RESUMEN
Ring 21 is an unstable structural abnormality of chromosome 21 that can lead to RUNX1 gene amplification. We present a unique case with a carrier patient of a constitutional ring chromosome 21 (partial monosomy and trisomy 21) with dysmorphic features and congenital malformations phenotype, who developed acute myeloid leukaemia with myelodysplasia-related changes and two ring 21 chromosomes with RUNX1 amplification. The patient's constitutional ring 21 chromosome showed alterations in tumour suppressor genes, and oncogenes, but not in RUNX1. RUNX1 gene expression at acute myeloid leukaemia diagnosis, showed no upregulation, so other genes may also be the genetic amplification targets in this patient. Copyright © 2016 John Wiley & Sons, Ltd.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Preescolar , Cromosomas Humanos Par 21/genética , Femenino , Amplificación de Genes , Humanos , Cromosomas en AnilloRESUMEN
The expression of activation-induced cytidine deaminase, B-aggressive lymphoma, cyclin D1 and serine/threonine kinase 15 genes, among others, is increased in B cells from patients with chronic hepatitis C virus (HCV) infection. It is unknown whether the level of expression of these genes in B cells is increased in patients with hepatitis C who have achieved a sustained virological response (SVR) but who have persistent, detectable HCV RNA, so-called occult infection. Eighty-three patients who achieved and SVR, 27 with detectable HCV and 56 without detectable HCV RNA, 28 chronic hepatitis C patients and 32 healthy controls were studied. RNA was extracted from B cells, and gene expression levels were measured by RT-PCR. Patients with chronic HCV and those who achieved an SVR (with and without persistent low-level HCV RNA) showed a statistically significant higher expression compared to healthy controls, of activation-induced cytidine deaminase (P = 0.004, P < 0.001 and P = 0.002, respectively), B-aggressive lymphoma (P < 0.001, P = 0.001 and P = 0.006) and cyclin D1 (P = 0.026, P = 0.001; P = 0.038). For activation-induced cytidine deaminase patients with an SVR and 'occult infection' had a statistically significantly higher expression level than patients with and SVR without 'occult infection' (P = 0.014). The higher expression levels found for activation-induced cytidine deaminase, together with other genes indicates that these B lymphomagenesis-related genes are upregulated following HCV therapy and this is more marked when HCV can be detected in PBMCs.
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Linfocitos B/patología , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/patología , ARN Viral/sangre , Respuesta Virológica Sostenida , Transcriptoma , Adulto , Anciano , Carcinogénesis , Femenino , Perfilación de la Expresión Génica , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Linfoma/fisiopatología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVES: Genetic background has been identified to be a major predictor of post-clopidogrel platelet inhibition in patients undergoing coronary stenting. However, there is a lack of data on clopidogrel response regarding genotype in patients undergoing carotid artery stenting (CAS). The influence of the most common allelic variants of CYP2C19 phenotypes and genotypes on response to baseline clopidogrel and on the pharmacodynamic effect of dose adjustment (high or standard dose of clopidogrel) in patients with high on-treatment reactivity after CAS was investigated. METHODS: Platelet reactivity was assessed before and 30 days after carotid stenting using the VerifyNow P2Y12 assay to obtain P2Y12 reactivity unit (PRU) values. RESULTS: A total of 209 patients (79.4% male, 44.1% currents smokers) were treated by CAS. Smokers improved responsiveness to clopidogrel (p = .034). With respect to CYP2C19 enzymatic function, 61 subjects (29.1%) were ultra-rapid metabolizers, 95 patients (45.5%) were extensive metabolizers, 51 (24.4%) were intermediate metabolizers, and two (0.96%) were poor metabolizers. Baseline PRU was significantly higher among intermediate-poor metabolizers compared with ultra-rapid (p = .001) or extensive metabolizers (p = .005). At 30 days follow up, in non-responding patients with the intermediate-poor metabolizer phenotype, the PRU value and inhibition percentage were significantly reduced with standard dose (p = .008; p = .0029) and high dose of clopidogrel (p = .00 0; p = .000). However, high dose clopidogrel did not achieve a more intense pharmacodynamic effect at 30 days (p = .994) compared with standard dose. CONCLUSIONS: In patients undergoing carotid stenting, those with the CYP2C19*2 allele had increased basal PRU values and in fact clopidogrel non-responders increased significantly among intermediate-poor metabolizers. Although high dose and standard dose clopidogrel therapy was effective in lowering the 30 day PRU values in patients with high on-treatment reactivity who are intermediate-poor metabolizers, the use of high dose clopidogrel did not result in statistically significantly greater reductions in reactivity compared with the standard dose.
