RESUMEN
The objective of the study is to find predictors of remission, radiographic progression (RP), and erosive disease in a cohort of patients with early onset rheumatoid arthritis (EORA) that followed a therapeutic protocol aiming at remission, in a real world tight-control setting. EORA patients were enrolled in a 3-year follow-up study. Clinical, biological, immunogenetic, and radiographical data were analyzed. Radiographs were scored according to Sharp-van der Heijde (SvdH) method. RP was defined by an increase of 3 units in 36 months. Remission was defined as DAS28 <2.6. A stepwise multiple logistic regression model was used to identify independent predictors of the three target outcomes. One hundred twenty-nine patients were included. Baseline disease activity was high. Significant overall improvement was observed, but only 33.3 % achieved remission. At 36 month, 50.4 % (65) of patients showed erosions. RP was observed in 62.7 % (81) of cases. Statistical analysis showed that baseline SvdH score was the only predictive factor associated with the three outcomes evaluated. Lower HAQ-DI and absence of autoantibodies were predictive of remission. Higher levels of ESR and presence of erosions at entry were predictive of RP. Independent baseline predictors of incident erosive disease were anti-CCP and RF positivity, symptom duration at baseline >3 months, and presence of HLA-DRB1 shared epitope. Radiographic damage at baseline was the main predictor of outcomes. Autoantibodies, HAQ and ESR at baseline, symptom duration before diagnosis, and HLA-DRB1 status had influence on clinical course and development of structural joint damage in Colombian RA patients.
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Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/patología , Adulto , Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Autoanticuerpos/sangre , Colombia , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Cadenas HLA-DRB1/genética , Humanos , Modelos Logísticos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Péptidos Cíclicos/inmunología , Estudios Prospectivos , Radiografía , Inducción de Remisión , Factor Reumatoide/inmunología , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Late-onset systemic lupus erythematosus (SLE) represents a specific subgroup that is defined as onset after 50 years of age. Late-onset lupus may have a different clinical course and serological findings, which may delay diagnosis and timely treatment. OBJECTIVES: The objective of this paper is to determine the clinical, serologic, and immunogenetic differences among Colombian patients with late-onset SLE versus conventional SLE patients. METHODOLOGY: This was a cross-sectional study in a Colombian population. Patients and their medical records were analyzed from the services of Rheumatology in Bogotá and met the criteria for SLE, according to the American College of Rheumatology (ACR) revised criteria for the classification of SLE.In a reference group of late-onset SLE patients (98 participants, with an onset after 50 years of age) and a group of conventional SLE patients (72 participants, with an onset of age of 49 years or less), multiple clinical variables (age, clinical criteria for lupus, alopecia, weight loss, fever, Raynaud's phenomenon) and multiple serological variables (blood count, blood chemistry profile, autoantibodies) were analyzed. Additionally, the HLA class II (DRB1) of all the patients was genotyped, including an additional group of patients without the autoimmune disease. Statistical analysis was performed using the STATA 10.0 package. RESULTS: In the group of late-onset lupus, there was a higher frequency of pleurisy (p = 0.002), pericarditis (p = 0.026), dry symptoms (p = 0.029), lymphopenia (p = 0.007), and higher titers of rheumatoid factor (p = 0.001) compared with the group of conventional SLE. Late-onset SLE patients had a lower seizure frequency (p = 0.019), weight loss (p = 0.009), alopecia (p < 0.001), and Raynaud's phenomenon (p = 0.013) compared to the conventional SLE group. In late-onset SLE, HLA DR17 (DR3) was found more frequently compared with individuals without autoimmune disease (OR 3.81, 95% CI 1.47 to 10.59) (p = 0.0016). CONCLUSION: In the Colombian SLE population analyzed, there may be a probable association of several clinical and serologic variants, which would allow the differentiation of variables in the presentation of the disease among patients with late-onset SLE vs. conventional SLE.
