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2.
Gene ; 767: 145179, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33002571

RESUMO

Balkan endemic nephropathy (BEN), a progressive chronic tubulointerstitial disease, occurs in the endemic focus of Croatia in a population of about 10,000 inhabitants. One of its most peculiar characteristics is a strong association with upper tract urothelial carcinoma (UTUC). Despite a high number of studies, currently there are insufficient data about the association of BEN and HLA genes. The aim of this study was to investigate the polymorphism of HLA-A, -B, and -DRB1 alleles and haplotypes among BEN patients and to determine whether an association between HLA and BEN exists. In this study, we investigated HLA-A, -B, and -DRB1 alleles and haplotypes in a population of patients with BEN (N = 111) and matched healthy controls (N = 190). All individuals were tested by PCR-SSO and PCR-SSP methods to assess the possible contribution of HLA alleles and haplotypes to the development of/protection from BEN. Our results showed a positive association between the presence of HLA-B*35:02 and DRB1*04:02 alleles and BEN (P = 0.0179 and P = 0.0151, respectively) in contrast to the protective effect of HLA-A*01:01, B*27:05 and B*57:01 alleles (P = 0.0111, P = 0.0330 and P = 0.0318, respectively). Moreover, when BEN patients' HLA haplotypes were compared to controls, two haplotypes were associated with BEN susceptibility among Croatians (HLA-A*02:01~B*08:01~DRB1*03:01 and HLA-A*02:01~B*27:02~DRB1*16:01, P = 0.0064 and P = 0.0023, respectively), while haplotypes HLA-A*02:01~B*27:05~DRB1*01:01 and HLA-A*02:01~B*38:01~DRB1*13:01 each showed a possible protective effect (P = 0.0495). Our results point toward genetic susceptibility to BEN and observed differences in both susceptible/protective HLA profiles indicate the necessity of further studies in order to elucidate the pathogenesis of this disease.


Assuntos
Nefropatia dos Bálcãs/genética , Nefropatia dos Bálcãs/imunologia , Antígenos HLA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Nefropatia dos Bálcãs/epidemiologia , Estudos de Casos e Controles , Croácia/epidemiologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Antígenos HLA/imunologia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos
3.
Am J Hum Genet ; 107(4): 612-621, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32888428

RESUMO

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.


Assuntos
Artrite Reumatoide/genética , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Psoríase/genética , Adulto , Alelos , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Cromossomos Humanos Par 6/química , Hipersensibilidade a Drogas/complicações , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Registros Eletrônicos de Saúde , Europa (Continente) , Feminino , Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Antígenos HLA-B/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Penicilinas/efeitos adversos , Proteína Tirosina Fosfatase não Receptora Tipo 22/imunologia , Psoríase/complicações , Psoríase/imunologia , Autorrelato , Linfócitos T/imunologia , Linfócitos T/patologia , Estados Unidos
4.
J Transl Med ; 18(1): 352, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933522

RESUMO

BACKGROUND: Understanding how HLA polymorphisms may affect both susceptibility, course and severity of Covid-19 infection could help both at the clinical level to identify individuals at higher risk from the disease and at the epidemiological one to explain the differences in the epidemic trend among countries or even within a specific country. Covid-19 disease in Italy showed a peculiar geographical distribution from the northern most affected regions to the southern ones only slightly touched. METHODS: In this study we analysed the regional frequencies for the most common Italian haplotypes from the Italian Bone Marrow Donor Registry (HLA-A, -B, -C and -DRB1 at four-digit level). Then we performed Pearson correlation analyses among regional haplotypes estimated frequency in the population and Covid-19 incidence and mortality. RESULTS: In this study we found that the two most frequent HLA haplotypes in the Italian population, HLA-A*:01:01g-B*08:01 g-C*07:01g-DRB1*03:01g and HLA-A*02.01g-B*18.01g-C*07.01g-DRB1*11.04g, had a regional distribution overlapping that of Covid-19 and showed respectively a positive (suggestive of susceptibility) and negative (suggestive of protection) significant correlation with both Covid-19 incidence and mortality. CONCLUSIONS: Based on these results, in order to define such HLA haplotypes as a factor effectively associated to the disease susceptibility, the creation of national networks that can collect patients' samples from all regions for HLA typing should be highly encouraged.


