RESUMO
BACKGROUND: Alopecia areata (AA) is a skin disease that produces hair loss in patches of skin. The underlying mechanism of AA is a loss of immune privilege of hair follicles, which are then attacked by natural killer (NK) cells. A previous genome-wide association study linked single nucleotide polymorphisms of the protein MHC class I chain-related A (MICA) to this disease. MICA is the ligand for the activating receptor NKG2D, expressed mainly by NK cells and CD8+ cytotoxic T cells. As the aforementioned study did not include short tandem repeats (STRs) of MICA, we decided to study these in relation to AA. AIM: To study the association of STRs with AA, alongside that of human leucocyte antigen (HLA) locus B, which is closely linked to MICA. METHODS: DNA amplicon size analysis was carried out, and HLA-B locus genomic typing was performed by PCR-sequence-specific oligonucleotide analysis. RESULTS: We observed an association between AA and both MICA*009 and HLA-B14; associations were also observed between HLA-B alleles and MICA alleles, which have both been previously found to be connected with AA, but never studied together. CONCLUSIONS: We conclude that it is important to study HLA-B and MICA together to avoid the influence of their association in experiments in which they are investigated separately.
Assuntos
Alopecia em Áreas/genética , Antígeno HLA-B14/genética , Antígenos de Histocompatibilidade Classe I/genética , Repetições de Microssatélites , Predisposição Genética para Doença , Genótipo , Antígenos HLA-B/genética , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
BACKGROUND: Class I human leukocyte antigens, especially the molecules encoded at the B locus (HLA-B), are associated with AIDS progression risk. Different groups of HLA-B alleles have been associated to a protective effect or increasing susceptibility to HIV infection and are expressed from the earliest stages of gestation. OBJECTIVE: The aim of this study was to evaluate which variants of HLA-B are associated with the risk of HIV vertical transmission in infected pregnant women and in their offspring, in a referral center in Salvador Bahia. METHODS: We performed HLA-B genotyping in 52 HIV-infected mothers and their children exposed to HIV-1 during pregnancy (N=65) in Salvador, Brazil. We compared the HLA-B alleles frequency in mothers, uninfected and infected children, according to the use of antiretroviral prophylaxis. RESULTS: Absence of antiretroviral antenatal and postnatal prophylaxis was significantly associated with vertical transmission of HIV-1 (p=<0.01, and p=<0.01 respectively). Frequency of HLA-B*14 (29.2%, p=0.002), HLA-B*18 (16.7%, p=0.04) or HLA-B*14:1 (20.8%, p=0.01) alleles subgroups were significantly higher in HIV-1 infected children and persisted (HLA-B*14, p=0.04) even after adjusting for use of antiretroviral prophylaxis. No significant difference in expression of HLA-B alleles was observed among mothers who transmitted the virus compared to those who did not. CONCLUSIONS: Expression of HLA-B*14 allele in children exposed to HIV-1 is predictive of vertical transmission and reinforces the important role of genetics in mother-to-child transmission.
Assuntos
Alelos , Infecções por HIV/genética , Infecções por HIV/transmissão , Antígeno HLA-B14/genética , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Brasil/epidemiologia , Criança , Estudos Transversais , Progressão da Doença , Feminino , Frequência do Gene , Técnicas de Genotipagem , Infecções por HIV/sangue , Antígeno HLA-B14/sangue , Humanos , Modelos Logísticos , Masculino , Valor Preditivo dos Testes , Valores de Referência , Medição de Risco , Fatores de Risco , Fatores SocioeconômicosRESUMO
ABSTRACT Background: Class I human leukocyte antigens, especially the molecules encoded at the B locus (HLA-B), are associated with AIDS progression risk. Different groups of HLA-B alleles have been associated to a protective effect or increasing susceptibility to HIV infection and are expressed from the earliest stages of gestation. Objective: The aim of this study was to evaluate which variants of HLA-B are associated with the risk of HIV vertical transmission in infected pregnant women and in their offspring, in a referral center in Salvador Bahia. Methods: We performed HLA-B genotyping in 52 HIV-infected mothers and their children exposed to HIV-1 during pregnancy (N = 65) in Salvador, Brazil. We compared the HLA-B alleles frequency in mothers, uninfected and infected children, according to the use of antiretroviral prophylaxis. Results: Absence of antiretroviral antenatal and postnatal prophylaxis was significantly associated with vertical transmission of HIV-1 (p = <0.01, and p = <0.01 respectively). Frequency of HLA-B*14 (29.2%, p = 0.002), HLA-B*18 (16.7%, p = 0.04) or HLA-B*14:1 (20.8%, p = 0.01) alleles subgroups were significantly higher in HIV-1 infected children and persisted (HLA-B*14, p = 0.04) even after adjusting for use of antiretroviral prophylaxis. No significant difference in expression of HLA-B alleles was observed among mothers who transmitted the virus compared to those who did not. Conclusions: Expression of HLA-B*14 allele in children exposed to HIV-1 is predictive of vertical transmission and reinforces the important role of genetics in mother-to-child transmission.
