RESUMO
Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 are genetic risk factors for Type 1 Diabetes Mellitus (T1DM) and Celiac disease (CD) in Caucasians, but their association with Taiwanese Han population is unknown. We screened 532 Taiwanese T1DM patients for CD biomarkers including anti-tissue transglutaminase (TGM2), anti-gliadin and anti-neoepitope antibodies (Abs), sequencing DQB1 genotypes, and characterized the TGM2 Abs. We report that 3.76% of Taiwanese patients had TGM2-Abs and all had no CD's symptoms. In contrast to Caucasian's CD patients, DQ2/DQ8 only constituted ~4/5 of TGM2-Abs positive patients, while the other ~1/5 patients belonged to different HLA genotypes. Either anti-gliadin or anti-neoepitope Abs coexisted with ~3/4 of TGM2-Abs positive patients that were likely due to gluten-ingestion, while the cause of TGM2-Abs production for other ~1/4 of patients was unknown. Purified anti-TGM2 IgA (TGA) and anti-TGM2 IgG (TGG) could bind on endothelial cells surface, recognized native better than denatured forms of TGM2, and TGA inhibited TGM2's transamidation activity by up to 80% but TGG had no effects. Epitope mapping of all TGM2-Abs positive sera demonstrated that TGM2-Abs had heterogeneity in specificities. This is the first study on the differences between Taiwanese Han group and Caucasian in HLA genotypes and properties of TGM2-Abs.
Assuntos
Autoanticorpos/genética , Diabetes Mellitus Tipo 1/genética , Proteínas de Ligação ao GTP/genética , Antígenos HLA-DQ/genética , Transglutaminases/genética , Adolescente , Doença Celíaca/genética , Criança , Pré-Escolar , Células Endoteliais/metabolismo , Feminino , Genótipo , Gliadina/genética , Humanos , Imunoglobulina A/genética , Lactente , Masculino , Proteína 2 Glutamina gama-Glutamiltransferase , TaiwanRESUMO
BACKGROUND AND AIMS: No report explored the combined effects of HLA-DPA1 and -DPB1 with long-term response to hepatitis B (HB) vaccination (HBVac). The specific aims of the study were to assess the combined effects and relative contributions of DPA1 and DPB1 genes. METHODS: The cases were 152 adolescents who had undetectable (<1.0â¯mIU/mL) post-booster anti-HBs titers and the controls were adolescents who had residual anti-HBsâ¯≥â¯10â¯mIU/mL at aged 16â¯years (nâ¯=â¯207) or had detectable (≥1.0â¯mIU/mL) anti-HBs titers after booster HBVac (nâ¯=â¯481). HLA-DPA1 and -DPB1 genotypes were determined by sequence-based typing. RESULTS: HLA-DPA1*01:03:01 was correlated with lower ORs of undetectable anti-HBs titers, while -DPA1*02:02:02 and -DPB1*05:01:01 were correlated with higher ORs. The ORs for HLA-DPA1*01:03:01-DPB1*05:01:01 and DPA1*02:02:02-DPB1*protective combinatory types were significantly less than 1.0. As compared with subjects who had no protective allele, the adjusted ORs (95% CI) were 0.545 (0.328-0.906), 0.350 (0.174-0.702), and 0.122 (0.058-0.257), for subjects who had protective alleles on DPA1only, DPB1 only, and both genes, respectively. Analyses of amino acid polymorphisms showed that subjects who carried Arg81-Pro158-Val191-Pro259αâ¯+â¯Met234ß and Gln62-Arg82αâ¯+â¯Met234ß combinations had 4.3-to-4.6 folds of risks. CONCLUSION: Both DPA1 and DPB1 genes contribute to the persistence of immunological response to primary infantile HBVac. The effects of HLA-DP risk alleles were dominated by the protective alleles and there were significant gene-gene interactions. Our findings provide evidences for the design of more potent HB vaccine.