Assuntos
Betacoronavirus , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Antígenos HLA/genética , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Infecções por Coronavirus/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Genética Populacional , Geografia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Incidência , Itália/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Pesquisa Médica Translacional
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1397-1405, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798433

RESUMO

OBJECTIVE: To analyze the characteristics of allelic and haplotypic polymorphisms of human leukocyte antigens at HLA-A, -B, -C, DRB1 and DQB1 loci in Guangxi Zhuang population. METHODS: Polymerase chain reaction-sequence based typing (PCR-SBT) was used to detect. The five loci (HLA-A, -B, -C, -DRB1, -DQB1) in 350 unrelated Zhuang ethnic individual from Guangxi region. Allelic and haplotypic frequencies were calculated by using Arlequin software 3.5.2.2. Phylogeny tree were constructed by using MEGA software 6.0, and SPSS software was used for principal component analysis. RESULTS: Among the five loci in the population, only HLA-A and DRB1 loci were observed as departures from Hardy-Weinberg expectations. A total of 19 HLA-A, 42 HLA-B, 22 HLA-C, 25 HLA-DRB1 and 15 HLA-DQB1 alleles were found in 350 samples. The most highest frequent alleles were A*11: 01(28.57%), B*46: 01(14.00%), C*01: 02(18.43%), DRB1*16: 02 (15.71%)and DQB1*05: 02 (35.00%) . The most common five loci haplotype was A*33: 03-C*03: 02-B*58: 01-DRB1*03: 01-DQB1*02: 01(6.86%). The phylogenetic tree analysis showed that Guangxi Zhuang population had a relative close genetic relationship with southern Han Chinese populations. CONCLUSION: This reaserch found that the HLA-A, B, C, DRB1 and DQB1 loci are highly polymorphic in Guangxi Zhuang population.


Assuntos
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Alelos , China , Frequência do Gene , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Filogenia
7.
J Hum Genet ; 65(12): 1075-1082, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32699345

RESUMO

The coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, has rapidly expanded to a global pandemic. However, numbers of infected cases, deaths, and mortality rates related to COVID-19 vary from country to country. Although many studies were conducted, the reasons of these differences have not been clarified. In this study, we comprehensively investigated 12,343 SARS-CoV-2 genome sequences isolated from patients/individuals in six geographic areas and identified a total of 1234 mutations by comparing with the reference SARS-CoV-2 sequence. Through a hierarchical clustering based on the mutant frequencies, we classified the 28 countries into three clusters showing different fatality rates of COVID-19. In correlation analyses, we identified that ORF1ab 4715L and S protein 614G variants, which are in a strong linkage disequilibrium, showed significant positive correlations with fatality rates (r = 0.41, P = 0.029 and r = 0.43, P = 0.022, respectively). We found that BCG-vaccination status significantly associated with the fatality rates as well as number of infected cases. In BCG-vaccinated countries, the frequency of the S 614G variant had a trend of association with the higher fatality rate. We also found that the frequency of several HLA alleles, including HLA-A*11:01, were significantly associated with the fatality rates, although these factors were associated with number of infected cases and not an independent factor to affect fatality rate in each country. Our findings suggest that SARS-CoV-2 mutations as well as BCG-vaccination status and a host genetic factor, HLA genotypes might affect the susceptibility to SARS-CoV-2 infection or severity of COVID-19.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/genética , Infecções por Coronavirus/mortalidade , Pneumonia Viral/genética , Pneumonia Viral/mortalidade , Fatores Etários , Vacina BCG/genética , Vacina BCG/uso terapêutico , Betacoronavirus/classificação , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Epitopos/genética , Genoma Viral , Saúde Global , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Humanos , Mutação , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/genética
8.
Int J Immunogenet ; 47(4): 324-328, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32623831