Assuntos
Humanos , Masculino , Feminino , Criança , Infecções por HIV/genética , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Alelos , Antígeno HLA-B14/genética , Valores de Referência , Fatores Socioeconômicos , Brasil/epidemiologia , Infecções por HIV/sangue , Modelos Logísticos , Estudos Transversais , Valor Preditivo dos Testes , Fatores de Risco , Medição de Risco , Progressão da Doença , Antígeno HLA-B14/sangue , Técnicas de Genotipagem , Frequência do GeneRESUMO
BACKGROUND & AIMS: Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. In this study we aimed to describe the presenting features and outcomes of patients with terbinafine hepatotoxicity and to investigate the role of human leukocyte antigen (HLA)-A*33:01. METHODS: Consecutive high causality cases of terbinafine hepatotoxicity enrolled into the Drug Induced Liver Injury Network were reviewed. DNA samples underwent high-resolution confirmatory HLA sequencing using the Ilumina MiSeq platform. RESULTS: All 15 patients with terbinafine hepatotoxicity were more than 40â¯years old (medianâ¯=â¯57â¯years), 53% were female and the median latency to onset was 38â¯days (range 24 to 114â¯days). At the onset of drug-induced liver injury, 80% were jaundiced, median serum alanine aminotransferase was 448â¯U/L and alkaline phosphatase was 333â¯U/L. One individual required liver transplantation for acute liver failure during follow-up, and 7 of the 13 (54%) remaining individuals had ongoing liver injury at 6â¯months, with 4 demonstrating persistently abnormal liver biochemistries at month 24. High-resolution HLA genotyping confirmed that 10 of the 11 (91%) European ancestry participants were carriers of the HLA-A*33:01, B*14:02, C*08:02 haplotype, which has a carrier frequency of 1.6% in European Ancestry population controls. One African American patient was also an HLA-A*33:01 carrier while 2 East Asian patients were carriers of a similar HLA type: A*33:03. Molecular docking studies indicated that terbinafine may interact with HLA-A*33:01 and A*33:03. CONCLUSIONS: Patients with terbinafine hepatotoxicity most commonly present with a mixed or cholestatic liver injury profile and frequently have residual evidence of chronic cholestatic injury. A strong genetic association of HLA-A*33:01 with terbinafine drug-induced liver injury was confirmed amongst Caucasians. LAY SUMMARY: A locus in the human leukocyte antigen gene (HLA-A*33:01, B*14:02, C*08:02) was significantly overrepresented in Caucasian and African American patients with liver injury attributed to the antifungal medication, terbinafine. These data along with the molecular docking studies demonstrate that this genetic polymorphism is a plausible risk factor for developing terbinafine hepatotoxicity and could be used in the future to help doctors make a diagnosis more rapidly and confidently.
Assuntos
Antifúngicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Colestase/induzido quimicamente , Antígenos HLA-A/genética , Terbinafina/efeitos adversos , Adulto , Idoso , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Antifúngicos/administração & dosagem , Antifúngicos/química , Biomarcadores/química , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Feminino , Seguimentos , Antígenos HLA-A/química , Antígeno HLA-B14/química , Antígeno HLA-B14/genética , Haplótipos , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Polimorfismo Genético , Estudos Prospectivos , Ligação Proteica , Terbinafina/administração & dosagem , Terbinafina/químicaRESUMO
HLA-B*14:02:16 differs from B*14:02:01:01 by a synonymous nucleotide substitution in codon 141.