Assuntos
Cadeias alfa de HLA-DP/genética , Cadeias alfa de HLA-DP/imunologia , Cadeias beta de HLA-DP/genética , Cadeias beta de HLA-DP/imunologia , Vacinas contra Hepatite B/imunologia , Adolescente , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Estudos de Associação Genética , Genótipo , Anticorpos Anti-Hepatite B/sangue , Vacinas contra Hepatite B/administração & dosagem , Humanos , Imunização Secundária , Masculino , Polimorfismo Genético , VacinaçãoRESUMO
The Xga and CD99 antigens of the human Xg blood group system show a unique and sex-specific phenotypic relationship. The phenotypic relationship is believed to result from transcriptional coregulation of the XG and CD99 genes, which span the pseudoautosomal boundary of the X and Y chromosomes. However, the molecular genetic background responsible for these blood groups has remained undetermined. During the present investigation, we initially conducted a pilot study aimed at individuals with different Xga/CD99 phenotypes; this used targeted next-generation sequencing of the genomic areas relevant to XG and CD99 This was followed by a large-scale association study that demonstrated a definite association between a single nucleotide polymorphism (SNP) rs311103 and the Xga/CD99 blood groups. The G and C genotypes of SNP rs311103 were associated with the Xg(a+)/CD99H and Xg(a-)/CD99L phenotypes, respectively. The rs311103 genomic region with the G genotype was found to have stronger transcription-enhancing activity by reporter assay, and this occurred specifically with erythroid-lineage cells. Such activity was absent when the same region with the C genotype was investigated. In silico analysis of the polymorphic rs311103 genomic regions revealed that a binding motif for members of the GATA transcription factor family was present in the rs311103[G] region. Follow-up investigations showed that the erythroid GATA1 factor is able to bind specifically to the rs311103[G] region and markedly stimulates the transcriptional activity of the rs311103[G] segment. The present findings identify the genetic basis of the erythroid-specific Xga/CD99 blood group phenotypes and reveal the molecular background of their formation.
Assuntos
Antígeno 12E7/genética , Antígenos de Grupos Sanguíneos/genética , Moléculas de Adesão Celular/genética , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Genótipo , Polimorfismo de Nucleotídeo Único , Feminino , Fator de Transcrição GATA1/genética , Humanos , MasculinoRESUMO
BACKGROUND: Type 1 diabetes (T1D) mellitus is an autoimmune disorder involving both complex genetic and environmental factors. The incidence rates are low in Asian countries, and the specific, explanatory genetic factors underlying this have been investigated. The aim of this study was to elucidate the association of human leukocyte antigen (HLA) alleles/haplotypes with T1D in Taiwan. METHODS: We performed direct comprehensive genotyping of 6 classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1) to 4-digit resolution in 104 unrelated T1D patients and 504 controls. Twenty-four of the 104 patients also exhibited thyroid autoimmunity. RESULTS: Three major susceptibility haplotypes were identified: DRB1*03:01-DQB1*02:01 (odds ratio [OR] = 5.39 under the dominant model, P = 2.3 × 10-13 ), DRB1*04:05-DQB1*04:01 (OR = 2.44, P = 5.0 × 10-4 ), and DRB1*09:01-DQB1*03:03 (OR = 2.02, P = 1.4 × 10-3 ); one protective haplotype was identified: DRB1*08:03-DQB1*06:01 (OR = 0.10, P = 1.6 × 10-3 ). DRB1*03:01-DQB1*02:01, the major T1D susceptibility haplotype, was found at a lower frequency in T1D patients with thyroid autoimmunity. The T1D protective allele DRB1*12:02 was shown to be protective against Graves' disease in our previous report. CONCLUSION: In addition to clarifying the roles of several known T1D HLA alleles and haplotypes, we discovered that the DRB1*08:03-DQB1*06:01 haplotype is protective against T1D. The DRB1*12:02 allele protected against both T1D and Graves' disease.