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Angioplastia/instrumentación , Plaquetas/efectos de los fármacos , Enfermedades de las Arterias Carótidas/terapia , Citocromo P-450 CYP2C19/genética , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Polimorfismo Genético , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Stents , Ticlopidina/análogos & derivados , Anciano , Angioplastia/efectos adversos , Plaquetas/metabolismo , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico , Clopidogrel , Citocromo P-450 CYP2C19/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Fenotipo , Inhibidores de Agregación Plaquetaria/metabolismo , Antagonistas del Receptor Purinérgico P2Y/metabolismo , Receptores Purinérgicos P2Y12/sangre , Receptores Purinérgicos P2Y12/efectos de los fármacos , Ticlopidina/administración & dosificación , Ticlopidina/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: Chromosomal rearrangements involving NUP98 gene have been associated with human leukemias such as de novo AML, therapy-related AML (t-AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). Genetic fusion NUP98-HOXA9, caused by t(7;11)(p15;p15), is a recurrent cytogenetic alteration in de novo acute myeloid leukemia (AML) usually found in young Asian patients and its description in therapy-related myeloid neoplasms (t-MN) is rare. Only one Asian case with molecular demonstration of the NUP98-HOXA9 fusion has been reported in therapy-related leukemia. NUP98-HOXA9 leukemogenic mechanism is derived from the transcription factor activity of the chimeric protein, which enhances the expression of genes related to cellular differentiation arrest and proliferation. PATIENTS AND METHODS: We studied a Caucasian woman with a therapy-related acute myeloid leukemia after Ewing's sarcoma. Molecular demonstration of the genetic fusion NUP98-HOXA9 was performed by RT-PCR, and gene expression was analyzed by real-time PCR, including four AML patients with MLL rearrangements for comparative analysis. Cytologic and flow cytometric analysis was also carried out. RESULTS: After cytologic and flow cytometric analysis diagnostics was therapy-related myeloid neoplasm (t-MN). The major component of blasts in the acute leukemia was with neutrophilic differentiation, but 13% erythroid lineage blasts were also found. Cytogenetic and FISH analysis revealed t(7;11)(p15;p15) and NUP98-HOXA9 fusion gene was demonstrated. Gene expression analysis showed upregulation of EVI1 and MEIS1 in the index patient, both of them previously related to a worst outcome. CONCLUSION: In this work, we include a detailed molecular, clinical, cytological, and cytometric study of the second t-AML bearing NUP98-HOXA9 genetic fusion.
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Proteínas de Unión al ADN/genética , Expresión Génica , Proteínas de Homeodominio/genética , Leucemia Mieloide Aguda/etiología , Células Mieloides/metabolismo , Proteínas de Neoplasias/genética , Neoplasias Primarias Secundarias , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Proto-Oncogenes/genética , Factores de Transcripción/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Manejo de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteína del Locus del Complejo MDS1 y EV11 , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Translocación GenéticaRESUMEN
OBJECTIVE: The aim of this study was to investigate the pattern of microRNA (miRNA) expression in CD19+ and CD4+ cells from asymptomatic patients with systemic lupus erythematosus (SLE). METHODS: A screening of the expression of 377 miRNAs was performed in human CD4+ and CD19+ cells isolated from the peripheral blood by using a TaqMan Human MicroRNA Array. Validation of differential expression pattern of those was performed using TaqMan assays in these cell populations obtained from a larger cohort of patients and controls. RESULTS: According to the screening assays, three miRNAs were differentially expressed (p value <0.1) in cell populations from both patients and controls: hsa-miR-143, hsa-miR-224 and hsa-miR-576-5p for CD4+ cells, and hsa-miR-10a, hsa-miR-31 and hsa-miR-345 for CD19+ cells. After validation, significant differences (p value <0.05) were confirmed only for hsa-miR-143 and hsa-miR-224 in CD4+ cells and for hsa-miR-10a and hsa-miR-345 in CD19+ cells. In all cases, the miRNAs were over expressed in SLE patients compared with healthy donors. CONCLUSIONS: Our results support a different pattern of miRNA expression in SLE patients.