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Edad de Inicio , Cadenas HLA-DRB1/genética , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Colombia , Estudios Transversales , Femenino , Genotipo , Humanos , Inmunogenética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Analysis of genetic susceptibility factors for Alzheimer's disease (AD) in populations with different genetic and environmental background may be useful to understand AD etiology. There are few genetic association studies of AD in Latin America. In the present work, we analyzed polymorphisms in 3 candidate genes; the LDL receptor related protein-1, the microtubule-associated protein Tau and the serotonin transporter genes in a sample of 106 Colombian AD patients and 97 control subjects. We did not find a significant allelic or genotypic association with any of the three polymorphisms analyzed using different statistical analysis, including a neural network model or different sample stratifications. To date, APOE polymorphisms are the only genetic risk factors identified for AD in the Colombian population. It may be factible that future combination of high-throughput genotyping platforms and multivariate analysis models may lead to the identification of other genetic susceptibility factors for AD in the Colombian population.
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Enfermedad de Alzheimer/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas tau/genética , Anciano , Alelos , Enfermedad de Alzheimer/epidemiología , Apolipoproteína E4/genética , Colombia/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de RiesgoRESUMEN
La patología gástrica inflamatoria es una causa importante de morbilidad en nuestro medio. Condiciones específicas como la gastritis crónica atrófica multifocal, la metaplasia intestinal y la displasia gástrica se encuentran asociadas con el proceso de múltiples pasos en el desarrollo del adenocarcinoma gástrico de tipo intestinal. En este estudio, descriptivo retrospectivo, se revisó el archivo de quirúrgicos del Hospital San Juan de Dios y de la Clínica Carlos Lleras Restrepo de Bogotá, en el periodo comprendido entre el 1 de enero de 1.999 y el 31 de Mayo de 2.000, encontrando 9.349 casos. Dentro de éstos, la patología gástrica correspondió a 18,6 por ciento (1.742), de los cuales 1585 casos ( 90 por ciento) correspondieron a patología no tumoral Se seleccionaron 1.387 casos de los diferentes tipos de gastritis, los cuales fueron clasificados de acuerdo al sistema Sydney modificado del consenso internacional de Houston de 1994. Se encontró una asociación de gastritis crónica y H. pylori del 74,62 por ciento. La gastritis crónica no atrófica se presentó más frecuentemente (73,46 por ciento), afectando personas entre los 40 y 60 años y su asociación con H. pylori fue del 80 por ciento. La gastritis crónica atrófica ocupó el segundo lugar en frecuencia (26,46 por ciento), predominando en mujeres, y con una asociación significativa a infección por H. Pylori (63,31 por ciento).Todos los casos de displasia se presentaron asociados con gastritis crónica atrófica multifocal. Además, se encontró que la presencia de gastritis crónica atrófica multifocal y displasia representan un mayor riesgo relativo (2,2) de desarrollo de adenocarcinoma gástrico
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Gastritis Atrófica/clasificación , Gastritis Atrófica/patologíaRESUMEN
We analyzed the Amerindian tribes, Guambiano, Ingano, and Paez of the southwest section of Colombia by major histocompatibility complex class II typing and blood group analysis in order to establish their genetic relationship. In addition, genetic admixture with Caucasian and African ancestry were determined based on blood group typing. The Paez showed admixture with Caucasian populations (22.4%), while the Ingano and Guambiano showed some admixture with Black populations (9.2 and 4.6%, respectively). The Ingano had MHC class II haplotypes found mainly in Amerindian and Asian populations with no evidence of class II haplotypes of African origin. MHC class II haplotypes of Amerindian and Asian populations and some haplotypes frequently found in European Caucasians and Asians and haplotypes of European Caucasians were found in Guambiano and Paez tribes. We compared our results with those previously reported for four Amerindian tribes on Northern Colombia. The presence of some MHC class II haplotypes in the Guambiano, Paez, and Ingano tribes and their absence in the Chibcha speaking groups of Northern Colombia suggest that these tribes originated, together with other Amerindians, from a separate migration or by genetic drift from an ancestral population. Therefore they are genetically distant from Chibcha speaking tribes of Colombia.