RESUMO

We analysed data from 80 patients who tested positive for SARS-CoV-2 RNA who had previously been HLA typed to support transplantation. Data were combined from two adjacent centres in Manchester and Leeds to achieve a sufficient number for early analysis. HLA frequencies observed were compared against two control populations: first, against published frequencies in a UK deceased donor population (n = 10,000) representing the target population of the virus, and second, using a cohort of individuals from the combined transplant waiting lists of both centres (n = 308), representing a comparator group of unaffected individuals of the same demographic. We report a significant HLA association with HLA- DQB1*06 (53% vs. 36%; p < .012; OR 1.96; 95% CI 1.94-3.22) and infection. A bias towards an increased representation of HLA-A*26, HLA-DRB1*15, HLA-DRB1*10 and DRB1*11 was also noted but these were either only significant using the UK donor controls, or did not remain significant after correction for multiple tests. Likewise, HLA-A*02, HLA-B*44 and HLA-C*05 may exert a protective effect, but these associations did not remain significant after correction for multiple tests. This is relevant information for the clinical management of patients in the setting of the current SARS-CoV-2 pandemic and potentially in risk-assessing staff interactions with infected patients.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Predisposição Genética para Doença/genética , Teste de Histocompatibilidade , Pneumonia Viral/imunologia , Alelos , Infecções por Coronavirus/patologia , Frequência do Gene , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Transplante de Órgãos , Pandemias , Pneumonia Viral/patologia , Transplantados
9.
Clin Exp Dermatol ; 45(6): 699-704, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32112449

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 DNA
10.
PLoS One ; 15(2): e0220754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027661

RESUMO

INTRODUCTION: Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins play an essential role in the adaptive immune response for the presentation of self and non-self peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug induced agranulocytosis (severe lower white blood cell count) in patients with B*27:05, B*38:02 and DRB1*08:03 alleles in different populations: Taiwanese, Vietnamese, Han Chinese and Caucasian. METHODS: In this study, informatics methods were used to investigate if any sequence or structural similarities exist between the two associated HLA-B alleles, compared with a set of "control" alleles assumed not be associated, which could help explain the molecular basis of the adverse drug reaction. We demonstrated using MHC Motif Viewer and MHCcluster that the two alleles do not have a propensity to bind similar peptides, and thus at a gross level the structure of the antigen presentation region of the two alleles are not similar. We also performed multiple sequence alignment to identify polymorphisms shared by the risk but not by the control alleles and molecular docking to compare the predicted binding poses of the drug-allele combinations. RESULTS: Two residues, Cys67 and Thr80, were identified from the multiple sequence alignments to be unique to these risk alleles alone. The molecular docking showed the poses of the risk alleles to favour the F-pocket of the peptide binding groove, close to the Thr80 residue, with the control alleles generally favouring a different pocket. The data are thus suggestive that Thr80 may be a critical residue in HLA-mediated anti-thyroid drug induced agranulocytosis, and thus can guide future research and risk assessment.


Assuntos
Agranulocitose/induzido quimicamente , Alelos , Antitireóideos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Antígenos HLA-B/genética , Informática Médica/métodos , Imunidade Adaptativa , Agranulocitose/etnologia , Sequência de Aminoácidos , Grupo com Ancestrais do Continente Asiático , Sítios de Ligação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etnologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Humanos , Metimazol/efeitos adversos , Propiltiouracila/efeitos adversos , Ligação Proteica
11.
Occup Environ Med ; 77(3): 201-206, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32024660