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Antígenos CD19/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Lupus Eritematoso Sistémico/genética , MicroARNs/genética , Adulto , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/métodosRESUMEN
BACKGROUND: Insulin resistance has been strongly associated with the attainment of sustained viral response (SVR) in hepatitis C patients. AIM: To determine, in a cohort of Spanish patients with chronic hepatitis C treated with peginterferon plus ribavirin (P+R), whether insulin resistance predicts SVR independently of interleukin-28B rs12979860 polymorphism. METHODS: Insulin resistance was measured as [HOMA-IR = Insulin (IU/mL)*glucose (mmol/L)/22.5]. Genotype, viral load and histological fibrosis using Scheuer score were also measured. Binary logistic regression analysis was used for statistical purposes. RESULTS: In a cohort of 240 patients [78% genotype 1, 24% showing advanced fibrosis, 71% high viral load (≥800 000 IU/mL), 31% IL28b genotype CC and 50% with HOMA >2] treated with P+R, 126 (53%) reached SVR. HOMA-IR index (HOMA <2: 63% vs. HOMA >2: 42%; P = 0.001 and IL28b (genotype CC: 68% vs. genotype CT/TT: 45%; P = 0.002) were significantly associated with SVR. In multivariable logistic regression analysis in the overall cohort, variables independently associated were: viral genotype OR: 0.29 (95% CI: 0.11-0.78), P = 0.01; fibrosis OR: 1.62 (95% CI: 1.22-2.16), P = 0.001; HOMA-IR OR: 1.22 (95% CI: 1.02-1.47), P = 0.03; and IL28B genotype OR: 2.43 (95% CI: 1.45-4.07), P = 0.001. The analyses also showed that degree of steatosis, HOMA-IR >2, mild fibrosis and IL28B CC genotype were significantly related to SVR in patients infected with HCV genotypes 1&4, but not in those with genotypes 2&3. No differences were seen in glucose, insulin level or HOMA-IR index segregated according to IL28B genotypes. CONCLUSION: Our results suggest that insulin resistance, fibrosis stage and IL28B polymorphisms were independent variables associated with sustained viral response.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Resistencia a la Insulina/genética , Interleucinas/genética , Polimorfismo de Nucleótido Simple , Adulto , Glucemia/análisis , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Genotipo , Técnicas de Genotipaje , Hepatitis C Crónica/genética , Humanos , Insulina/sangre , Interferón-alfa/uso terapéutico , Interferones , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Análisis de Regresión , Ribavirina/uso terapéutico , Resultado del Tratamiento , Carga ViralRESUMEN
It is unknown whether hepatitis C virus (HCV)-specific cellular immune responses can develop in seronegative sexual partners of chronically HCV-infected patients and whether they have occult infection. Thirty-one heterosexual partners of patients with chronic HCV were studied, fifteen of them with HCV transmission risks. Ten healthy individuals and 17 anti-HCV seropositive patients, without viremia, were used as controls. Virus-specific CD4+ and CD8+ T-cell responses were measured by flow cytometry against six HCV peptides, situated within the nonstructural (NS) proteins NS3, NS4 and NS5, through intracellular detection of gamma interferon (IFN-γ) or interleukin 4 (IL-4) production and CD69 expression. Sexual partners had a higher production of IFN-γ and IL-4 by CD4+ cells against NS3-p124 (P = 0.003), NS5b-p257 (P = 0.005) and NS5b-p294 (P = 0.012), and CD8+ cells against NS3-p124 (P = 0.002), NS4b-p177 (P = 0.001) and NS3-p294 (P = 0.004) as compared with healthy controls. We observed elevated IFN-γ production by CD4+ T cells against NS5b-p257 (P = 0.042) and NS5b-p294 (P = 0.009) in the sexual partners with HCV transmission risks (sexual, professional and familial altogether) than in those without risks. RNA was extracted from peripheral blood mononuclear cells (PBMC), and detection of HCV-RNA positive and replicative (negative) strands was performed by strand-specific real-time PCR. In four sexual partners, the presence of positive and negative HCV- RNA strands in PBMC was confirmed. Hence, we found an HCV-specific cellular immune response as well as occult HCV infection in seronegative and aviremic sexual partners of chronically HCV-infected patients.
