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1.
Clin Exp Rheumatol ; 40(8): 1510-1516, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35383566

RESUMEN

OBJECTIVES: To characterise what immunogenetic alterations are present in a Spanish family having several members with a familial cold-induced autoinflammatory syndrome (FCAS), a kind of autoinflammatory disease (AID). METHODS: We present the case of two sisters (cases 1 and 2) with a similar clinical picture since their childhood. The symptoms start after exposure to cold and consist of recurrent fever, papules or urticaria, and oedema in hands and fingers. The mother had similar symptomatology as her daughters, which remitted after her first pregnancy, whereas the father is healthy. Patients and their parents were genotyped in a panel of 14 candidate genes using Next-Generation Sequencing (NGS). Real-time PCR was used to quantify IL1ß mRNA levels from LPS-stimulated monocytes. ELISA was used to measure the IL1ß and IL18 concentrations in supernatants and sCD25 levels in sera. IL1ß, IL4, IL6, IL8, IL10, IL17A, IL18 and TNF-α serum levels were assessed using xMAP® Technology. RESULTS: All the genetic variants found in this family are benign with two exceptions: NLRC4 p.Leu339Pro (present in both cases and their mother) and PSTPIP1 p.Gln219His (present in Case 1 and her father). The monocytes stimulated of the individuals with the NLRC4 variant produce higher levels of IL1ß (protein and mRNA). Levels of TNF-α, IL4, and IL6 were higher in Case 1 than in the age-matched controls. CONCLUSIONS: The familial segregation and the clinical picture compatible with FCAS suggest that NLRC4 p.Leu339Pro causes the AIDs syndrome diagnosed in several family members.


Asunto(s)
Síndromes Periódicos Asociados a Criopirina , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Portadoras/genética , Niño , Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/genética , Femenino , Humanos , Interleucina-18 , Interleucina-4 , Interleucina-6 , Proteína con Dominio Pirina 3 de la Familia NLR/genética , ARN Mensajero/genética , Factor de Necrosis Tumoral alfa
2.
Clin Exp Rheumatol ; 34(6 Suppl 102): S41-S45, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27050764

RESUMEN

OBJECTIVES: The functional variant R620W of the protein tyrosine phosphatase non receptor-22 (PTPN22) gene plays an important role in susceptibility to several immuno-mediated pathologies. Behçet's disease (BD) is a complex disease related to the immune system with a demonstrated genetic base. The HLA class I genes are the most important genetic factors in BD although other genes are also involved in the susceptibility to this disease. The PTPN22 has been proposed as a candidate gene in BD but this association has not been clearly demonstrated yet. The aim of this study was to assess the association of PTPN22 with BD. METHODS: A cohort composed of 404 Spanish BD patients and 1517 unrelated healthy individuals ethnically matched was genotyped in rs2476601 (R620W). Five tag SNPs: rs1217412, rs2476599, rs3789607, rs3765598 and rs1217419 (spanning a 57 Kb region between 3'UTR and 5'UTR) and rs2488457 (located at the promoter region) were also studied in order to perform a screening of the complete gene. Genotyping was performed using TaqMan® assays. The rs2476601 data were included in a meta-analysis together with those published till the date. The rest of SNPs were used in a case-control study. RESULTS: No evidence of the association of rs2476601 with BD in the meta-analysis (P = 0.504 in the model of alleles) was found. In the case-control study, no statistically significant differences were observed when comparing the distribution of variants in patients and controls. CONCLUSIONS: Our results do not support a major role of the PTPN22 gene in BD.


Asunto(s)
Síndrome de Behçet/genética , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/enzimología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Masculino , Oportunidad Relativa , Fenotipo , Regiones Promotoras Genéticas , Factores de Riesgo , España
3.
Clin Exp Rheumatol ; 33(6 Suppl 94): S96-100, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26393284

RESUMEN

OBJECTIVES: Behçet's disease (BD) is an immune-mediated and complex disease associated with HLA class I and other genes. The aim of this study was to contribute to a better understanding of the relationship of the 32-bp deletion in the CCR5 gene (CCR5Δ32) and this disease by conducting a case-control study in the Spanish population and also a meta-analysis including all the studies available to date. METHODS: A cohort composed of 348 BD Spanish patients and 477 unrelated healthy and ethnically matched individuals were genotyped in CCR5Δ32 using polymerase chain reaction (PCR) and capillary electrophoresis with fluorescent detection. In the meta-analysis, data from a total of seven populations extracted from four previous studies along with data of the present study were included. RESULTS: Regarding the case-control study, no statistically significant differences were observed when the patient and control groups were compared (allelic model: 0.07 in patients vs. 0.06 in controls, p=0.303). In the meta-analysis, no evidence of association of the CCR5Δ32 polymorphism with BD was observed (pMH=0.091; OR=1.22; 95%CI 0.98 to 1.52 in the allelic model). CONCLUSIONS: The results of this meta-analysis discard a major role of the CCR5Δ32 polymorphism in BD.


