RESUMEN
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.
Asunto(s)
Autoanticuerpos/genética , Diabetes Mellitus Tipo 1/genética , Proteínas de Unión al GTP/genética , Antígenos HLA-DQ/genética , Transglutaminasas/genética , Adolescente , Enfermedad Celíaca/genética , Niño , Preescolar , Células Endoteliales/metabolismo , Femenino , Genotipo , Gliadina/genética , Humanos , Inmunoglobulina A/genética , Lactante , Masculino , Proteína Glutamina Gamma Glutamiltransferasa 2 , TaiwánRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Antígenos HLA/genética , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Técnicas de Genotipaje/métodos , Enfermedad de Graves/epidemiología , Enfermedad de Graves/genética , Prueba de Histocompatibilidad/métodos , Humanos , Masculino , Taiwán/epidemiología , Tiroiditis Autoinmune/epidemiología , Tiroiditis Autoinmune/genéticaRESUMEN
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.
Asunto(s)
Autoanticuerpos/inmunología , Cadenas beta de HLA-DQ/inmunología , Cadenas HLA-DRB1/inmunología , Herpes Zóster/inmunología , Interferón gamma/inmunología , Infecciones por Mycobacterium no Tuberculosas/inmunología , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Autoanticuerpos/genética , Coinfección/genética , Coinfección/inmunología , Coinfección/mortalidad , Femenino , Frecuencia de los Genes , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Herpes Zóster/genética , Herpes Zóster/mortalidad , Herpesvirus Humano 3/inmunología , Prueba de Histocompatibilidad , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Interferón gamma/sangre , Subunidad p40 de la Interleucina-12/sangre , Subunidad p40 de la Interleucina-12/inmunología , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/genética , Infecciones por Mycobacterium no Tuberculosas/mortalidad , Estudios Seroepidemiológicos , Latencia del Virus/inmunologíaRESUMEN
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.
Asunto(s)
Estudio de Asociación del Genoma Completo , Cadenas beta de HLA-DP/genética , Vacunas contra Hepatitis B/inmunología , Hepatitis B/inmunología , Hepatitis B/prevención & control , Inmunización Secundaria , Memoria Inmunológica/genética , Polimorfismo de Nucleótido Simple , Adolescente , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Técnicas de Genotipaje , Humanos , Lactante , Masculino , Análisis Multivariante , Riesgo , Factores de TiempoRESUMEN
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.
Asunto(s)
Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Antígenos HLA/genética , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Secuencia de Bases , Femenino , Estudios de Asociación Genética , Marcadores Genéticos/genética , Prueba de Histocompatibilidad/estadística & datos numéricos , Humanos , Masculino , Datos de Secuencia Molecular , Prevalencia , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Sensibilidad y Especificidad , Taiwán/epidemiologíaRESUMEN
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.
Asunto(s)
Pueblo Asiatico/genética , Antígenos HLA/genética , Polimorfismo de Nucleótido Simple , Región de Flanqueo 3' , Región de Flanqueo 5' , Alelos , China , Frecuencia de los Genes , Genotipo , Antígenos HLA-B/genética , Cadenas beta de HLA-DQ/genética , Proyecto Mapa de Haplotipos , Humanos , Desequilibrio de LigamientoRESUMEN
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.
Asunto(s)
Alelos , Galactosiltransferasas/genética , Regulación de la Expresión Génica/genética , Genotipo , Sistema del Grupo Sanguíneo P/genética , Polimorfismo de Nucleótido Simple , Femenino , Galactosiltransferasas/biosíntesis , Humanos , Intrones/genética , Masculino , Sistema del Grupo Sanguíneo P/metabolismo , Proyectos PilotoRESUMEN
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.
Asunto(s)
Genotipo , Cadenas beta de HLA-DP/genética , Vacunas contra Hepatitis B/administración & dosificación , Vacunas contra Hepatitis B/inmunología , Inmunización Secundaria , Adolescente , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Sitios Genéticos , Cadenas beta de HLA-DP/metabolismo , Hepatitis B/prevención & control , Anticuerpos contra la Hepatitis B/inmunología , Humanos , Masculino , Oportunidad Relativa , Factores de Riesgo , VacunaciónAsunto(s)
Alelos , Pueblo Asiatico/genética , Autoanticuerpos/inmunología , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Interferón gamma/antagonistas & inhibidores , Asia Sudoriental , Estudios de Asociación Genética , Cadenas beta de HLA-DQ/genética , Cadenas beta de HLA-DQ/inmunología , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Prueba de Histocompatibilidad , HumanosRESUMEN
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.
Asunto(s)
Infecciones por Citomegalovirus/inmunología , Síndromes de Inmunodeficiencia/inmunología , Memoria Inmunológica , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T/inmunología , Anciano , Antígenos CD28/inmunología , Relación CD4-CD8 , Ensayos Clínicos Fase II como Asunto , Estudios Transversales , Citocinas/inmunología , Femenino , Humanos , Inmunoterapia , Subunidad alfa del Receptor de Interleucina-7/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/patología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
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.
Asunto(s)
Anticuerpos/inmunología , Eritrocitos/inmunología , Antígenos HLA-DR/inmunología , Inmunización , Envejecimiento , Alelos , Secuencia de Aminoácidos , Transfusión Sanguínea , Femenino , Glicoforinas/inmunología , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Cadenas HLA-DRB1 , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Fenotipo , Alineación de Secuencia , Caracteres Sexuales , TaiwánRESUMEN
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.
Asunto(s)
Autoanticuerpos/sangre , Antígenos HLA-DQ/genética , Neutropenia/inmunología , Enfermedades Autoinmunes/epidemiología , Estudios de Casos y Controles , Preescolar , Femenino , Granulocitos/inmunología , Cadenas beta de HLA-DQ , Antígenos HLA-DR/genética , Humanos , Lactante , Isoantígenos/inmunología , Masculino , Neutropenia/diagnóstico , Neutropenia/epidemiología , Taiwán/epidemiologíaRESUMEN
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.