Assuntos
Diabetes Mellitus Tipo 1/genética , Antígenos HLA/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Técnicas de Genotipagem/métodos , Doença de Graves/epidemiologia , Doença de Graves/genética , Teste de Histocompatibilidade/métodos , Humanos , Masculino , Taiwan/epidemiologia , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/genéticaAssuntos
Alelos , Povo Asiático/genética , Autoanticorpos/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Interferon gama/antagonistas & inibidores , Sudeste Asiático , Estudos de Associação Genética , Cadeias beta de HLA-DQ/genética , Cadeias beta de HLA-DQ/imunologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Teste de Histocompatibilidade , HumanosRESUMO
BACKGROUND: End stage renal disease (ESRD) is prevalent in Taiwan. Human leukocyte antigens (HLA) have been found to be associated with the pathogenesis of autoimmune diseases, allergies and inflammatory bowel diseases, and there are emerging evidences of correlations between HLA genotypes and renal diseases such as diabetic nephropathy, IgA nephropathy, and glomerulonephritis. The aim of this study is to investigate detailed HLA subtypes in a case-control study of Taiwanese individuals. METHODS: The polymorphisms of HLA class I and II antigens in ESRD patients and a healthy control group were retrospectively analyzed. The information of 141 ESRD patients was obtained from the medical record of the Keelung branch of Chang Gung Memorial Hospital and was compared to the HLA type of a control group comprized of 190 healthy unrelated Taiwanese from one of our previous studies. In order to standardize the HLA designation of prior low-resolution typings with the more advanced DNA based typings, all HLA-A, -B and -DR were analyzed using a low resolution serologic equivalent. RESULTS: The current work suggests that HLA-DR3 (odds ratio = 1.91, 95 % CI = 1.098-3.324, P = 0.024, Pc = 0.312) and HLA-DR11 (odds ratio = 2.06, 95 % CI = 1.133-3.761, P = 0.021, Pc = 0.273) may represent susceptibility risk factors for the development of ESRD in Taiwanese individuals. On the other hand, HLA-DR8 (odds ratio = 0.47, 95 % CI = 0.236-0.920, p = 0.027. Pc = 0.351) may be a protective factor. HLA-A and -B antigens did not show any contribution of progression to ESRD. However, we note that the significance of all these findings is lost when the results are corrected for multiple comparisons according to Bonferroni. Further investigation with a larger group of patients and control is needed to resolve this issue. CONCLUSIONS: HLA typing might be a useful clinical method for screening patients with high risk of progression to ESRD.
Assuntos
Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Sequência de Bases , Feminino , Estudos de Associação Genética , Marcadores Genéticos/genética , Teste de Histocompatibilidade/estatística & dados numéricos , Humanos , Masculino , Dados de Sequência Molecular , Prevalência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Taiwan/epidemiologiaRESUMO
Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10(-32)) and HLA-DRB1*08:03 (Pcombined=1.83 × 10(-9)) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10(-21), 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.
Assuntos
Agranulocitose/induzido quimicamente , Antitireóideos/efeitos adversos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA , Agranulocitose/genética , Antígenos HLA-B , Cadeias HLA-DRB1 , Humanos , Razão de ChancesRESUMO
BACKGROUND AND AIM: Hepatitis B (HB) vaccination is highly effective in reducing the risk of hepatitis B virus infection. However, breakthrough and chronic hepatitis B virus infections in vaccinated subjects raised concern about its long-term efficacy. The specific aim of the study was to explore the host genetic determinants of long-term immunological memory against HB vaccination. METHODS: We conducted a case-control study nested in a cohort of HB booster recipients who had received primary HB vaccination during infancy but failed to reside an anti-HBs titers ≥ 10 mIU/mL at the age of 15-18 years. We used a genome-wide single nucleotide polymorphism (SNP) array plate to scan autosomal chromosomes and assayed the human leukocyte antigen (HLA)-DPB1 genotype by sequence-based techniques. RESULTS: We found that 10 of the 112 candidate SNPs (P-value < 5.0 × 10(-5) ) clustered within a 47-Kb region of the HLA-DP loci. All the minor alleles of these HLA-DP candidate SNPs were correlated with lower likelihoods of nonresponse to HB vaccine. There was a significant linkage disequilibrium between these HLA-DP candidate SNPs and HLA-DPB1 protective alleles. Multivariate analyses showed that rs7770370 was the most significant genetic factor. As compared with rs7770370 GG homozygotes, adjusted odds ratios were 0.524 (95% confidence interval, 0.276-0.993) and 0.095 (95% confidence interval, 0.030-0.307) for AG heterozygotes and AA homozygotes, respectively. CONCLUSION: Our results showed that rs7770370 was the most significant genetic factor of response to HB booster. The rs7770370 and nearby SNPs may also contribute to the long-term immunological memory against HB vaccination.