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Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Inmunidad Celular , Adulto , Anciano , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Antígenos Virales/inmunología , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/química , Linfocitos T CD8-positivos/inmunología , Femenino , Citometría de Flujo , Heterosexualidad , Humanos , Interferón gamma/biosíntesis , Interleucina-4/biosíntesis , Lectinas Tipo C/análisis , Masculino , Persona de Mediana EdadRESUMEN
Impaired innate inflammatory response has a key role in the Crohn's disease (CD) pathogenesis. The aim of this study was to investigate the possible role of the TLR10-TLR1-TLR6 gene cluster in CD susceptibility. A total of 508 CD patients (284, cohort 1 and 224, cohort 2) and 576 controls were included. TLR10-TLR1-TLR6 cluster single-nucleotide polymorphisms genotyping, NOD2 mutations and TLR10 mRNA quantification were performed using TaqMan assays. Nucleotide-binding oligomerization domain containing 2 (NOD2) and Toll-like receptor (TLR) loci interaction was analyzed by logistic regression and multifactor-dimensionality reduction (MDR). Entropy-based analysis was used to interpret combination effects. One TLR10 haplotype (TLR10(GGGG)) was found associated with CD susceptibility in both cohorts, individuals with two copies had approximately twofold more risk of CD susceptibility than individuals having no copies (odds ratio=1.89, P-value=0.0002). No differences in the mRNA levels were observed among the genotypes. The strongest model for predicting CD risk according to the MDR analysis was a two-locus model including NOD2 mutations and TLR10(GGGG) haplotype (P(c)<0.0001). The interaction gain attributed to the combination of both genes was negative (IG=-2.36%), indicating redundancy or independent effects. Our results support association of the TLR10 gene with CD susceptibility. The effect of TLR10 would be independent of NOD2, suggesting different signaling pathways for both genes.
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Enfermedad de Crohn/genética , Predisposición Genética a la Enfermedad , Proteína Adaptadora de Señalización NOD2/genética , Receptor Toll-Like 10/genética , Adolescente , Adulto , Alelos , Estudios de Casos y Controles , Niño , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Fenotipo , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 1/genética , Receptor Toll-Like 6/genética , Adulto JovenRESUMEN
The outcome of chronic hepatitis C virus infection varies, depending on viral and host factors. Those mechanisms involved in the control of the innate and adaptive response could have an influence on the outcome of infection. The PTPN22 gene encodes an intracellular lymphoid-specific phosphatase (Lyp) with a lymphocyte activating downregulatory effect. A single-nucleotide polymorphism (SNP) C1858T located on this gene has been associated with autoimmune diseases and bacterial infections. The aim of this study was to assess whether the PTPN22 C1858T polymorphism is related to the outcome of hepatitis C viral infection. A total of 69 patients with spontaneous viral clearance (SVC), 281 patients with chronic hepatitis C (CHC), and 1036 individuals not infected with hepatitis C (NIC) were included in this study. Patients with CHC were stratified according to Scheuer score of hepatic fibrosis from F0-F2 (n = 200) and F3-F4 (n = 81), and according to their response to therapy in patients with sustained responses (SR; n = 103) and non-sustained response (NSR; n = 104). Genotyping of the C1858T polymorphism was performed using TaqMan probes. No statistically significant differences in the distribution of PTPN22 C1858T polymorphism were observed upon comparison of patient group with the NIC group. Also, when the different patient groups were compared to one another, no statistically significant differences were detected: the SVC with the CHC group (10.2% versus 12.5%; p = 0.6), the F0-F2 with the F3-F4 group (11.5% versus 14.8%; p = 0.5), and the NSR with the SR group (11.5% versus 14.6%; p = 0.4). Our results do not support a major role of this polymorphism of the PTPN22 gene in the outcome of chronic hepatitis C virus infection in the Spanish population.
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Hepacivirus/patogenicidad , Hepatitis C/genética , Interacciones Huésped-Patógeno , Mutación Missense , Polimorfismo Genético , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Adulto , Anciano , Femenino , Genotipo , Hepacivirus/fisiología , Hepatitis C/metabolismo , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Proteína Tirosina Fosfatasa no Receptora Tipo 22/metabolismo , Población Blanca/genéticaRESUMEN
AIM: To assess whether CCL2 or interactions between this chemokine and its receptor (CCR2) are associated with outcomes of chronic hepatitis C and with responses to antiviral therapy. METHODS: Two hundred and eighty-four patients with chronic hepatitis C and 193 non-infected matched controls were included in this study. Patients were categorized according to their Scheuer score of hepatic fibrosis as F0-F2 (n = 202) or F3-F4 (n = 82) and according to their response to anti-Hepatitis C virus (HCV) therapy as sustained response (SR, n = 101) or non-sustained response (NSR, n = 98). Genotyping of the -2518 (A/G) CCL2 was performed using PCR-RFLP, genotyping of the 190 (A/G) CCR2 using a PCR-ARMS system, and genotyping of the rs3138042 (G/A) CCR2 using Taqman probes. RESULTS: Univariate analyses identified 4 parameters (infection duration time, viral genotype, gender and AST levels) that tended to influence fibrosis and 7 parameters (CCL2G, CCL2ACCR2A, viremia levels, fibrosis stage, viral genotype, infection duration time and AST levels) that significantly influenced or tended to influence response to treatment. Multivariate analysis identified gender and AST levels as parameters that independently influenced fibrosis stage and viral genotype and infection duration time were the two parameters that independently influenced response to treatment. CONCLUSION: Our results indicate that the mutations studied in the gene pair CCL2/CCR2 do not play a major role in the outcome and response to treatment for HCV infection in the Spanish population.
