RESUMO
AIMS: Asparaginase (ASP) hypersensitivity is a well-known challenge in the treatment of lymphoblastic malignancies. In terms of cost considerations, the cheap native Escherichia coli ASP, the most immunogenic form of this medication, is used in the first line in middle-income countries. Previously, the role of the HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 haplotype had been established to associate with E. coli ASP hypersensitivity. We investigated a possible cost-effective genetic testing method to identify patients harbouring the risk HLA haplotype in order to pave the way for safer ASP treatment. METHODS: In 241 patients with previously determined HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 haplotype and known ASP hypersensitivity status, 4 candidate HLA-tagging single-nucleotide polymorphisms (SNP)s were measured, and the performance of the different sets of these tag SNPs was evaluated. RESULTS: We identified a combination of 2 SNPs - rs28383172 and rs7775228 - as a tag for HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 haplotype with sensitivity and specificity values >95%. In line with previous findings, we found complete concordance between HLA-DRB1*07:01 and rs28383172. With bioinformatics methods, the results were also confirmed in the 1000 Genomes dataset in different ethnic groups. CONCLUSION: Rs28383172 and rs7775228 are suitable for identifying HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02 carriers. Compared to the rest of the population, patients with hypersensitivity-prone genotype would benefit more from the administration of less immunogenic PEGylated ASP before the hypersensitivity evolves, incurring minimal extra cost.
Assuntos
Asparaginase , Hipersensibilidade a Drogas , Cadeias HLA-DRB1 , Humanos , Alelos , Asparaginase/efeitos adversos , Hipersensibilidade a Drogas/genética , Escherichia coli , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
HLA-DRB1*07:147Q differs from HLA-DRB1*07:01:01:01 by one nucleotide substitution leading to a premature stop codon in exon 4.
Assuntos
Transplante de Rim , Humanos , Cadeias HLA-DRB1/genética , Alelos , Éxons/genética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
The novel allele HLA-DRB1*07:23 shows a single nucleotide change in comparison to DRB1*07:01:01:01.
Assuntos
Alelos , Cadeias HLA-DRB1/genética , Teste de Histocompatibilidade , Análise de Sequência de DNA , Sequência de Bases , Humanos , Dados de Sequência Molecular , Homologia de Sequência do Ácido NucleicoRESUMO
HLA-DRB1*07:143N and HLA-DRB1*07:144 differ from DRB1*07:01:01:01 by single mismatches in exons 3 and 2 respectively.
Assuntos
Cadeias HLA-DRB1 , Humanos , Cadeias HLA-DRB1/genética , Sequência de Bases , Alinhamento de Sequência , Alelos , Éxons/genéticaRESUMO
Two novel HLA alleles, HLA-B*58:140 and HLA-DRB1*07:145, were identified.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Humanos , Alelos , Cadeias HLA-DRB1/genética , Antígenos HLA-B/genética , Federação RussaRESUMO
Two novel HLA-DRB1 alleles identified by NGS, HLA-DRB1*04:362 and HLA-DRB1*07:148.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias HLA-DRB1/genética , AlelosRESUMO
One nucleotide replacement in codon 177 of HLA-DRB1*07:01:01:01 results in a novel allele, HLA-DRB1*07:130.
Assuntos
Cadeias HLA-DRB1 , Alelos , Sequência de Bases , Códon , Éxons/genética , Cadeias HLA-DRB1/genética , HumanosRESUMO
One nucleotide substitution in codon 107 of HLA-DRB1*07:01:01:01 results in a novel allele HLA-DRB1*07:136.
Assuntos
Povo Asiático , Alelos , Povo Asiático/genética , Sequência de Bases , Códon , Cadeias HLA-DRB1/genética , Teste de Histocompatibilidade , Humanos , Análise de Sequência de DNA , TaiwanRESUMO
A nucleotide mutation in codon 34 of HLA-DRB1*07:01:01:01 results in a novel allele HLA-DRB1*07:129N.
Assuntos
Nucleotídeos , Alelos , Sequência de Bases , Éxons/genética , Cadeias HLA-DRB1/genética , Teste de Histocompatibilidade , Humanos , Mutação , Análise de Sequência de DNARESUMO
Interstitial lung abnormalities (ILA) are defined as the presence of different patterns of increased lung density, including ground glass attenuation and reticular opacities on chest high-resolution computed tomography (HRCT). In this study, we included 90 subjects with ILA and 189 healthy controls (HC) from our Aging Lung Program. We found that subjects with ILA are older, have a significant smoking history, and have worse pulmonary function than HC (p < 0.05). When we evaluated the allele frequencies of the human leukocyte antigen (HLA) system, we found that HLA-DRB1*07 was associated with a higher risk for ILA (p < 0.05, OR = 1.95, 95% CI = 1.06-3.57). When we compared subjects with subpleural ILA vs. HC, the association with HLA-DRB1*07 became stronger than the whole ILA group (p < 0.05, OR = 2.29, 95% CI = 1.24-4.25). Furthermore, subjects with subpleural ILA and central ILA display differences in allele frequencies with HLA-DRB1*14 (3.33% vs. 13.33%, p < 0.05) and *15 (3.33% vs. 20%, p < 0.05). Our findings indicate that the HLA-DRB1*07 allele contributes to the risk of ILA, especially those of subpleural locations.