Assuntos
Estudo de Associação Genômica Ampla , Cadeias beta de HLA-DP/genética , Vacinas contra Hepatite B/imunologia , Hepatite B/imunologia , Hepatite B/prevenção & controle , Imunização Secundária , Memória Imunológica/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Técnicas de Genotipagem , Humanos , Lactente , Masculino , Análise Multivariada , Risco , Fatores de TempoRESUMO
BACKGROUND: The molecular mechanism for the formation of the P1/P2 blood groups remains unsolved. It has been shown that the P1/P2 polymorphism is connected to the different A4GALT gene expression levels in P1 and P2 red blood cells. STUDY DESIGN AND METHODS: The present investigation conducted a pilot investigation that involved the detailed and stepwise screening of single-nucleotide polymorphisms (SNPs) in the A4GALT gene, followed by a larger-scale association study. The transcription-inducing activity by the different genotypes of SNPs was analyzed using reporter assays. RESULTS: A total of 416 different SNP sites in the A4GALT genes from four P1 and four P2 individuals were analyzed in the pilot investigation, and 11 SNP sites, distributed in the A4GALTâ Intron 1 region, exhibited an association with the P1/P2 phenotypes. In the follow-up association study, the genotypes at the 11 SNPs of a total of 338 individuals across four different ethnic populations were determined, and the results show that two SNPs, rs2143918 and rs5751348, are consistently associated with the P1/P2 phenotypes. Reporter assays demonstrated significantly higher transcription-inducing activity by the SNPs bearing the P(1)-allele genotype than by the SNPs bearing the P(2)-allele genotype and that the difference in transcriptional activity was determined by the different genotypes at SNP rs5751348. CONCLUSION: The results of this investigation demonstrate a consistent association of A4GALTâ SNPs rs2143918 and rs5751348 with the P1/P2 phenotypes and suggest that SNP rs5751348 may lead to allelic variations in A4GALT gene expression and consequently leads to the formation of the P1/P2 phenotypes.
Assuntos
Alelos , Galactosiltransferases/genética , Regulação da Expressão Gênica/genética , Genótipo , Sistema do Grupo Sanguíneo P/genética , Polimorfismo de Nucleotídeo Único , Feminino , Galactosiltransferases/biossíntese , Humanos , Íntrons/genética , Masculino , Sistema do Grupo Sanguíneo P/metabolismo , Projetos PilotoRESUMO
BACKGROUND: Genetic variation associated with human leukocyte antigen (HLA) genes has immunological functions and is associated with autoimmune diseases. To date, large-scale studies involving classical HLA genes have been limited by time-consuming and expensive HLA-typing technologies. To reduce these costs, single-nucleotide polymorphisms (SNPs) have been used to predict HLA-allele types. Although HLA allelic distributions differ among populations, most prediction model of HLA genes are based on Caucasian samples, with few reported studies involving non-Caucasians. RESULTS: Our sample consisted of 437 Han Chinese with Affymetrix 5.0 and Illumina 550 K SNPs, of whom 214 also had data on Affymetrix 6.0 SNPs. All individuals had HLA typings at a 4-digit resolution. Using these data, we have built prediction model of HLA genes that are specific for a Han Chinese population. To optimize our prediction model of HLA genes, we analyzed a number of critical parameters, including flanking-region size, genotyping platform, and imputation. Predictive accuracies generally increased both with sample size and SNP density. CONCLUSIONS: SNP data from the HapMap Project are about five times more dense than commercially available genotype chip data. Using chips to genotype our samples, however, only reduced the accuracy of our HLA predictions by only ~3%, while saving a great deal of time and expense. We demonstrated that classical HLA alleles can be predicted from SNP genotype data with a high level of accuracy (80.37% (HLA-B) ~95.79% (HLA-DQB1)) in a Han Chinese population. This finding offers new opportunities for researchers in obtaining HLA genotypes via prediction using their already existing chip datasets. Since the genetic variation structure (e.g. SNP, HLA, Linkage disequilibrium) is different between Han Chinese and Caucasians, and has strong impact in building prediction models for HLA genes, our findings emphasize the importance of building ethnic-specific models when analyzing human populations.