Asunto(s)
Cadenas alfa de HLA-DP/genética , Cadenas alfa de HLA-DP/inmunología , Cadenas beta de HLA-DP/genética , Cadenas beta de HLA-DP/inmunología , Vacunas contra Hepatitis B/inmunología , Adolescente , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Genotipo , Anticuerpos contra la Hepatitis B/sangre , Vacunas contra Hepatitis B/administración & dosificación , Humanos , Inmunización Secundaria , Masculino , Polimorfismo Genético , VacunaciónRESUMEN
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.
Asunto(s)
Interleucina-4/genética , Síndrome Mucocutáneo Linfonodular/genética , Polimorfismo de Nucleótido Simple , Niño , Preescolar , Enfermedad de la Arteria Coronaria/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Lactante , Recién Nacido , Masculino , TaiwánRESUMEN
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.
Asunto(s)
Antígenos CD/genética , Enfermedad de Graves/epidemiología , Enfermedad de Graves/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Edad de Inicio , Alelos , Antígeno CTLA-4 , Niño , Preescolar , ADN/biosíntesis , ADN/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Oportunidad Relativa , Polimorfismo de Longitud del Fragmento de Restricción , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/metabolismo , Taiwán/epidemiología , Pruebas de Función de la Tiroides , Tirotropina/sangre , Tiroxina/sangreRESUMEN
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.
Asunto(s)
Antígeno 12E7/genética , Antígenos de Grupos Sanguíneos/genética , Moléculas de Adhesión Celular/genética , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Genotipo , Polimorfismo de Nucleótido Simple , Femenino , Factor de Transcripción GATA1/genética , Humanos , MasculinoRESUMEN
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 enigmatic pediatric disease are still poorly understood. The purpose of this study was to investigate whether polymorphisms of the human leukocyte antigen DRB1 (HLA-DRB1) gene are associated with KD and the development of coronary artery lesions (CAL) in Taiwanese children. Genomic DNA was extracted from whole blood samples from 145 children with KD and 331 healthy controls. The HLA-DRB1 gene was genotyped by polymerase chain reaction (PCR) and sequence-based typing assays. We found that the distribution of HLA-DRB1 allele families and alleles in children with KD did not differ from that in healthy controls. Stratified analysis did not demonstrate any association between particular HLA-DRB1 allele families or alleles and the development of CAL in children with KD. These findings suggest that susceptibility to KD and CAL is not associated with the HLA-DRB1 gene in a Taiwanese population. If immunogenetic determinants are involved in this disease and its complications in Taiwanese children, they must involve genes other than HLA-DRB1.
Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Antígenos HLA-DR/genética , Síndrome Mucocutáneo Linfonodular/genética , Niño , Preescolar , Enfermedad de la Arteria Coronaria/genética , Cadenas HLA-DRB1 , Humanos , Lactante , TaiwánRESUMEN
Polymorphisms in human leukocyte antigen (HLA) genes have been implicated in the risk for cervical cancer. Association of certain class II HLA alleles with cervical cancer has been documented in various ethnic populations. The implications of such an association, however, are controversial. We analyzed 126 Chinese women with cervical squamous cell carcinoma (CSCC) and 289 healthy controls to test associations of certain HLA-DRB1 alleles. We then performed meta-analyses combining our own experimental data and data from nine other published studies. We found no significant differences in HLA-DRB1 allele frequencies in both CSCC and HPV-16-positive CSCC patients and control subjects. Meta-analysis provided evidence that four allele families (HLA-DRB1*04, *07, *11, and *15) and seven alleles (HLA-DRB1*0403, *0405, *0407, *0701, *1501, *1502, and *1503) were positively associated and two allele families (HLA-DRB1*09 and *13) and four alleles (HLA-DRB1*0901, *1301, *1302, and *1602) were negatively associated with CSCC in all studies or in Caucasian subgroups. In conclusion, our meta-analysis confirms the apparent association between certain HLA-DRB1 allele families and alleles and CSCC, suggesting that oncogenesis in this disease may be related to defects in immunoregulation. Larger studies may be needed, particularly in various ethnic groups, to further substantiate these associations.
Asunto(s)
Carcinoma de Células Escamosas/genética , Antígenos HLA-DR/genética , Polimorfismo Genético , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/inmunología , China/epidemiología , Femenino , Frecuencia de los Genes , Cadenas HLA-DRB1 , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/inmunologíaRESUMEN
The CBLB gene functions as a negative regulator of autoimmunity. Impairment of the Cbl-b signaling pathway may contribute to human autoimmune disease. dbSNP rs2305035 is a C/T polymorphism located in exon 10 of the CBLB gene. We report an association study of this polymorphism in children with Graves' disease. The patients were 158 unrelated children (125 girls) with Graves' disease, aged 9.8 +/- 3.3 years. The controls consisted of 237 adults without a history of autoimmune disease. The C allele and phenotype frequencies of patients and controls were 247 (78.2%) vs 356 (75.1%) (OR = 1.19, p >0.05) and 151 (95.6%) vs 221 (93.2%) (OR = 1.56, p >0.05), respectively. The allelic polymorphism in patients and controls with and without DRB1*09012 were also not significantly different. This study demonstrates that the C/T polymorphism in exon 10 of the CBLB gene is not associated with Graves' disease in children.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Graves/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Adolescente , Secuencia de Bases , Estudios de Casos y Controles , Niño , Preescolar , Cartilla de ADN , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Polimorfismo de Longitud del Fragmento de Restricción , TaiwánRESUMEN
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.