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Antivirales/uso terapéutico , Quimiocina CCL2/fisiología , Hepatitis C/tratamiento farmacológico , Interferón Tipo I/uso terapéutico , Receptores de Quimiocina/fisiología , Ribavirina/uso terapéutico , Adulto , Anciano , Biopsia , Quimiocina CCL2/genética , Femenino , Genotipo , Hepatitis C/etnología , Hepatitis C/genética , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación/genética , Receptores CCR2 , Receptores de Quimiocina/genética , Proteínas Recombinantes , España , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of this study was to investigate the possible role of the caspase 7 (CASP7) in susceptibility to rheumatoid arthritis (RA). METHODS: Genotyping of three single nucleotide polymorphisms (SNPs) of the CASP7 gene: rs11593766 (G/ T), rs2227310 (C/G) and rs2227309 (G/A) was performed in a total of 906 RA patients and 528 matched healthy controls using TaqMan assays. All the subjects were of Spanish Caucasian origin. A relative quantification of mRNA encoding the non-functional variant of procaspase 7 (isoform beta) vs functional isoforms was performed in total RNA from 32 healthy individuals using real-time PCR. RESULTS: Only the rs2227309 SNP was found to be associated with susceptibility to RA. Frequency of the G allele was significantly higher among RA patients [overall frequency of the G allele 74.0% in cases vs 68.4% in controls, P = 0.001, Odds ratio (OR) = 1.32, 95% Confidence intervals (95% CI) 1.11-1.56] and a higher frequency of GG homozygous individuals was found in the RA patient group (overall frequency of GG genotype 56.0% in cases and 46.4% in controls, P = 0.0005, OR = 1.47, 95%CI 1.18-1.83). A statistically significant deviation was observed to compare the relative expression of the procaspase 7 isoform beta in samples from individuals stratified according their rs2227309 genotypes (AA + AG: 1.36 +/- 0.55, n = 19, vs GG: 2.35 +/- 0.74, n = 13; P = 0.0002). CONCLUSION: Our results support involvement of the CASP7 gene in the susceptibility to RA. The higher production of the no functional variant of CASP7 by individuals with a particular genotype could be the basis of this association.
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Artritis Reumatoide/genética , Caspasa 7/genética , Artritis Reumatoide/enzimología , Secuencia de Bases , Estudios de Casos y Controles , Caspasa 7/metabolismo , Estudios de Cohortes , Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , ARN Mensajero/genéticaRESUMEN
BACKGROUND: Asporin belongs to a family of proteins associated with the cartilage matrix. OBJECTIVE: To investigate the role of the functional polymorphism consisting of an aspartic acid (D) repeat polymorphism located in the ASPN gene in the susceptibility to and clinical outcome of rheumatoid arthritis. METHODS: A total of 803 Spanish Caucasian patients with rheumatoid arthritis and 904 controls of the same ethnic origin and matched for age and sex were included in the study. The asporin D repeat polymorphism was genotyped using polymerase chain reaction with a fluorescent primer. RESULTS: No significant differences were detected in the distribution of the 10 alleles found in our population on comparing patients with rheumatoid arthritis with control groups. Nevertheless, individuals bearing D14 produced rheumatoid factor more often than the rest (85.7% v 72.1%, p = 0.006, odds ratio (OR) = 2.35, 95% confidence interval 1.21 to 4.50), and the mean (SD) onset age was higher in the group of individuals bearing D13 (50.09 (13.94)) compared with the rest (47.21 (14.31)), although the difference did not reach significance (p = 0.06). CONCLUSION: The results do not support a major role for asporin D repeat polymorphism in the susceptibility to rheumatoid arthritis. Nevertheless, they support the influence of this gene on the outcome of the disease.