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Antígenos de Grupos Sanguíneos/genética , Genes MHC Clase II/genética , Antígenos HLA-D/genética , Haplotipos/genética , Indígenas Sudamericanos/genética , Pueblo Asiatico/genética , Población Negra/genética , Tipificación y Pruebas Cruzadas Sanguíneas , Análisis por Conglomerados , Colombia , Emigración e Inmigración , Frecuencia de los Genes/genética , Humanos , Población Blanca/genéticaRESUMEN
Apolipoprotein E e4 (APOEe4) allele has been associated with an increased risk for Alzheimer's disease (AD) in diverse populations. Few studies have been carried out in Hispano-Americans and results are inconclusive due to ethnic diversity. This study determined the frequency of APOE alleles in a group of 61 Caucasian-Mestizos patients with probable AD, and 61 age- and sex-matched controls. APOEe4 frequency was 36.8% for patients, and 8.2% for controls (P < 0.0001; OR 7.6). Genotype frequencies differ between the two groups (P < 0.0001). Genotype 3/3 was the most common. Frequency of genotypes 3/4, 4/4 and 2/4 were higher in patients than in the controls. Our results show a highly significant association of APOEe4 with AD, and implies the importance of APOEe4 as a risk factor in this population.
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Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Anciano , Anciano de 80 o más Años , Apolipoproteína E4 , Estudios de Casos y Controles , Estudios de Cohortes , Colombia , Femenino , Frecuencia de los Genes , Genotipo , Hispánicos o Latinos/genética , Humanos , Indígenas Sudamericanos/genética , Masculino , Persona de Mediana Edad , Valores de Referencia , Población Blanca/genéticaRESUMEN
Blood samples from 409-452 unrelated Colombian Caucasian-Mestizo individuals were amplified and typed for six short tandem repeat (STR) markers (HUMF13A01, HUMFES/FPS, HUMVWA, HUMCSF1PO, HUMTPOX, HUMTH01). The allele frequencies, genotype frequencies, heterozygosity, mean paternity exclusion chance, polymorphism information content, discrimination power, assumption of independence within and between loci and Hardy Weinberg equilibrium were determined. The results demonstrate that all markers conform to Hardy-Weinberg equilibrium expectations. In addition, the results demonstrate the assumption of independence within and between the loci analysed. The mean exclusion chance (MEC) was 0.9851 for all six STR loci analysed and the discrimination power (DP) was 0.9999973. Therefore, this Colombian population database can be used in identity testing to estimate the frequency of a multiple PCR-based locus DNA profile in forensic cases as well as in paternity testing.
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Población Negra/genética , Frecuencia de los Genes/genética , Indígenas Sudamericanos/genética , Repeticiones de Minisatélite/genética , Polimorfismo Genético/genética , Población Blanca/genética , Colombia , Análisis Discriminante , Tamización de Portadores Genéticos , Genotipo , Humanos , Desequilibrio de Ligamiento , Paternidad , Reproducibilidad de los ResultadosRESUMEN
Blood samples from 489 unrelated Caucasian Mestizo and 252 individuals of African descent in Colombia were amplified and typed for three short tandem repeat (STR) markers (D12S1090, D3S1744, and D18S849). All markers conformed to Hardy-Weinberg equilibrium expectations in both populations studied. In addition, heterozygosity, mean exclusion chance, polymorphism information content, discrimination power, and the assumption of independence within and between loci were determined. The mean exclusion chance for all three STR markers is 0.9750 in the Caucasian Mestizo population and 0.9731 in the African Colombian Population. The discrimination power is 0.999925 and 0.999911 in the Caucasian Mestizo and African Colombian respectively.