Assuntos
Povo Asiático/genética , Antígenos HLA/genética , Polimorfismo de Nucleotídeo Único , Região 3'-Flanqueadora , Região 5'-Flanqueadora , Alelos , China , Frequência do Gene , Genótipo , Antígenos HLA-B/genética , Cadeias beta de HLA-DQ/genética , Projeto HapMap , Humanos , Desequilíbrio de LigaçãoRESUMO
Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the human leukocyte antigen (HLA)-DP loci that were significantly correlated with outcomes of hepatitis B virus (HBV) infection. We performed a case-control study nested in a well-characterized cohort of booster recipients to assess whether genetic variants of HLA-DPB1 are also associated with response to hepatitis B (HB) vaccination. The cases and controls were 171 and 510 booster recipients whose post-booster titers of antibodies against HBV surface antigen (anti-HBs) were undetectable and detectable, respectively. The HLA-DPB1 genotype was determined using sequence-based techniques. The frequencies of HLA-DPB1 alleles were significantly different between cases and controls (p = 1.7 × 10(-8)). The HLA-DPB1 05:01 and 09:01 alleles were significantly more frequent in the cases, and 02:01:02, 02:02, 03:01:01, 04:01:01, and 14:01, were significantly more frequent in the controls. The adjusted odds ratio (OR) of undetectable post-booster anti-HBs titers was significantly correlated with the number of risk alleles (p for trend = 3.8 × 10(-5)). For the number of protective alleles, the trend was significantly inversed (p for trend = 1.3 × 10(-5)). As compared with subjects with two risk alleles, adjusted OR were 0.34 (95 % confidence interval [CI] 0.21-0.55) and 0.20 (95 % CI 0.08-0.48) for subjects with 1 and 2 protective alleles, respectively. The HLA-DPB1 02:02, 04:01:01, 05:01 and 09:01 alleles were also significantly correlated with the likelihoods of undetectable pre-booster anti-HBs titers. Our results indicated that HLA-DPB1 is significantly correlated with response to booster HB vaccination in adolescent who had received postnatal active HB vaccination. HLA-DBP1 may also determine the long-term persistence of response to HB vaccination.
Assuntos
Genótipo , Cadeias beta de HLA-DP/genética , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/imunologia , Imunização Secundária , Adolescente , Estudos de Casos e Controles , Feminino , Frequência do Gene , Loci Gênicos , Cadeias beta de HLA-DP/metabolismo , Hepatite B/prevenção & controle , Anticorpos Anti-Hepatite B/imunologia , Humanos , Masculino , Razão de Chances , Fatores de Risco , VacinaçãoRESUMO
Adult patients with disseminated nontuberculous mycobacterial (dNTM) infections usually have severe immune system defects. Recently, several studies have shown that anti-IFN-γ autoantibodies may play an important role in the pathogenicity of dNTM infections. A considerable proportion of reported cases of anti-IFN-γ autoantibodies show either clinical or laboratory evidence of autoimmune disease. In the present study, we identified 19 formerly healthy adults who later developed dNTM infections, of whom 17 were further investigated immunologically. High-titer anti-IFN-γ autoantibodies capable of inhibiting IL-12 production in vitro were found in the plasma of all of these patients. In addition to dNTM infection, 35% and 71% of our patients also suffered from salmonellosis and herpes zoster, respectively. This observation suggests that IFN-γ may be crucial in controlling salmonella infection and reactivating latent varicella-zoster virus infection in humans. 2 HLA alleles, DRB1*16:02 DQB1*05:02 (odds ratio 8.68; 95% confidence interval, 3.47-21.90; P = 1.1 × 10(-6); Pc = 3.08 × 10(-5) and odds ratio 7.16; 95% confidence interval, 3.02-17.05; P = 1 × 10(-7); Pc = 1.4 × 10(-6), respectively), were found in 82% (14 of 17) of our patients. In conclusion, our data suggest that anti-IFN-γ autoantibodies may play a critical role in the pathogenesis of dNTM infections and reactivation of latent varicella-zoster virus infection and are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02.