Asunto(s)
Síndrome de Behçet/genética , Receptores CCR5/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Medición de Riesgo , Factores de Riesgo , España
4.
Clin Exp Rheumatol ; 33(6 Suppl 94): S117-22, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26486764

RESUMEN

OBJECTIVES: The aim of this study was to investigate the role of the TLR8, a mediator of innate inflammatory response, in susceptibility to two immune-mediated disorders characterised by dysregulation of the immune response, Crohn's and Behçet's diseases (CD and BD). METHODS: A total of 844 CD, 371 BD patients and 1385 controls were genotyped in 8 tag single nucleotide polymorphisms (tSNPs) in the locus TLR8 (chromosome X). All these tSNPs have a minor allele frequency greater than 0.05 in the Caucasian population. RESULTS: The rs2407992 and the rs5744067 were associated with susceptibility to BD and CD, respectively (OR=1.34, 95%CI=1.10-1.62, p=0.0025 and OR=0.82, 95%CI=0.68-0.99, p=0.045, respectively). Although after stratification by gender, statistically significant differences in the distribution of the aforementioned SNPs were only observed in the females groups (BD OR=1.31, 95%CI=1.06-1.64, p=0.012 and CD OR=0.84, 95%CI=0.72-0.98, p=0.044) the trend was similar among males. Since the rs5744067 and rs2407992 are located in the same linkage disequilibrium block, we performed a haplotypic analysis by combination of the tSNPs. One haplotype (H1) was identified as a protective factor in BD (OR=0.75, 95%CI=0.62-0.90, p=0.0027) and another (H2) as a protective factor in CD (OR=0.78, 95%CI=0.64-094, p=0.0102). No statistically significant differences in the mean of the levels of expression attributable to the haplotype variants were found in the in silico analysis performed. CONCLUSIONS: Our results suggest a relationship between the TLR8 and the susceptibility to CD and BD. Nevertheless, these differences could not be imputed to the levels of expression.


Asunto(s)
Síndrome de Behçet/genética , Enfermedad de Crohn/genética , Haplotipos , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 8/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/inmunología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Simulación por Computador , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/inmunología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Factores Protectores , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , España , Receptor Toll-Like 8/inmunología , Adulto Joven
5.
Clin Exp Rheumatol ; 33(6 Suppl 94): S36-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26005883

RESUMEN

OBJECTIVES: Behçet's disease (BD) is an immune-mediated and complex disease which has been associated with HLA class I molecules although other genes such as IL23R and IL10 have also been involved in the susceptibility to BD. Recently, an association of variants of the JAK1 and TNFAIP3 genes with the disease has been reported in the Chinese Han population. The aim of the present work was to asses whether the association described in Asian populations is replicated in Europeans. METHODS: This study includes a total of 1155 Spanish subjects of European origin (372 BD and 783 unrelated healthy individuals). Patients were recruited from different hospitals and controls were collected in the same geographic regions and they matched with patients in age and gender. A total of five SNPs, two in the JAK1 gene: rs2780815 and rs310241 and the other three in the TNFAIP3: rs10499194, rs9494885 and rs610604, were included in this study. The genotyping of these SNPs was performed using a real time PCR system (TaqMan® SNP Genotyping Assays). RESULTS: No statistically significant differences were found when the patient and control groups were compared. The distribution of the risk alleles was similar in patients with and without eye manifestations and in patients with and without HLA-B*51. CONCLUSIONS: The association of variants of the genes JAK1 and the TNFAIP3 with BD which has been described in the Chinese population was not replicated in Europeans.


Asunto(s)
Síndrome de Behçet/genética , Proteínas de Unión al ADN/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Janus Quinasa 1/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/enzimología , Síndrome de Behçet/etnología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Factores de Riesgo , España/epidemiología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa
6.
Front Immunol ; 14: 1080047, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37638008

RESUMEN

Introduction: The knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules. Objective: This study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD. Methods: We analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism. Discussion: Our results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.