RESUMO

OBJECTIVES: Trichloroethylene (TCE) -induced hypersensitivity syndrome (TIHS) is a potentially life-threatening disease. Several genetic susceptibility biomarkers have been found to be associated with TIHS, and this systematic prospective study has been conducted to evaluate the utility of these genetic susceptibility biomarkers in preventing the disease. METHODS: The newly hired TCE-exposed workers were recruited from March 2009 to October 2010. HLA-B*13:01 genotyping and 3-month follow-up procedure were conducted. All workers were monitored for adverse reaction by telephone interview every week. The workers with early symptoms of TIHS were asked to go to the hospital immediately for further examination, diagnosis and treatment. The medical expense record data of patients with TIHS were collected for cost-effectiveness analysis in 2018. RESULTS: Among 1651 workers, 158 (9.57%) were found to carry the HLA-B*13:01 allele and 16 (0.97%) were diagnosed with TIHS. HLA-B*13:01 allele was significantly associated with an increased TIHS risk (relative risk=28.4, 95% CI 9.2 to 86.8). As a risk predictor of TIHS, HLA-B*13:01 testing had a sensitivity of 75%, a specificity of 91.1% and an area under curve of 0.83 (95% CI 0.705 to 0.955), the positive and negative predictive values were 7.6% and 99.7%, respectively. The incidence of TIHS was significantly decreased in HLA-B*13:01 non-carriers (0.27%) compared with all workers (0.97%, p=0.014). Cost-effectiveness analysis showed that HLA-B*13:01 screening could produce an economic saving of $4604 per TIHS avoided. CONCLUSIONS: Prospective HLA-B*13:01 screening may significantly reduce the incidence of TIHS and could be a cost effective option for preventing the disease in TCE-exposed workers.


Assuntos
Dermatite/genética , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Exposição Ocupacional , Tricloroetileno/efeitos adversos , Adulto , Biomarcadores , China , Análise Custo-Benefício , Dermatite/prevenção & controle , Hipersensibilidade a Drogas/prevenção & controle , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Programas de Rastreamento/economia , Polimorfismo Genético , Valor Preditivo dos Testes , Estudos Prospectivos , Adulto Jovem
12.
BMC Infect Dis ; 20(1): 59, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959123

RESUMO

BACKGROUND: Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. METHODS: Patients were divided into four groups: Group 1- TB+/HIV+ (n = 88; 11 of them with IRIS), Group 2- HIV+ (n = 24), Group 3- TB+ (n = 24) and Group 4- healthy volunteers (n = 26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. RESULTS: Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB onset (aOR = 2.39, P = 0.04), whereas HLA-B*08 and female gender were associated with protection against TB onset (aOR = 0.23, P = 0.03, and aOR = 0.33, P = 0.01, respectively). Not carrying KIR2DL3 (aOR = 0.18, P = 0.03) and carrying HLA-C*07 (aOR = 0.32, P = 0.04) were associated with protection against TB onset among HIV-infected patients. An increased risk for IRIS onset was associated with having a CD8 count ≤500 cells/mm3 (aOR = 18.23, P = 0.016); carrying the KIR2DS2 gene (aOR = 27.22, P = 0.032), the HLA-B*41 allele (aOR = 68.84, P = 0.033), the KIR2DS1 + HLA-C2 pair (aOR = 28.58, P = 0.024); and not carrying the KIR2DL3 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), and the KIR2DL1 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), CONCLUSIONS: These results suggest the participation of these genes in the immunopathogenic mechanisms related to the conditions studied. This is the first study demonstrating an association of HLA-B*41, KIR2DS2, and KIR + HLA-C pairs with IRIS onset among TB-HIV co-infected individuals.


Assuntos
Infecções por HIV/complicações , Infecções por HIV/genética , HIV-1 , Síndrome Inflamatória da Reconstituição Imune/etiologia , Síndrome Inflamatória da Reconstituição Imune/genética , Tuberculose/complicações , Tuberculose/genética , Brasil , Coinfecção/tratamento farmacológico , Coinfecção/genética , Coinfecção/patologia , Feminino , Seguimentos , Frequência do Gene/genética , Marcadores Genéticos , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Humanos , Síndrome Inflamatória da Reconstituição Imune/patologia , Masculino , Receptores KIR/genética , Fatores Sexuais , Tuberculose/tratamento farmacológico , Tuberculose/patologia
13.
Basic Clin Pharmacol Toxicol ; 126(2): 133-143, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31483922