Assuntos
Autoanticorpos/imunologia , Cadeias beta de HLA-DQ/imunologia , Cadeias HLA-DRB1/imunologia , Herpes Zoster/imunologia , Interferon gama/imunologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoanticorpos/genética , Coinfecção/genética , Coinfecção/imunologia , Coinfecção/mortalidade , Feminino , Frequência do Gene , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Herpes Zoster/genética , Herpes Zoster/mortalidade , Herpesvirus Humano 3/imunologia , Teste de Histocompatibilidade , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Interferon gama/sangue , Subunidade p40 da Interleucina-12/sangue , Subunidade p40 da Interleucina-12/imunologia , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/mortalidade , Estudos Soroepidemiológicos , Latência Viral/imunologiaRESUMO
BACKGROUND: Graves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR] â=â1.33, Bonferroni corrected combined P [P(Bc)] â=â1.17 x 10⻲), DPB1*05:01 (OR â=â2.34, P(Bc)â=â2.58 x 10⻹°), DQB1*03:02 (OR â=â0.62, P(Bc) â=â1.97 x 10⻲), DRB1*15:01 (OR â=â1.68, P(Bc)â=â1.22 x 10⻲) and DRB1*16:02 (OR â=â2.63, P(Bc) â=â1.46 x 10â»5) were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk. CONCLUSIONS/SIGNIFICANCE: These GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation.
Assuntos
Doença de Graves/etnologia , Doença de Graves/genética , Antígenos HLA/genética , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , Família , Predisposição Genética para Doença , Genótipo , Antígenos HLA-DP , Antígenos HLA-DR , Humanos , TaiwanRESUMO
Host factors play an important role in determining the immune response and development of leprosy. The human leukocyte antigen system (HLA) has repeatedly been found to be associated with the pathogenesis of leprosy. This study analyzes the polymorphism of the HLA class I and II antigens in multibacillary leprosy patients and a healthy control group to provide predictable prognostic indicators and/or a differential diagnostic for the disease. Sixty-5 multibacillary leprosy patients from Lo-Sheng Leprosarium and 190 healthy Taiwanese were used as cases and controls, respectively. A serologic method was initially used for HLA-A and HLA-B antigen determination, and sequence-based typing was later applied for HLA-DRB1 allele typing. Although no significant associations were found with HLA-A or HLA-B antigens, this study shows a strong HLA-DRB1*0405 association with resistance to multibacillary leprosy, supporting results previously reported in the literatures.
Assuntos
Antígenos HLA-DR/genética , Imunidade Inata/genética , Hanseníase Multibacilar/genética , Povo Asiático/genética , Frequência do Gene/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadeias HLA-DRB1 , Humanos , TaiwanRESUMO
Although immunodeficiency is usually considered a prerequisite of oncogenesis, a detailed immune pro- file in cancer has not yet been described. Without such profiling, it is not surprising that there is a vast discrepancy in the responses of cancer patients to immunotherapy. Our results show that the integrity of the immune system deteriorates with cancer progression by displaying a trend toward decreasing levels of functional T cells, including CD4, naïve, and central memory T cells, and an expansion of hyporesponsive populations such as CD28â» and CMV-specific T cells. One hundred and one patients constitute the study group for the observational study reported in this paper. Forty-eight patients with newly diagnosed stages III and IV and 53 patients with extensively treated stage IV disease. The costimulatory molecules CD27 and CD28 were downregulated in all patients. Among the proinflammatory cytokines (IL-6, TNF-α, IFN-γ), only IL-6 differed significantly among the groups, increasing as the cancer stage progressed. Plasma IL-7 did not diVer among the participants. The relative deficits of naïve T cells in cancer patients may be associated with the downregulation of IL-7Rα expression rather than changes in the circulating levels of IL-7. The downregulation of IL-7Rα expression was shown to be associated with increased levels of intracellular CMV. The present study suggests that the immune impairment in patients with cancer is associated with multiple factors, such as the stage of cancer, consequence of CMV infection and impact of treatment.