Asunto(s)
Síndrome de Behçet , Arteritis de Células Gigantes , Granulomatosis con Poliangitis , Humanos , Síndrome de Behçet/genética , Antígenos HLA-A , Antígenos HLA-E
7.
Front Immunol ; 14: 1152498, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37122702

RESUMEN

Purpose: CAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to identify phenotypic features as early biomarkers associated with toxicity and outcomes. Experimental design: In this study, monitoring by flow cytometry and digital PCR (dPCR), and immunophenotypic characterization of circulating CAR-T cells from 48 patients treated with Tisa-cel or Axi-cel was performed. Results: Validation of the flow cytometry reagent for the detection of CAR-T cells in blood revealed CD19 protein conjugated with streptavidin as the optimal detection method. Kinetics of CAR-T cell expansion in blood confirmed median day of peak expansion at seven days post-infusion by both flow cytometry and digital PCR. Circulating CAR-T cells showed an activated, proliferative, and exhausted phenotype at the time of peak expansion. Patients with increased expansion showed more severe CRS and ICANs. Immunophenotypic characterization of CAR-T cells at the peak expansion identified the increased expression of co-inhibitory molecules PD1 and LAG3 and reduced levels of the cytotoxicity marker CD107a as predictors of a better long-term disease control. Conclusions: These data show the importance of CAR-T cells in vivo monitoring and identify the expression of PD1LAG3 and CD107a as early biomarkers of long-term disease control after CAR-T cell therapy.


Asunto(s)
Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Cinética , Linfocitos B/patología , Linfocitos T/patología , Linfoma de Células B Grandes Difuso/patología
8.
J Med Virol ; 84(11): 1727-36, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22997075

RESUMEN

CD81, the scavenger receptor-BI (SR-BI) and the low-density lipoprotein receptor (LDLR) are involved in peripheral blood mononuclear cells (PBMCs) hepatitis C virus (HCV) entry. To investigate if these molecules are altered by HCV, 20 controls and 66 patients: 37 untreated and 29 sustained virological responders, were studied. CD81 and LDLR expression, measured the percentage of cells expressing the HCV-receptors and their mean fluorescence intensity (MFI), was analyzed on lymphocytes and monocytes, as well as SR-BI on monocytes by flow cytometry. RNA was extracted from PBMCs and detection of the HCV-RNA positive and negative strands was performed by strand-specific RT-PCR. A statistically significant increase of CD81 expression was observed on lymphocytes, a higher percentage of LDLR on lymphocytes and monocytes, as well as SR-BI on monocytes was found in the patients as compared to the controls (P < 0.05 in all cases). Untreated patients showed a higher percentage of LDLR(+) lymphocytes than sustained virological responders (P = 0.025). Nineteen sustained virological responders bore the HCV-RNA positive strand in PBMCs; nine of them the negative strand too. Sustained virological responders with occult infection and viral replication, showed a higher expression of LDLR on lymphocytes (P < 0.05) and a higher LDLR MFI on monocytes (P = 0.011) than those without viral replication. In conclusion, HCV exposure modifies expression levels of the receptors studied, being LDLR related with HCV replication, not only in the classic but also in the occult infection.


Asunto(s)
Hepatitis C/inmunología , Linfocitos/química , Monocitos/química , Receptores de LDL/análisis , Receptores Virales/análisis , Receptores Depuradores de Clase B/análisis , Tetraspanina 28/análisis , Adulto , Anciano , Femenino , Citometría de Flujo , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa
9.
Sci Rep ; 12(1): 11219, 2022 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-35780200

RESUMEN

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case-control study includes a cohort (women, 18-60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, ßAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal-Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (rs = 0.67, p ≤ 0.001) and ßAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.


Asunto(s)
Factor Activador de Células B , Lupus Eritematoso Sistémico , Nefritis Lúpica , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Adolescente , Adulto , Factor Activador de Células B/genética , Factor Activador de Células B/metabolismo , Antígeno de Maduración de Linfocitos B/genética , Antígeno de Maduración de Linfocitos B/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Nefritis Lúpica/genética , Nefritis Lúpica/metabolismo , Persona de Mediana Edad , Isoformas de Proteínas , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Adulto Joven
10.
Hepatology ; 52(1): 33-7, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20578254