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Población Negra/genética , Frecuencia de los Genes , Indígenas Norteamericanos/genética , Secuencias Repetidas en Tándem/genética , Colombia , Medicina Legal/métodos , Genética de Población , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Genes linked to the major histocompatibility complex (MHC), have been implicated in atopic asthma. Asthma is highly prevalent in the Venezuelan population (estimated at 20%) and genetic markers are needed to identify populations at risk and plan intervention strategies. OBJECTIVE: To study the influence of the MHC class I and class II genes in the susceptibility to atopic asthma. METHODS: MHC-class I HLA-A, -C, -B and MHC-class II HLA-DR, -DQ, -DP gene haplotype frequencies were determined in 135 Venezuelan mestizos, 71 belong to 20 atopic asthmatic families and 64 unrelated controls. The index cases were 20 atopic asthmatics with positive skin-prick tests and specific serum immunoglobulin E (IgE) for Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f). To ascertain the genes associated with susceptibility to atopy and/or asthma, two control groups were studied, 41 non-atopic subjects with skin-prick negative test, and undetectable levels of specific IgE and 23 non-asthmatic atopic subjects with detectable specific IgE to Der p and Der f. A linkage analysis was performed in those families with two or more atopic siblings (with or without asthma). RESULTS: MHC-class I genes analysis showed that HLA-Cw7 was absent in the asthmatic patients studied, whereas the frequency of this allele was 14.3% in non-atopic controls (P = 0.0 17, PC = 0.19) and 20.8% in the atopic controls (P = 0.0066, PC = 0.07). MHC-class II gene analysis showed a significant increase of the HLA-DRB1*11 in the asthmatic patients compared with non-atopic controls (allele frequencies of 25.6 vs 4.4% P = 0.0017, PC = 0.02). There were no significant differences among asthmatic and atopic controls in the frequency of HLA-DRB1*11 (25.6 vs 17.4%). In contrast, the HLA-DRB1*1101+ haplotypes were significantly higher in asthmatics compared with atopic and non-atopic controls (19.6% vs 2.2% vs 2.3%, PC<0.05). The HLA-DRB1*1101, DQA1*0501, DQB1*0301 haplotype was found significantly increased in the patients vs non-atopic controls (15.4 vs 1.1%, PC< 0.01). The serum levels of specific IgE were detectable in both atopic asthmatics and atopic controls; however, it was higher in atopic asthmatics vs atopic controls Der p (median, 58.7 vs 2.7 kU/L, P<0.001) and Der f (median, 46.9 vs 2.7 kU/L, P<0.001). No linkage between MHC genes and mite-atopy could be documented on informative families with two or more atopic siblings. CONCLUSIONS: We have identified an association between the haplotype HLA-DRB1*1101, DQA1*0501, DQB1*0301 and atopic asthma that confers susceptibility to develop mite-sensitive asthma to atopics (relative risk, RR 8.2), and to non-atopic controls (RR = 15.8) that carry this haplotype. Conversely, the allele HLA-Cw7 was absent in the asthmatics studied and had higher frequencies in the atopic (RR = 0.05) and non-atopic (RR = 0.08) controls. Thus, it may have a protective role for developing atopic asthma in the population studied.
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Asma/genética , Asma/inmunología , Adolescente , Adulto , Alelos , Antígenos Dermatofagoides , Asma/sangre , Niño , Preescolar , Salud de la Familia , Femenino , Frecuencia de los Genes , Genes MHC Clase I , Genes MHC Clase II , Ligamiento Genético , Glicoproteínas/inmunología , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Haplotipos , Humanos , Inmunoglobulina E/sangre , Escala de Lod , Masculino , Persona de Mediana Edad , Pruebas Cutáneas , VenezuelaRESUMEN
BACKGROUND: Recipient antidonor cytotoxic T-cell activity has been associated with graft loss and acute rejection in renal allograft recipients. The role of immunologic mechanisms in the development of chronic graft rejection is controversial. We analyzed all living related renal transplants performed at Children's Hospital (Boston, MA) from 1983 to 1995 to assess whether cell-mediated cytotoxicity, determined in vitro and measured before transplantation, was predictive of chronic rejection. METHODS: Eighty-three patients were studied retrospectively. Fifty-seven patients with one haplotype-matched renal transplants from living related donors were studied to determine the association between cell-mediated lympholysis (CML) level, acute rejection, chronic rejection, and graft failure. Acute rejection was defined by the decision to treat. Chronic rejection was defined by histology and/or the absolute serum creatinine value using an increasing serum creatinine level >1.0 mg/dl for children less than 3, a creatinine level >1.5 mg/dl for children between 3 and 10 years of age, and a creatinine level >2.0 mg/dl for children above 10 years of age. Return to dialysis or retransplantation was considered graft failure. RESULTS: Of the 57 haploidentical patients, there were 33 males and 24 females. The mean age at transplant was 11.1 years (SD=6.7). Twelve patients developed chronic rejection, 24 patients developed acute rejection, and 7 patients had graft failure. Pretransplant cytotoxic T lymphocyte activity was associated with chronic rejection (P=0.001) and graft failure (P=0.013) but only marginally with acute rejection (P=0.058). Controlling for age and sex, Cox's proportional hazards model revealed that CML level was predictive of time to chronic rejection (P<0.01) but not acute rejection (P=0.11). It was estimated that every 1-unit increase in CML level raises the monthly risk of chronic rejection by 7%. Ten children received HLA-identical kidneys from their siblings. There were no episodes of chronic rejection after 5 years. Two patients with high CML levels had episodes of acute rejection; both patients responded to treatment. CONCLUSION: Our data demonstrate an association between pretransplant cell-mediated cytotoxicity and the occurrence of chronic rejection in living related one-haploidentical renal transplants in pediatric patients.