Assuntos
Doadores de Sangue , Códon , Variação Genética , Antígeno HLA-B14/genética , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Sequência de Bases , Genótipo , Humanos , Masculino , Reação em Cadeia da Polimerase , Análise de Sequência de DNA/métodos , Homologia de Sequência , Mutação SilenciosaRESUMO
The split specificities of HLA-B14 (B64, B65) are assigned to the B*14:01 (B64) and B*14:02 (B65) products only. Of the further 50 B*14 expressed products, only B*14:03 and B*14:06 are officially designated as HLA-B14. The B*14:08 product differs from B64 by a single amino acid substitution of W97R, while the B*14:53 specificity (which is a "short" B14 and neither B64 nor B65) differs from B64 by three residues (W97S, Y113H and F116Y). Comprehensive testing of B*14:08:01 cells (using 49 alloantisera with B64 or B64, B65 specificities, and five monoclonal antibodies with B65 or B64, B65 activity) showed that the B*14:08 specificity is, like the B*14:53 product, neither B64 nor B65 and appears as a "short" B14 specificity. To help understand the serological reactivity of the B*14:08 and B*14:53 products, and B64 and B65, we identified seven published epitopes (11AV, 97W, 61ICT, 116F, 131S+163T, 170RH and 420) and, by inspection, 29 motifs, that encompass one or more of B64, B65 and various HLA-B14 cross-reactive group specificities. We then considered the possession of these epitopes and motifs by the products of B*14:01 to B*14:06, B*14:08 and B*14:53. Seventeen of the 29 motifs fully complied with the one-/two-patch functional epitope concept for amino acid proximity, as determined by Cn3D software, the remainder partially complied. The nature and patterns of epitopes and motifs possessed by both B*14:08 and B*14:53 specificities supported their designation as HLA-B14 but non-B64/B65. Also that epitope 97W, with 11S or 11A, is critical for serological B64 and B65 reactivity. And conversely, that epitope 116F, and several identified motifs, are probably unimportant for HLA-B14 antibody reactivity. The previous submission that the B*14:03 specificity is HLA-B65 was compatible with its epitope/motif pattern. B*14:04 cells would also be expected to react as B65, based on its epitope/motif pattern, and not as B64 as previously implied. Also, from their epitope/motif patterns, and external serological information, it is probable that the B*14:05 and B*14:06 specificities will both appear as "short" HLA-B14, non-B64/B65. Several epitopes and motifs encompassed a range of HLA-B specificities included in the serological HLA-B14 cross-reactive group, thus supporting these original serological findings.
Assuntos
Substituição de Aminoácidos/genética , Epitopos/imunologia , Antígeno HLA-B14/imunologia , Isoanticorpos/imunologia , Alelos , Motivos de Aminoácidos/genética , Motivos de Aminoácidos/imunologia , Substituição de Aminoácidos/imunologia , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos/imunologia , Reações Cruzadas/imunologia , Epitopos/genética , Antígeno HLA-B14/genética , Humanos , Isoanticorpos/genéticaRESUMO
The new B*50:51 allele was found in 3 Caucasians from Southern Spain.
Assuntos
Alelos , Antígeno HLA-B14/genética , Recombinação Genética , Feminino , Humanos , MasculinoRESUMO
Full-length sequences of HLA-B*07:05:01:01, B*14:01:01 and B*18:02, confirmed by cloning and sequencing in Chinese donors.
Assuntos
Alelos , Éxons , Antígeno HLA-B14/genética , Antígeno HLA-B18/genética , Antígeno HLA-B7/genética , Polimorfismo Genético , Povo Asiático , Sequência de Bases , Clonagem Molecular , Códon/química , Expressão Gênica , Antígeno HLA-B14/imunologia , Antígeno HLA-B18/imunologia , Antígeno HLA-B7/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Íntrons , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , Doadores de TecidosRESUMO
The B*14:41N allele was identified in a The National Marrow Donor Program (NMDP) Hispanic donor typed by our Mexican Registry-DONORMO.
Assuntos
Antígeno HLA-B14/genética , Hispânico ou Latino/genética , Sistema de Registros , Doadores não Relacionados , Sequência de Bases , Medula Óssea , Éxons/genética , Humanos , México , Dados de Sequência Molecular , Alinhamento de SequênciaRESUMO
BACKGROUND: CD4 T-lymphocyte (CD4) counts and HIV plasma RNA concentration (RNA) are 2 key HIV disease markers. The complex interplay between virus and host genetics may contribute to differences in viral set point and CD4 status. Determining the effects of host genetic variation on HIV disease markers is often complicated by the use of antiretroviral therapy. In this study, the association between genetic variants and baseline HIV RNA and CD4 counts was examined in a large cohort of antiretroviral naïve children. METHODS: Specimens from 1053 HIV-infected children were screened for single nucleotide polymorphisms in 78 regions from 17 genes. Linear regression with a robust variance estimator was used to test the association between genetic markers with HIV RNA and CD4 count, controlling for age, race/ethnicity and study. False discovery rate (FDR) controlling was used to adjust for multiple testing. RESULTS: The study population was 60% black, 26% Hispanic and 13% white; median age 2.35 years; 55% female. Baseline median CD4 count was 780/mm; median log10 HIV RNA was 5.17 copies/mL. For analyses of the associations of genetic makers with baseline CD4 count, 6 HLA and 4 additional markers exhibited P < 0.05, but none met the criteria for statistical significance with FDR controlled at 0.05. For baseline HIV RNA, HLA DRB1*15, DRB1*10, B-27/57, B-14, Cw-8, B-57 were statistically significant with FDR controlled at 0.05. CONCLUSIONS: These results provide strong evidence that HLA DRB1*15, DRB1*10, B-27/57, B-14, Cw-8, B-57 are associated with HIV RNA and play a role in HIV pathogenesis in infected children.