RESUMEN

UNLABELLED: Genetic host factors may modify the course of the hepatitis C virus (HCV) infection. Very recently, a genome-wide scan that reported association of the IL28B locus with response to treatment in HCV infection was published. The aim of the current study was to investigate the relationship of this locus with outcome of HCV infection in a cohort constituted by a total of 731 Spanish individuals. From these, 284 were subjects with persistent infection, 69 were individuals who naturally cleared the virus, and 378 were noninfected subjects. Genotyping of the rs12979860 (C>T) in the IL28B locus was performed using a TaqMan 5' allelic discrimination assay. The CC genotype was overrepresented among patients infected with viral genotypes non-1 (66.7% versus 39.1% in patients infected with viral genotype-1, P = 8.5 x 10(-5), odds ratio [OR] = 0.32, 95% confidence interval [CI] 0.17-0.60); patients with spontaneous resolution of infection (72.5% versus 45.6% of the individuals with persistent infection, P = 6.2 x 10(-5), OR = 0.32; 95%CI, 0.18-0.57); and lastly, patients with sustained response (60.2% versus 32.1% found in patients with nonsustained response, P = 3.1 x 10(-5), OR = 0.31; 95%CI, 0.17-0.56). CONCLUSION: We have found different rates of viral genotype infection depending on the IL28B variant as well as an association of this locus with natural and treatment-mediated response.


Asunto(s)
Hepacivirus/genética , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Interleucinas/genética , Estudios de Cohortes , Femenino , Sitios Genéticos , Variación Genética , Genotipo , Humanos , Interferones , Masculino , España
11.
Hum Genet ; 128(2): 221-9, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20549518

RESUMEN

Human HAVCR1 gene maps on 5q33.2, a region linked with susceptibility to allergic and autoimmune diseases. The aims of the present study were to define the haplotypes of HAVCR1 gene taking into account both HapMap Project SNP haplotypes and exon 4 variants, to investigate a possible relationship between these haplotypes and mRNA expression levels, and to assess whether HAVCR1 gene is involved in susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Genotyping of three ins/del variants in the exon 4 was performed by fragment length analysis. Five tag SNPs genotypes and mRNA levels were determined using TaqMan assays. We defined four major haplotypes in our population: the two major haplotypes (named haplotypes A and B) bear both the 5383_5397del variant and the two most common SNP sets found in the CEU population. Quantification analysis revealed that genotype B/B had the highest median of mRNA expression levels (vs. BX + XX, p < 0.0001). Additionally, frequency of the genotype BB was significantly higher in RA patients than in controls (12.3 vs. 5.9% in controls, p = 0.0046, p (c) = 0.014, OR = 2.23, 95% CI 1.23-4.10). Our results support a relationship between HAVCR1 haplotypes and mRNA expression levels, and suggest an association of this gene with autoimmune diseases.


Asunto(s)
Haplotipos , ARN Mensajero/metabolismo , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Fenómenos Bioquímicos , Susceptibilidad a Enfermedades/complicaciones , Susceptibilidad a Enfermedades/inmunología , Exones , Genotipo , Humanos , Pruebas Inmunológicas , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Fenómenos Fisiológicos , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , ARN Mensajero/inmunología
12.
J Neurointerv Surg ; 12(5): 499-504, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31653753

RESUMEN

BACKGROUND: The management of clopidogrel in hyper-responders has not been well described. We report the treatment and dose adjustment individualization with clopidogrel oral solution (COS) in hyper-responder patients with an unruptured intracranial aneurysm treated with a stent. METHODS: A prospective study (2015-2018) in patients receiving clopidogrel prior to endovascular treatment was performed. Platelet reactivity after clopidogrel therapy was evaluated with the VerifyNow PRU test. Initial values ≤80 PRU (P2Y12 reactivity units) were classified as a hyper-response according to prior evidence. Patients were treated with clopidogrel for 7-10 days before stent treatment. Seven days post-procedure the dose of COS was gradually reduced (30 mg-20 mg-10 mg-5 mg) every 5 days to 5 mg (1 mL)/day. RESULTS: Twenty patients with 24 aneurysms were classified as having a hyper-response to clopidogrel. Mean age was 55.2 years (range 42-64) and 80% were women. Mean baseline PRU value and the percentage of platelet inhibition were 16.4±11.5 PRU and 92.05±7.5%, respectively. The mean time used to decrease the dose of clopidogrel to 5 mg/day was 27±4.3 days. Modified dosing strategies were shown to increase the final PRU values and to decrease the percentage of platelet inhibition (137.42±27.4 and 41.5±14.8%, respectively). Two of the 20 patients with dose adjustment of oral solution of clopidogrel (5 mg/day) in our cohort exhibited a delayed conversion to hypo-response. No patients suffered thromboembolic events related to the dose adjustment of clopidogrel with 5 mg/day during the follow-up. CONCLUSION: Reduction of the daily maintenance dose of clopidogrel in hyper-responder patients could provide a similar antiplatelet effect to the standard dose of clopidogrel, allowing a PRU value in the optimal range.