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Rechazo de Injerto , Inmunidad Celular , Trasplante de Riñón/inmunología , Linfocitos T Citotóxicos/inmunología , Adolescente , Adulto , Niño , Preescolar , Femenino , Supervivencia de Injerto , Haploidia , Prueba de Histocompatibilidad , Humanos , Inmunidad Celular/genética , Lactante , Masculino , Resultado del TratamientoRESUMEN
Genes of the major histocompatibility complex (MHC) are associated with susceptibility to different immune and nonimmune mediated diseases. We had reported that the drug adverse reaction, clozapine-induced agranulocytosis (CA), is associated with different HLA types and HSP70 variants in Ashkenazi Jewish and non-Jewish patients, suggesting that a gene within the MHC region is associated with CA. This study was designed to find common genetic markers for this disorder in both ethnic groups. The tumor necrosis factor (TNF) microsatellites d3 and b4 were found in higher frequencies in both Jewish and non-Jewish patients: 51 of 66 (77%) and 48 of 66 (57%), respectively. Comparisons of these frequencies with those of controls, 28 of 66 (42%) and 18 of 66 (27%), were statistically significant (corrected P value = .001 for the d3 allele and .0005 for the b4 allele). On the other hand, the TNF microsatellite b5 was underrepresented in the group of patients, 9 of 66 (14%), when compared with the control subjects, 43 of 66 (65%) (corrected P value = .0005), probably related to protection from CA. Our results show a strong association of some genetic variants of the TNF loci with susceptibility to CA in two different ethnic groups suggesting involvement of TNF and/or associated gene(s) products in the pathogenesis of this hematologic-drug adverse reaction.
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Agranulocitosis/genética , Antipsicóticos/efectos adversos , Clozapina/efectos adversos , Judíos , Complejo Mayor de Histocompatibilidad/genética , Factor de Necrosis Tumoral alfa/genética , Agranulocitosis/inducido químicamente , Agranulocitosis/etnología , Europa (Continente)/etnología , Femenino , Frecuencia de los Genes , Ligamiento Genético , Humanos , Masculino , Polimorfismo Genético , Estados Unidos/etnologíaRESUMEN
Previous studies showed that almost all Ashkenazi Jewish patients with pemphigus vulgaris carried the extended haplotype [HLA-B38, SC21, DRB1*0402, DQB1*0302] or [HLA-B35, SC31, DRB1*0402, DQB1*0302] or class II fragments of them. Non-Jewish patients carried [HLA-B55, SB45, DRB1*1401, DQB1*0503] or its class II fragments. In the present study of 20 Iranian patients with pemphigus vulgaris, 17 were found to carry DRB1*0402, DQB1*0302 haplotypes, also found among normal Iranian haplotypes and the same as that of the Jews. These findings suggest that the pemphigus MHC susceptibility gene among Iranians derived from the same ancestor as that in the Ashkenazim. The ancient Jews were under Persian domination from 500 B.C. until 300 B.C. and in the 8th century A.D., a Tataric people living in the kingdom of Khazar on the Western shore of the Caspian Sea and the Northern shore of the Black Sea, near Persia, converted to Judaism, providing possible opportunities for gene mixing in two populations that are distinct and separate today.