Assuntos
Infecções por Citomegalovirus/imunologia , Síndromes de Imunodeficiência/imunologia , Memória Imunológica , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Idoso , Antígenos CD28/imunologia , Relação CD4-CD8 , Ensaios Clínicos Fase II como Assunto , Estudos Transversais , Citocinas/imunologia , Feminino , Humanos , Imunoterapia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologiaRESUMO
BACKGROUND: Autoimmune neutropenia in children is caused by granulocyte-specific autoantibodies. These antibodies react to the patient's own neutrophils but disappear when the neutropenia spontaneously remits. This study reviewed our experience with autoimmune neutropenia in children and investigated possible associations with HLA-DR and HLA-DQ alleles. STUDY DESIGN AND METHODS: From 1993 to 2006, our laboratory received 155 blood samples from children with neutropenia. Of these samples, 55 had granulocyte-specific autoantibodies on the indirect granulocyte immunofluorescence test. As the children had no other disorders associated with neutropenia, they were diagnosed with primary autoimmune neutropenia. HLA-DRB1 and -DQB1 allele typing was performed in 31 cases, and the results were compared with those of 190 normal healthy unrelated Taiwanese controls. RESULTS: The mean ages of onset and resolution of neutropenia were 9.8 months (median, 9.0 months; range, 4-28 months) and 22.5 months (median, 20.0 months; range, 13-44 months), respectively. The male-to-female ratio was 1.2:1. The mean absolute neutrophil count was 190 per microL (standard deviation, 213/microL). Most patients (74%) had antibodies against HNA-1a. Autoimmune neutropenia in children in Taiwan was significantly associated with HLA-DQB1*0503 (odds ratio, 6.48; p = 0.0002; p(c) = 0.003) allele. CONCLUSION: In Taiwan, autoimmune neutropenia in children is associated with HLA-DQB1*0503. The autoantibody in autoimmune neutropenia is most commonly anti-HNA-1a.
Assuntos
Autoanticorpos/sangue , Antígenos HLA-DQ/genética , Neutropenia/imunologia , Doenças Autoimunes/epidemiologia , Estudos de Casos e Controles , Pré-Escolar , Feminino , Granulócitos/imunologia , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Humanos , Lactente , Isoantígenos/imunologia , Masculino , Neutropenia/diagnóstico , Neutropenia/epidemiologia , Taiwan/epidemiologiaRESUMO
BACKGROUND: Anti-"Mi(a)" is one of the most important irregular red blood cell antibodies found in Taiwan. The aim of this study was to investigate whether specific HLA-DRB1 alleles are associated with anti-"Mi(a)" production. STUDY DESIGN AND METHODS: A case-control retrospective study was performed on 68 patients showing presence of anti-"Mi(a)" and 219 unrelated control subjects from the Mackay Memorial Hospital. HLA-DRB1 genotyping was carried out using sequence-based typing method. Fisher's exact test using 2 x 2 contingency tables was used to analyze significance of the association between DRB1 polymorphisms and presence of anti-"Mi(a)" in patients. RESULTS: HLA-DRB1*0901 allele frequency in the anti-"Mi(a)" group (30%) was significantly higher than in the control group (16%) with an odds ratio of 2.27 (95% confidence interval, 1.44-3.55; p = 0.0005; p(c) = 0.016). CONCLUSION: HLA-DRB1*0901 is significantly more prevalent in the anti-"Mi(a)" patients group than in the control group. It is suggested that cells from DR9 individuals might present processed "Mi(a)" antigen-allospecific peptides more effectively than cells from individuals carrying other DR phenotypes. Finally, it was predicted that two epitopes, derived from the MiIII glycophorin amino acid sequence, were likely to bind preferentially with the DR9 molecule. Further work will be necessary to determine if these epitopes are responsible for anti-"Mi(a)" alloimmunization.