Asunto(s)
Clopidogrel/administración & dosificación , Aneurisma Intracraneal/sangre , Aneurisma Intracraneal/terapia , Inhibidores de Agregación Plaquetaria/administración & dosificación , Stents , Adulto , Anciano , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estudios Prospectivos
14.
Front Immunol ; 10: 2755, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31849952

RESUMEN

Behçet's disease (BD) is an immune-mediated vasculitis related to imbalances between the innate and adaptive immune response. Infectious agents or environmental factors may trigger the disease in genetically predisposed individuals. HLA-B51 is the genetic factor stronger associated with the disease, although the bases of this association remain elusive. NK cells have also been implicated in the etiopathogenesis of BD. A family of NK receptors, Killer-cell Immunoglobulin-like Receptor (KIR), with a very complex organization, is very important in the education and control of the NK cells by the union to their ligands, most of them, HLA class I molecules. This study aimed to investigate the contribution of certain KIR functional polymorphisms to the susceptibility to BD. A total of 466 BD patients and 444 healthy individuals were genotyped in HLA class I (A, B, and C). The set of KIR genes and the functional variants of KIR3DL1/DS1 and KIR2DS4 were also determined. Frequency of KIR3DL1*004 was lower in patients than in controls (0.15 vs. 0.20, P = 0.005, Pc = 0.015; OR = 0.70; 95% CI 0.54-0.90) in both B51 positive and negative individuals. KIR3DL1*004, which encodes a misfolded protein, is included in a common telomeric haplotype with only one functional KIR gene, KIR3DL2. Both, KIR3DL1 and KIR3DL2 sense pathogen-associated molecular patterns but they have different capacities to eliminate them. The education of the NK cells depending on the HLA, the balance of KIR3DL1/KIR3DL2 licensed NK cells and the different capacities of these receptors to eliminate pathogens could be involved in the etiopathogenesis of BD.


Asunto(s)
Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Receptores KIR3DL1/genética , Alelos , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética/métodos , Genotipo , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Masculino , Oportunidad Relativa , Receptores KIR/genética
15.
Sci Rep ; 9(1): 2777, 2019 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-30808881

RESUMEN

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established genetic base. In a previous study, using a next generation sequencing approach, we found many rare variants and some functional polymorphisms in genes related to autoinflammatory syndromes (AID): CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A in our BD cohort. Our strategy did not allow us to establish either number of patients with variants, proportion of individuals accumulating them or relationship with other genetic factors. With the goal to answer these questions, the individual samples were sequenced. Additionally, three functional polymorphisms: NLRP3 p.Gln703Lys, NOD2 p.Arg702Trp and p.Val955Ile were genotyped using TaqMan assays. A total of 98 patients (27.6%) carried at least one rare variant and 13 of them (3.7%) accumulated two or three. Functional regression model analysis suggests epistatic interaction between B51 and MEFV (P = 0.003). A suggestive protective association of the minor allele of NOD2 p.Arg702Trp (P = 0.01) was found in both, B51 positive and negative individuals. Therefore, a high percentage of patients with BD have rare variants in AID genes. Our results suggest that the association of MEFV with BD could be modulated by the HLA molecules; whereas the protective effect of NOD2 p.Arg702Trp would be independent of HLA.


Asunto(s)
Síndrome de Behçet/patología , Epistasis Genética , Predisposición Genética a la Enfermedad , Antígenos HLA-B/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Mediadores de Inflamación/metabolismo , Polimorfismo Genético , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Síndrome de Behçet/genética , Estudios de Cohortes , Proteínas del Citoesqueleto/genética , Femenino , Genotipo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Pirina/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética
16.
United European Gastroenterol J ; 6(3): 349-357, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29774148