Asunto(s)
Genes MHC Clase II , Marcadores Genéticos , Judíos/genética , Complejo Mayor de Histocompatibilidad/genética , Pénfigo/genética , Pénfigo/inmunología , Asia , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Haplotipos , Humanos , Irán , Reacción en Cadena de la PolimerasaRESUMEN
Pemphigus vulgaris (PV) is an autoimmune disease of the skin and mucous membranes characterized by an autoantibody response against an epidermal cadherin. We performed high resolution HLA class II typing in 19 patients with PV from Rawalpindi, Pakistan and 19 non-Jewish European PV patients from Boston by sequence-specific oligonucleotide probe hybridization. The results were compared with two separate ethnically matched control populations. WE found that PV patients from Pakistan had significantly increased frequencies of DRB1*1404 (p = 0.01), DQA1*0101 (p = 0.02), and DQB1*0503 (p = 0.01). Among the patients of non-Jewish European ancestry, DRB1*1401 (p < 10(-6)), DQA1*0101 (p < 10(-5)) and DQB1*0503 (p < 10(-6)), were increased in PV patients. Formal linkage analysis between the major histocompatibility complex and the PV antibody was performed in 67 relatives of the 19 Pakistani patients. The results showed strong evidence for linkage of HLA-DRB1*1404, DQA1*0101, DQB1*0503, with the presence of PV antibody in relatives' families with a significant logarithm of the odds score of 6.06. Based on the three dimensional structure of class II molecules, we propose that HLA-DQA1*0101 and DQB1*0503, encode a negatively charged P9 peptide binding pocket of the DQ molecule and are significantly associated with susceptibility to PV in non-Jewish populations.
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Autoanticuerpos/inmunología , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Pénfigo/genética , Pénfigo/inmunología , Alelos , Autoanticuerpos/análisis , Mapeo Cromosómico , Susceptibilidad a Enfermedades/inmunología , Europa (Continente)/etnología , Genes MHC Clase II , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/química , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Cadenas HLA-DRB1 , Humanos , Immunoblotting , Estructura Molecular , Hibridación de Ácido Nucleico , Sondas de Oligonucleótidos/genética , Pakistán/etnología , Linaje , Pénfigo/etnología , Reacción en Cadena de la PolimerasaRESUMEN
The human MLL (mixed-lineage leukemia or myeloid-lymphoid leukemia) gene belongs to the trithorax gene family of which the Drosophila trithorax (trx) gene is known to regulate homeotic genes through alternative RNA splicing. To test if such a splicing mechanism also operates in MLL, we evaluated mRNA transcripts from a large number of normal and malignant human cells, making use of RT-PCR, PCR cloning, DNA sequencing and Northern blot analysis. Our findings indicate that different cell types transcribe MLL mRNA species lacking exons that generally encode putative regulatory domains such as AT hooks (exon 3), repression domain (exon 6), zinc finger motifs (exon 8) and activation domain (exon 18). Such findings suggest that posttranscriptional regulation by alternative RNA splicing may play an important role in MLL gene expression and provides the rationale for a mechanism by which this gene, with multiple functional domains, could produce discrete protein products that may prove critical in the regulation of human homeobox genes.
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Empalme Alternativo , Proteínas de Unión al ADN/genética , Neoplasias/genética , Proto-Oncogenes , Factores de Transcripción , Secuencia de Aminoácidos , Composición de Base , Secuencia de Bases , Diferenciación Celular , Células Cultivadas , ADN , ADN de Neoplasias , Exones , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia/genética , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide , Reacción en Cadena de la Polimerasa , Células Tumorales Cultivadas , Dedos de Zinc/genéticaRESUMEN
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease seen primarily in elderly persons. It is characterized clinically by the development of tense bullae and by the presence of an antibasement membrane antibody. In BP, the antigens involved in the autoimmunity are epidermal basement membrane peptides BPAg1 and BPAg2. We have compared high resolution typing of major histocompatibility complex class II loci (HLA-DRB1, DQB1) in 21 patients with BP, 17 with ocular cicatricial pemphigoid (OCP), and 22 with oral pemphigoid (OP) to a panel of 218 haplotypes of normal individuals. We found that the three diseases (BP, OCP, and OP) have significant association with DQB1*0301 (P = 0.005, P < 0.0001, and P = 0.001, respectively). The frequencies of alleles DQB1*0302, 0303, and 06, which share a specific amino acid sequence from position 71 to 77 (Thr-Arg-Ala-Glu-Leu-Val-Thr) were also increased (P = 0.01). We suggest that an identical major histocompatibility complex class II allele (DQB1*0301) is a common marker for enhanced susceptibility and that the same amino acid residues in positions 71-77 (DQB1*0301, -0302, -0305, -0602, -0603 alleles) are found in patients with BP, OCP and OP. Our findings propose that the autoimmune response in the three different clinical variants of pemphigoid, involves the recognition by T cells of a class II region of DQB1, bound to a peptide from the basement membrane of conjunctiva, oral mucosa, and skin.