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Artritis Reumatoide/genética , Proteínas de la Matriz Extracelular/genética , Repeticiones de Minisatélite , Polimorfismo Genético , Adulto , Edad de Inicio , Artritis Reumatoide/sangre , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factor Reumatoide/análisis , España/etnología , Estados UnidosRESUMEN
Four patients of 283 liver-transplant recipients (1.4%) developed de novo immune-mediated hepatitis approximately 2 years after transplantation. Antibodies showing an unusual liver/kidney cytoplasmic staining pattern were detected in the sera of all four patients and one of them was used to screen a human liver cDNA expression library with the aim of identifying the antigenic target of these newly developed antibodies. After cloning and sequencing the gene, it was identified as the gene encoding the glutathion-S-transferase T1 (GSTT1), a 29-kD molecular weight protein, expressed abundantly in liver and kidney. Sera from the other three patients also contained anti-GSTT1 antibodies, two of them demonstrated by immunoblot analysis against the recombinant antigen and the other, which was negative by immunoblot, gave a positive reaction when used directly to screen the same library, suggesting it to be directed to a conformational epitope. The GSTT1 enzyme is the product of a single polymorphic gene that is absent from 20% of the Caucasian population. When we analysed the GSTT1 genotype of the four patients described above, we found that this gene is absent from all of them. Three donor paraffin embedded DNA samples were available and were shown to be positive for GSSTT1 genotype. In accordance with these results, we suggest that this form of post-transplant de novo immune hepatitis, that has been reported as autoimmune hepatitis by others, could be the result of an antigraft reaction in individuals lacking the GSTT1 phenotype, in which the immune system recognizes the GSTT1 protein as a non-self antigen, being the graft dysfunction not the result of an autoimmune reaction, but the consequence of an alo-reactive immune response.
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Glutatión Transferasa/inmunología , Hepatitis/etiología , Isoanticuerpos/biosíntesis , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/inmunología , Secuencia de Bases , ADN Complementario/genética , Técnica del Anticuerpo Fluorescente Indirecta , Genotipo , Glutatión Transferasa/genética , Hepatitis/enzimología , Hepatitis/genética , Hepatitis/inmunología , Humanos , Isoantígenos/genética , Hígado/enzimología , Hígado/inmunología , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Donantes de TejidosRESUMEN
We studied a 57-year-old female patient with clinical and biochemical evidences of McArdle's disease. Her muscle biopsy also revealed signs of mitochondrial proliferation, scattered RRF, and a deficit in complex I of the respiratory chain. Molecular genetic analysis showed that the patient was heterozygous for the most common mutation at codon 49 in the myophosphorylase gene. Mitochondrial DNA analysis of muscle tissue revealed an additional G-to-A transition at nucleotide position 7444 in the cytochrome c oxidase subunit I (COI) gene.
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ADN Mitocondrial/genética , Complejo IV de Transporte de Electrones/genética , Glucógeno Fosforilasa de Forma Muscular/genética , Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Mitocondrias Musculares/genética , NADH NADPH Oxidorreductasas/genética , Mutación Puntual/genética , Codón/genética , Análisis Mutacional de ADN , Complejo I de Transporte de Electrón , Metabolismo Energético/genética , Exones/genética , Femenino , Glucógeno/genética , Glucógeno/metabolismo , Glucógeno Fosforilasa de Forma Muscular/deficiencia , Enfermedad del Almacenamiento de Glucógeno Tipo V/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo V/fisiopatología , Humanos , Persona de Mediana Edad , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/patología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , NADH NADPH Oxidorreductasas/deficienciaRESUMEN
The presence of certain vitamin D receptor (VDR) genotypes has been associated with low bone mineral density (BMD) in elderly populations as well as with accelerated bone loss in patients with rheumatoid arthritis (RA). In the present study, VDR genotypes from 120 Spanish patients with RA were investigated. Three VDR gene polymorphisms (BsmI, ApaI and TaqI) were investigated using polymerase chain reaction followed by enzymatic digestion. The distributions of VDR allelic frequencies were similar in patients and controls and therefore no influence of VDR polymorphisms on rheumatoid arthritis susceptibility could be demonstrated. However, in an analysis of the clinical features of the different VDR-related genetic subgroups, the BB/tt genotype, defined by the BsmI and TaqI restriction site polymorphisms, was identified to be weakly associated with an early onset RA in female patients. This VDR genotype has been associated with a low BMD level in various studies. When patients were stratified according to the presence of the shared HLA epitope SE, it was found that SE + female patients bearing the BB/tt genotype showed the earliest disease onset. The mechanisms by which the VDR polymorphism is associated with RA is unknown, but they could be related to the immunoregulatory properties of vitamin D.