RESUMO

Metronidazole, a widely used drug for the treatment of infections with anaerobic and facultative anaerobic bacteria and protozoa, can frequently cause metronidazole-induced cutaneous adverse reactions (McADRs). The aim of the present study was to investigate the association between human leucocyte antigen (HLA) alleles and McADRs in a Chinese Han population. The frequency of HLA-B*24:02 carriers among the McADR patients was 73.3%, which was significantly higher than that of the population controls (32.16%, OR = 5.80, 95% CI = [1.80-18.72], Pc = 0.004) and of the metronidazole-tolerant patients (26.67%, OR = 7.56, 95% CI = [2.02-28.35], Pc = 0.004). Molecular docking showed that metronidazole and one of its major metabolites had the potential to bind in the HLA groove and that there was a relatively stable binding state of the HLA-B*24:02-metronidazole/the metabolite complex. The CDR3 repertoires of both T cell receptor (TCR)Vα and Vß of the patients showed a significantly skewed or an oligoclonal distribution. The TCRVß CDR3 of the patients shared a similar motif, "CASSxxxxxxQxF." The current study demonstrated that both the HLA-A*24:02 allele and TCR are involved in the pathogenesis of McADRs.


Assuntos
Anti-Infecciosos/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Erupção por Droga/etiologia , Antígeno HLA-A24/genética , Metronidazol/efeitos adversos , Adulto , Idoso , Alelos , Anti-Infecciosos/administração & dosagem , Estudos de Casos e Controles , Erupção por Droga/genética , Feminino , Antígenos HLA-B/genética , Humanos , Masculino , Metronidazol/administração & dosagem , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Projetos Piloto , Receptores de Antígenos de Linfócitos T/metabolismo , Adulto Jovem
14.
Pharmacogenet Genomics ; 30(2): 21-25, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31658186

RESUMO

Allopurinol, a common medication to treat gout, is associated with severe cutaneous adverse reactions, and the occurrence is highly predicted by an individual's HLA-B*58:01 carrier status. Guidelines endorse preemptive testing in select Asian populations before initiating allopurinol. The Hmong, an Asian subpopulation originally from China who now live dispersed around the world, have a 2.5-fold higher risk of gout when compared to non-Hmong in Minnesota. Given the concern for severe cutaneous adverse reactions when prescribing allopurinol, we quantified the carrier status of HLA-B*58:01 in Hmong from two independent cohorts in Minnesota. Using a community-based participatory research approach, HLA-B*58:01 carrier status was determined in 49 US-born Hmong without a history of gout or allopurinol use. Further, 47 Hmong patients undergoing clinical evaluation to receive gout pharmacotherapy were also tested. The frequency of HLA-B*58:01 positive carrier status in these two cohorts were compared to published data from a Han Chinese (n = 2910) and a Korean cohort (n = 485) using a Fisher's exact test with a Bonferroni-corrected P-value <0.025 for significance. With one uninterpretable result, we identified two out of 95 people (2.1%) who carried HLA-B*58:01. This 2.1% incidence in these Hmong adults is notably lower than Han Chinese (19.6%, P < 0.0001) and Korean (12.2%, P = 0.0016) populations. Though commonly understood to be of Chinese descent, the lower prevalence within the Hmong underscores the risk of generalizing genotypic findings from Chinese to Asian subpopulations. We suggest no change to the current guidelines recommending which populations should be tested for HLA-B*58:01 before allopurinol use until further validation.


Assuntos
Alopurinol/efeitos adversos , Hipersensibilidade a Drogas/genética , Técnicas de Genotipagem/métodos , Antígenos HLA-B/genética , Adolescente , Adulto , China/etnologia , Hipersensibilidade a Drogas/etnologia , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota , Prevalência , República da Coreia/etnologia , Adulto Jovem
15.
Lancet Haematol ; 7(1): e50-e60, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669248

RESUMO

BACKGROUND: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. METHODS: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. FINDINGS: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype. INTERPRETATION: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. FUNDING: The National Institutes of Health, USA.


Assuntos
Éxons/genética , Doença Enxerto-Hospedeiro/genética , Antígenos HLA-B/genética , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
16.
Mol Biol Evol ; 37(3): 639-650, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31651980

RESUMO

Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individual's HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.


Assuntos
Infecções por HIV/imunologia , HIV-1/fisiologia , Antígenos HLA/genética , Peptídeos/imunologia , Proteínas Virais/química , Apresentação do Antígeno , Variação Genética , Genoma Viral , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/imunologia , Antígenos HLA/imunologia , Antígenos HLA-B/genética , Heterozigoto , Humanos , Carga Viral
17.
Hum Immunol ; 81(1): 8-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31859128

RESUMO

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".