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Antígenos HLA-DQ/genética , Penfigoide Ampolloso/inmunología , Alelos , Secuencia de Aminoácidos , Frecuencia de los Genes , Antígenos HLA-DQ/química , Cadenas beta de HLA-DQ , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Haplotipos , Humanos , Datos de Secuencia Molecular , Población BlancaRESUMEN
Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene through a reciprocal chromosomal translocation is found in 5% of adult acute myeloid (AML) and 10% of pediatric acute lymphoid (ALL) leukemia. More than 25 different reciprocal chromosomal translocations, with an 11q23 breakpoint, fuse the MLL gene (also named ALL-1, HRX and Htrx1) to a second partner gene. These leukemias have poor prognosis and frequently have a monocytic, lymphoid or biphenotypic (myeloid and lymphoid) antigen expression in blast cells. Approximately 20-30% of patients diagnosed as having adult de novo, AML have normal chromosomes by metaphase analysis and the majority of these patients have good prognosis. With the use of reverse transcriptase-polymerase chain reaction (RT-PCR) technique and Southern blot analysis, we found that seven of 34 such patients (21%) had a tandem partial duplication of exons 2 to 6 or 2 to 8 of the MLL gene. These seven patients showed a median survival of 2.7 months, compared to a 6.8 months median survival for all other patients in the study. If confirmed on a large series of patients, our findings may help differentiate AML with normal karyotype and poor prognosis from those with normal karyotype and a more favorable prognosis.
Asunto(s)
Proteínas de Unión al ADN/genética , Leucemia Mieloide/genética , Familia de Multigenes , Proteínas de Neoplasias/genética , Proto-Oncogenes , Empalme del ARN , Factores de Transcripción , Enfermedad Aguda , Adulto , Secuencia de Bases , Médula Ósea/patología , Cromosomas Humanos Par 11/genética , Exones/genética , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Cariotipificación , Leucemia Mieloide/mortalidad , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide , Reacción en Cadena de la Polimerasa , Pronóstico , Tasa de Supervivencia , Translocación Genética/genéticaRESUMEN
We report here the cloning, sequencing, functional analysis and DNase I footprinting of the human c-rel promoter region. The results revealed an 824-bp BsaAI-StuI minimal promoter region with a large number of NF-kappa B, Ap2 and Sp1-binding sites, some of them variants of known consensus sequences. This is the first promoter in the Rel/NF-kappa B/I kappa B family to be subjected to a detailed footprinting analysis for the binding of transcription activator proteins. Our finding of 14 Ap2-binding sites may indicate why the human c-rel promoter, unlike the chicken c-rel promoter, has a strong function and is highly responsive to phorbol esters. The presence of five NF-kappa B and six Sp1-binding sites in turn adds to growing evidence that, in mammals, the promoter of the Rel/NF-kappa B/I kappa B family may utilize multiple NF-kappa B- and Sp1-binding sites for their interactive regulation. Furthermore, there are putative binding sites for the PU.1 and Oct 1/2 transcription activator proteins, also present in the mouse c-rel promoter, which may help explain the preferential transcription of the c-rel gene in B- and T-lymphoid cells.
Asunto(s)
Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión , Clonación Molecular , ADN/metabolismo , Huella de ADN , Humanos , Ratones , Datos de Secuencia Molecular , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-relRESUMEN
Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat-shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.