Assuntos
Anticorpos/imunologia , Eritrócitos/imunologia , Antígenos HLA-DR/imunologia , Imunização , Envelhecimento , Alelos , Sequência de Aminoácidos , Transfusão de Sangue , Feminino , Glicoforinas/imunologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Cadeias HLA-DRB1 , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , Alinhamento de Sequência , Caracteres Sexuais , TaiwanRESUMO
BACKGROUND: The CTLA4 gene is involved in the activity of T cells. AIM: To determine the association between Graves' disease (GD) susceptibility and CT60 polymorphism of the CTLA4 gene. PATIENTS: 189 children with GD and 620 healthy controls. METHODS: We determined the genotype with restriction fragment length polymorphism and compared results. RESULTS: Genotype G/G was significantly associated with GD (odds ratio [OR] = 1.71, 95% confidence interval [CI] 1.20-2.44, Pc = 0.006); however, allele A could reverse its effect. Allele G was significantly more frequent (OR = 1.61, 95% CI 1.18-2.19, Pc = 0.0049) but allele A (OR = 0.62, 95% CI 0.46-0.85, Pc = 0.0049) and phenotype A (OR = 0.58, 95% CI 0.41-0.83, Pc = 0.006) were less frequent in patients with GD than in controls. CONCLUSION: The CT60 SNP was associated with susceptibility to GD. The G allele increased the risk of GD.
Assuntos
Antígenos CD/genética , Doença de Graves/epidemiologia , Doença de Graves/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Idade de Início , Alelos , Antígeno CTLA-4 , Criança , Pré-Escolar , DNA/biossíntese , DNA/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Razão de Chances , Polimorfismo de Fragmento de Restrição , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/metabolismo , Taiwan/epidemiologia , Testes de Função Tireóidea , Tireotropina/sangue , Tiroxina/sangueRESUMO
BACKGROUND: Although some previous studies have reported that genetic and immunological factors play important roles in the pathogenesis of Kawasaki disease (KD), the etiological factors of this enigmatical pediatric disease are still poorly understood. PURPOSE: This study aims to investigate whether polymorphisms of the CD40 ligand (CD40L) gene are associated with KD and the development of coronary artery lesions (CAL) in the Taiwanese children. MATERIALS AND METHODS: The CD40L -3459 A/G and IVS4+121 A/G single nucleotide polymorphisms (SNPs) were genotyped in 167 children with KD and 1,010 ethnically matched healthy controls by TaqMan assay. RESULTS: None of the CD40L polymorphisms was associated with susceptibility or CAL development of KD, and this finding was supported by the haplotype analysis. CONCLUSION: In summary, these results provide little support for specific CD40L SNPs in the susceptibility or CAL development of KD in Taiwanese children. However, it will be necessary to validate or replicate this association in other independent large-size ethnic groups.
Assuntos
Ligante de CD40/genética , Estenose Coronária/genética , Síndrome de Linfonodos Mucocutâneos/genética , Adulto , Povo Asiático , Ligante de CD40/imunologia , Criança , Pré-Escolar , Estenose Coronária/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Polimorfismo de Nucleotídeo Único , TaiwanRESUMO
Although some previous studies have reported that genetic and immunologic factors play important roles in the pathogenesis of Kawasaki disease (KD), the etiologic factors of this enigmatical pediatric disease are still poorly understood. This study aims to investigate whether polymorphisms of the interleukin-4 gene (IL-4; -590 C/T in the promoter region and 8375 A/G in intron 3) are associated with KD and the development of coronary artery lesions (CALs) in Taiwanese children. Genomic DNA was extracted from whole-blood samples from 150 children with KD and 472 ethnically matched healthy control subjects. The IL-4 -590 C/T and 8375 A/G single nucleotide polymorphisms (SNPs) were genotyped by a real-time polymerase chain reaction system with the Pre-Developed TaqMan Allelic Discrimination Assay. No significant associations between IL-4 SNPs and susceptibility of KD with CALs were found. In addition, no evidence for associations between IL-4 SNPs and CAL development was found. These results suggest that IL-4 -590 C/T and 8375 A/G SNPs do not confer a relevant role in the susceptibility or CAL development of KD in Taiwanese children.