RESUMEN

BACKGROUND: Eosinophilic esophagitis (EoE) is an antigen-driven disease mediated by an abnormal immune Th2 response. OBJECTIVE: The objective of this article is to investigate genes associated with regulating immune responses leading to disease susceptibility. METHODS: Twenty-seven tag single nucleotide polymorphisms (tSNPs) selected in five candidate genes (TLR3, TLR4, FOXP3, FLG and TSLP) were genotyped in 218 EoE patients and 376 controls. Skin prick tests were carried out in EoE patients with a panel of 17 aeroallergens and 22 plant- and animal-derived foods. RESULTS: Five tSNPs located in the TSLP locus and one tSNP located in the TLR3 locus were significantly associated with EoE. The interactions between TLR3 and TSLP loci were analyzed. TLR3+/TSLP- and TLR3-/TSLP+ individuals showed a significantly reduced susceptibility to EoE compared to TLR3-/TSLP- individuals (OR = 0.66, p = 0.036 and OR = 0.23, p = 0.00014, respectively). Likewise, TLR3+/TSLP+ individuals showed the most decreased susceptibility of developing EoE (OR = 0.16, p = 0.0001). However, the interaction gain attributed to the combination of both genes was negative (IG = -4.52%), which indicated redundancy or independent effect. Additionally, TLR3 locus was found to be associated with aeroallergen and food sensitization in EoE patients (OR = 9.67, pc = 0.025 and OR = 0.53, pc = 0.048, respectively). CONCLUSION: TLR3 constitutes a novel genetic susceptibility locus for developing EoE, and the effects would be independent of TSLP.

17.
Sci Rep ; 7(1): 8453, 2017 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-28814775

RESUMEN

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.


Asunto(s)
Síndrome de Behçet/genética , Predisposición Genética a la Enfermedad/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Inflamasomas/genética , Mutación , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Desaminasa/genética , Proteínas del Citoesqueleto/genética , Femenino , Humanos , Inflamación/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína Adaptadora de Señalización NOD2/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pirina/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética
18.
PLoS One ; 11(8): e0161305, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27548383

RESUMEN

Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.


Asunto(s)
Síndrome de Behçet/genética , Contactinas/genética , Predisposición Genética a la Enfermedad , Antígeno HLA-B51/genética , Subunidad p35 de la Interleucina-12/genética , Receptores de Interleucina/genética , Alelos , Síndrome de Behçet/inmunología , Síndrome de Behçet/patología , Estudios de Casos y Controles , Contactinas/inmunología , Frecuencia de los Genes , Sitios Genéticos , Antígeno HLA-A3/genética , Antígeno HLA-A3/inmunología , Antígenos HLA-B/genética , Antígenos HLA-B/inmunología , Antígeno HLA-B51/inmunología , Humanos , Inmunoensayo , Subunidad p35 de la Interleucina-12/inmunología , Modelos Logísticos , Análisis por Micromatrices , Modelos Moleculares , Receptores de Interleucina/inmunología , España
19.
Haematologica ; 90(5): 707-10, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15921397

RESUMEN

The aim of this study was to analyze the mutation pattern causing hemophilia A in a population from Southern Spain. Mutation analysis identified the mutation in 99 of the 109 unrelated patients enrolled in the Hemophilia Registry from Andalusia. About 54% of non-inversion mutations identified were previously unreported.


Asunto(s)
Cromosomas Humanos X/genética , Factor VIII/genética , Hemofilia A/genética , Mutación Missense , Sustitución de Aminoácidos , Inversión Cromosómica , Islas de CpG/genética , Análisis Mutacional de ADN , Hemofilia A/epidemiología , Humanos , Intrones/genética , Masculino , Reacción en Cadena de la Polimerasa , España/epidemiología
20.
Genet Test ; 9(1): 37-40, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15857185

RESUMEN

Familial adenomatous polyposis (FAP) is a disease characterized by the presence of hundreds of adenomatous polyps in the colon and rectum which, if not treated, develop into colorectal cancer. FAP is an autosomal dominantly inherited disorder caused by mutation in the APC gene. The aim of this study was to search for germ-line mutations of the APC gene in unrelated FAP families from southern Spain. By direct sequencing of all APC gene exons, we found the mutation in 13 of 15 unrelated FAP families studied. We identified eight novel mutations: 707delA (exon6), 730_731delAG (exon7), 1787C-->G and 1946_1947insG (exon14), 2496delC, 2838_2839delAT, 2977A-->T, and 3224dupA (exon15). Two patients presented de novo germ-line mutations. Genotype-phenotype correlations for extraintestinal and extracolonic manifestations were studied. Intrafamilial phenotypic variability was observed in two families with mutations in exon/intron boundary, probably due to alternative splicing.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Genes APC , Mutación de Línea Germinal , Genotipo , Humanos , Fenotipo , España
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