RESUMEN
Routine typing of a potential bone marrow donor by sequence-specific oligonucleotide probes (SSOP) and sequence based typing (SBT) produced inconclusive subtyping results, suggesting a new allele. A magnetic bead-based method, haplotype specific extraction (HSE), was used to separate the diploid sample into its haploid components. The sample was then re-typed using standard SBT, revealing a new human leukocyte antigen (HLA) allele, since named B*1576. HSE used in conjunction with standard SBT is a convenient and simple tool for resolving ambiguous and novel allele combinations without the need for amplification or subcloning.
Asunto(s)
Alelos , Antígenos HLA-B/genética , Haplotipos/genética , Secuencia de Bases , ADN/química , ADN/genética , ADN/aislamiento & purificación , Antígeno HLA-B15 , Prueba de Histocompatibilidad/métodos , Humanos , Datos de Secuencia Molecular , Polimorfismo Genético , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico , Población Blanca/genéticaRESUMEN
BACKGROUND: Severe aplastic anemia (SAA) is defined as pancytopenia caused by bone marrow failure. The pathogenesis of SAA is thought to involve autoimmune processes. Increased susceptibility to autoimmunity has been shown to be associated with several different HLA alleles. In SAA, few large studies based on data mainly from adults describe a positive HLA correlation with HLA-DR2 (DRB1*15) and HLA-B14. PROCEDURE: This study explored the HLA constitution of 181 children with SAA who were enrolled in the prospective multi-center study SAA94 between January 1994 and January 2002. The control group consisted of 303 healthy individuals of comparable demographic background. Allelic frequencies between patients and controls are compared using Fisher's exact test. RESULTS: In our pediatric cohort, we describe a positive association with HLA-B14 (P = 0.0039), but no association of HLA-DR2 with SAA. CONCLUSION: HLA associations appear to be different in children and adults with SAA. This might point towards a difference in pathophysiology between at least part of the children and adults.
Asunto(s)
Anemia Aplásica/genética , Antígenos HLA/genética , Adolescente , Alelos , Niño , Preescolar , Femenino , Antígenos HLA-B/genética , Antígeno HLA-B14 , Antígeno HLA-DR2/genética , Humanos , Lactante , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Mycophenolate mofetil (MMF) is a routinely used immunosuppressive agent that selectively blocks T- and B-lymphocyte proliferation. The present study was designed to investigate the effects of this drug on human leukocyte(HLA) antibody production in general and donor-specific antibody (DSA) formation in particular in 154 recipients of renal allografts. PATIENTS AND METHODS: Renal allograft recipients were subdivided into three groups. Group 1 patients (n = 60) had received MMF since transplantation in combination with either cyclosporin A or tacrolimus and steroids. Group 2 patients (n = 29) had received an MMF-free immunosuppressive regimen initially followed by addition of MMF some time later. Group 3 patients (n = 65) had received no MMF. Cyclosporin A or tacrolimus in combination with azathioprine and/or steroids were used for immunosuppression. DSA were demonstrated by enzyme-linked immunosorbent assay (ELISA) for detection of panel-reactive antibodies of HLA class I and II specificity. RESULTS: The HLA antibodies were found in 16.7%, 27.6% and 30.8% of transplant recipients in groups 1, 2 and 3, respectively. DSA were found in 8.3%, 17.2% and 20.0%, and non-DSA in 10.0%, 20.7% and 24.6%, of patients in groups 1, 2 and 3, respectively. CONCLUSION: The MMF reduces anti-HLA class I and II antibody production and consequently DSA production in renal allograft recipients. Our data indicate this effect to be more pronounced in patients given MMF immediately after transplantation than in those in whom MMF is introduced some time later. The presence of DSA in the serum of renal allograft recipients is associated with poorer graft function (higher serum creatinine and more rejection episodes).
