPA-1a alloimmunization is associated with DRB3*01:01, which is associated with several DR-DQ haplotypes. However, it is not known to what extent these haplotypes contribute to the prevalence of HPA-1a alloimmunization. HPA-1a-alloimmunized women, identified in a prospective study, and random donors were typed for selected DRB3, DRB4, DRB1, DQA1 and DQB1 alleles to determine allele and DR-DQ haplotype frequencies. DRB3*01:01 was carried by 94% HPA-1a-immunized women compared to 27% in the general population. In the first population, the DR3-DQ2 haplotype was overrepresented (P < .003). The prevalence of HPA-1a alloimmunization was estimated to be about twice as frequent with DR3-DQ2 compared to DR13-DQ6, together accounting for about 90% of DRB3*01:01-positive individuals. Further, we examined DQB1*02 and DRB4*01:01 alleles for their reported association with HPA-1a alloimmunization, in the context of DR-DQ haplotypes. Since ~ 80% of DQB1*02 alleles are linked to the DR3-DQ2 haplotype, the association might be coincidental. However, the DQB1*02:02-associated DR7-DQ2 haplotype was also overrepresented in alloimmunized women, suggesting a role for this allele or haplotype in HPA-1a alloimmunization. As DRB4*01:01 is predominantly associated with the DR7-DQ2 haplotype in HPA-1a-alloimmunized individuals, the reported association with FNAIT may be coincidental. Typing for DR-DQ haplotypes revealed important genetic associations with HPA-1a alloimmunization not evident from typing individual alleles, and the presence of different DRB3-associated DR-DQ haplotypes showed different prevalence of HPA-1a alloimmunization.