Assuntos
Genótipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Brasil , Feminino , Técnicas de Genotipagem , Humanos , Masculino
18.
Immunology ; 159(2): 178-182, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31613998

RESUMO

Hepatitis B virus (HBV) infection causes a self-limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin-like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA-A-Bw4 and HLA-C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004-0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA-A-Bw4 and HLA-C2 was highly sensitive to predict the outcome of HBV infection.


Assuntos
Antígenos HLA-B/genética , Antígenos HLA-C/genética , Hepatite B Crônica/prevenção & controle , Alótipos Gm de Imunoglobulina/genética , Receptores KIR2DL3/genética , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Antígenos HLA-B/imunologia , Antígenos HLA-C/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Interações Hospedeiro-Patógeno , Humanos , Alótipos Gm de Imunoglobulina/imunologia , Fenótipo , Fatores de Proteção , Receptores KIR2DL3/imunologia , Medição de Risco , Fatores de Risco
19.
Front Immunol ; 11: 565730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33391255

RESUMO

The world is dealing with one of the worst pandemics ever. SARS-CoV-2 is the etiological agent of COVID-19 that has already spread to more than 200 countries. However, infectivity, severity, and mortality rates do not affect all countries equally. Here we consider 140 HLA alleles and extensively investigate the landscape of 3,723 potential HLA-I A and B restricted SARS-CoV-2-derived antigens and how 37 countries in the world are predicted to respond to those peptides considering their HLA-I distribution frequencies. The clustering of HLA-A and HLA-B allele frequencies partially separates most countries with the lowest number of deaths per million inhabitants from the other countries. We further correlated the patterns of in silico predicted population coverage and epidemiological data. The number of deaths per million inhabitants correlates to the predicted antigen coverage of S and N derived peptides and its module is influenced if a given set of frequent or rare HLA alleles are analyzed in a given population. Moreover, we highlighted a potential risk group carrying HLAs associated with an elevated number of deaths per million inhabitants. In addition, we identified three potential antigens bearing at least one amino acid of the four-length insertion that differentiates SARS-CoV-2 from previous coronavirus strains. We believe these data can contribute to the search for peptides with the potential to be used in vaccine strategies considering the role of herd immunity to hamper the spread of the disease. Importantly, to the best of our knowledge, this work is the first to use a populational approach in association with COVID-19 outcome.


Assuntos
Antígenos Virais , Antígenos HLA-A , Antígenos HLA-B , Glicoproteína da Espícula de Coronavírus , Antígenos Virais/genética , Antígenos Virais/imunologia , /imunologia , Simulação por Computador , Feminino , Frequência do Gene , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Humanos , Masculino , Fosfoproteínas/imunologia , /imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1133-1135, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703144

RESUMO

OBJECTIVE: To identify a novel human leukocyte antigen (HLA) B allele in a Chinese Han individual and construct its three-dimensional structure. METHODS: The initial HLA genotyping was performed by PCR-sequence-based typing (PCR-SBT). The ambiguous allele was confirmed with single-strand DNA sequencing. The DNA sequence was analyzed to identify the difference between the novel allele and its closest matching allele. Finally, the three-dimensional molecular structure of the novel allele was constructed using a Swiss-Model. RESULTS: One allele of the subject at the HLA-B locus was B*44:03:01, whilst the other was a novel allele which differed from the closest matching allele B*51:01:01:01 by nucleotide (nt) 329 A to C in exon 2, resulting in an amino acid change at codon 86 (p.Asn86Thr). CONCLUSION: A novel HLA-B allele has been identified and officially named as HLA-B*51:159 by the WHO Nomenclature Committee for Factors of the HLA System. The three-dimensional structure of B*51:159 was simulated.


Assuntos
Grupo com Ancestrais do Continente Asiático , Antígenos HLA-B/química , Antígenos HLA-B/genética , Alelos , Sequência de Bases , Humanos , Conformação Molecular , Análise de Sequência de DNA
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