Asunto(s)
Formación de Anticuerpos/efectos de los fármacos , Antígenos HLA/inmunología , IMP Deshidrogenasa/antagonistas & inhibidores , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Azatioprina/uso terapéutico , Transfusión Sanguínea , Ciclosporina/uso terapéutico , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunosupresores/inmunología , Trasplante de Riñón/fisiología , Masculino , Persona de Mediana Edad , Ácido Micofenólico/inmunología , Reoperación , Esteroides/uso terapéutico , Tacrolimus/uso terapéuticoRESUMEN
PURPOSE: In advanced gastric cancer (tumor stages T2-T4), associations with polymorphisms of the interleukin-1 (IL-1) gene cluster have been made. In early-stage gastric cancer, which we defined as adenocarcinoma confined to the mucosa or submucosa (stage T1), the role of host genetic susceptibility remains to be determined. PATIENTS AND METHODS: Eighty-eight patients with early-stage gastric cancer (stage T1, 77 positive for Helicobacter pylori) and 145 controls were genotyped for polymorphisms in the IL-1 gene cluster and the tumor necrosis factor alpha (TNF-A) gene. Statistical analysis was performed using the chi2 test and the Fisher's exact test, respectively. RESULTS: The homozygous genotype IL-1RN*2/2 of the IL-RN gene was strongly associated with early-stage gastric cancer (P < .0001), whereas further associations with the IL-1 gene cluster were not observed. A weak association of the TNF-A-308A allele with the diffuse type of early-stage gastric cancer, and an association with a composite of two or three proinflammatory polymorphisms, which predispose to increased production of the proinflammatory cytokines IL-1beta and TNF-alpha, could also be demonstrated. CONCLUSION: The genotype IL-1RN*2/2 seems to be associated with early-stage gastric cancer. As opposed to advanced-stage gastric cancer, further proinflammatory cytokine polymorphisms were not associated independently, but might act in combination and mirror early steps of gastric carcinogenesis in hosts colonized by Helicobacter pylori. However, these findings await confirmation in future trials and should be underscored by gene expression studies.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Predisposición Genética a la Enfermedad , Receptores de Interleucina-1/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adenocarcinoma/epidemiología , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Probabilidad , Pronóstico , Valores de Referencia , Medición de Riesgo , Distribución por Sexo , Neoplasias Gástricas/epidemiología , Análisis de SupervivenciaRESUMEN
Three different Venezuelan Amerindian tribes were studied for human leukocyte antigen (HLA)-DPA1 and DPB1 allelic variability using polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) and sequence-based typing in a selected group of samples. These tribes are geographically (two from the Perija Mountain range and one from the Orinoco Delta) and linguistically distinct: the Bari (from Campo Rosario and Saymaidoyi villages) and the Warao have been classified within the Chibcha linguistic family, whereas the Yucpa (from the Aroy, Marewa, and Peraya villages) are Carib speaking. Venezuelan Indians, like other Native American tribes, show a markedly reduced number of different HLA-DP alleles (range, 2-7) and haplotypes (range, 4-11) in comparison with neighboring Venezuelan mestizo and other non-Indian populations. Some HLA-DPB1 (*0402 and *1401) alleles characteristic for all Amerindian tribes are present also in these populations. Despite general similarities, each tribe and, in some cases, some subtribes show their own pattern of allele and haplotype distribution apparently more as a result of linguistic than to geographic variation.
Asunto(s)
Antígenos HLA-DP/genética , Alelos , Frecuencia de los Genes , Variación Genética , Cadenas alfa de HLA-DP , Cadenas beta de HLA-DP , Haplotipos , Humanos , Indígenas Sudamericanos/clasificación , Indígenas Sudamericanos/genética , Lingüística , Filogenia , Polimorfismo Genético , VenezuelaRESUMEN
BACKGROUND: There is growing evidence that hypocretin deficiency plays a pivotal role in human narcolepsy. Based on the physiological role of hypocretins in the regulation of food intake, one might suspect that narcoleptic patients should display reduced energy intake and as a consequence a reduced body weight compared to healthy controls. METHODS: The body mass indices (BMIs) of 30 male narcoleptic patients were compared with large community-based reference samples. Because it is unclear whether increased BMI is an acquired consequence of the disease or a genetically determined premorbid feature of narcolepsy, we additionally examined the influence of the HLA-DR2 antigen, strongly associated with narcolepsy, on the BMI in a group of 117 healthy male volunteers. RESULTS: Narcoleptic patients displayed higher age- and gender-specific BMI percentiles compared to a community-based sample from the German (normal) population. Within the patient sample, BMI distribution did not significantly differ between subjects who had previously received pharmacological treatment compared to drug-naive patients, or between the HLA-DR2 positive and negative healthy subjects. CONCLUSIONS: The results of the present study suggest that an increased BMI in narcolepsy is neither associated with the HLA-DR2 antigen per se nor with medication, but is more likely to be a consequence of disease-associated neuroendocrine abnormalities.