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1.
J Neurointerv Surg ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653753

RESUMO

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.

2.
Sci Rep ; 9(1): 2777, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808881

RESUMO

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.

3.
United European Gastroenterol J ; 6(3): 349-357, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29774148

RESUMO

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.

4.
Sci Rep ; 7(1): 8453, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28814775

RESUMO

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.

5.
PLoS One ; 11(8): e0161305, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27548383

RESUMO

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.


Assuntos
Síndrome de Behçet/genética , Contactinas/genética , Predisposição Genética para Doença , Antígeno HLA-B51/genética , Subunidade p35 da Interleucina-12/genética , Receptores de Interleucina/genética , Alelos , Síndrome de Behçet/imunologia , Síndrome de Behçet/patologia , Estudos de Casos e Controles , Contactinas/imunologia , Frequência do Gene , Loci Gênicos , Antígeno HLA-A3/genética , Antígeno HLA-A3/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígeno HLA-B51/imunologia , Humanos , Imunoensaio , Subunidade p35 da Interleucina-12/imunologia , Modelos Logísticos , Análise em Microsséries , Modelos Moleculares , Receptores de Interleucina/imunologia , Espanha
6.
Clin Exp Rheumatol ; 34(6 Suppl 102): S41-S45, 2016 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27050764

RESUMO

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.


Assuntos
Síndrome de Behçet/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/enzimologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Razão de Chances , Fenótipo , Regiões Promotoras Genéticas , Fatores de Risco , Espanha
7.
Clin Exp Rheumatol ; 33(6 Suppl 94): S117-22, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26486764

RESUMO

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.


Assuntos
Síndrome de Behçet/genética , Doença de Crohn/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Receptor 8 Toll-Like/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/imunologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Simulação por Computador , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores Sexuais , Espanha , Receptor 8 Toll-Like/imunologia , Adulto Jovem
8.
Clin Exp Rheumatol ; 33(6 Suppl 94): S96-100, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26393284

RESUMO

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.


Assuntos
Síndrome de Behçet/genética , Receptores CCR5/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Espanha
9.
Clin Exp Rheumatol ; 33(6 Suppl 94): S36-9, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26005883

RESUMO

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.


Assuntos
Síndrome de Behçet/genética , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Janus Quinase 1/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/enzimologia , Síndrome de Behçet/etnologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Espanha/epidemiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
10.
J Rheumatol ; 42(4): 695-701, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25641891

RESUMO

OBJECTIVE: Behçet disease (BD) is a multifactorial disease in which infectious agents have been proposed as triggers in genetically predisposed individuals. The aim of our study was to investigate the role of innate immunity receptors, specifically the nucleic acid sensors, in susceptibility to BD. METHODS: Seventy-four tag single nucleotide polymorphisms (tSNP) selected in 9 candidate genes (DDX58, IFIH1, TLR3, TLR7, TLR8, AIM2, IFI16, ZBP1, and TLR9) were genotyped in 371 patients and 854 controls. Assays of mRNA expression and allele-specific transcript quantification (ASTQ) were performed in 110 and 50 controls, respectively. RESULTS: Patients and controls were genotyped and 2 tSNP (rs6940 in IFI16 and rs855873 in AIM2) were associated with BD. To confirm this association, these tSNP were genotyped in 850 additional controls, and the total cohort was randomly divided into 2 cohorts. The association of these 2 tSNP with the disease remained in both cohorts. One haplotype (rs6940T-rs855873G) was identified as a risk factor (OR 1.41, 95% CI 1.06-1.86, p = 0.015), and another (rs6940A-rs855873A) as a protective factor (OR 0.65, 95% CI 0.47-0.90, p = 0.009). Samples with the risk haplotype had lower IFI16 expression levels than samples with the protective (0.99 ± 0.29 vs 1.23 ± 0.50, p = 0.022). Consistently, in the ASTQ assays performed with the nonsynonymous rs6940 SNP, the risk allele had lower IFI16 expression levels than the protective (p = 0.027). CONCLUSION: Our findings suggest association of IFI16, a cytosolic sensor of dsDNA and mediator of the AIM2 inflammasome-dependent pathway, in susceptibility to BD. Differences genetically determined in the levels of this molecule could be the cause of this association.


Assuntos
Síndrome de Behçet/genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Adulto , Alelos , Feminino , Genótipo , Haplótipos , Humanos , Inflamassomos/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
PLoS One ; 9(7): e102100, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25019531

RESUMO

Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population.


Assuntos
Aminopeptidases/metabolismo , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Epistasia Genética/genética , Antígenos HLA-B/metabolismo , Adulto , Aminopeptidases/genética , Feminino , Frequência do Gene , Antígenos HLA-B/genética , Haplótipos/genética , Humanos , Modelos Logísticos , Masculino , Antígenos de Histocompatibilidade Menor , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Espanha/epidemiologia
14.
Arthritis Res Ther ; 15(5): R145, 2013 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-24286189

RESUMO

INTRODUCTION: According to genome wide association (GWA) studies as well as candidate gene approaches, Behçet's disease (BD) is associated with human leukocyte antigen (HLA)-A and HLA-B gene regions. The HLA-B51 has been consistently associated with the disease, but the role of other HLA class I molecules remains controversial. Recently, variants in non-HLA genes have also been associated with BD. The aims of this study were to further investigate the influence of the HLA region in BD and to explore the relationship with non-HLA genes recently described to be associated in other populations. METHODS: This study included 304 BD patients and 313 ethnically matched controls. HLA-A and HLA-B low resolution typing was carried out by PCR-SSOP Luminex. Eleven tag single nucleotide polymorphisms (SNPs) located outside of the HLA-region, previously described associated with the disease in GWA studies and having a minor allele frequency in Caucasians greater than 0.15 were genotyped using TaqMan assays. Phenotypic and genotypic frequencies were estimated by direct counting and distributions were compared using the χ(2) test. RESULTS: In addition to HLA-B*51, HLA-B*57 was found as a risk factor in BD, whereas, B*35 was found to be protective. Other HLA-A and B specificities were suggestive of association with the disease as risk (A*02 and A*24) or protective factors (A*03 and B*58). Regarding the non-HLA genes, the three SNPs located in IL23R and one of the SNPs in IL10 were found to be significantly associated with susceptibility to BD in our population. CONCLUSION: Different HLA specificities are associated with Behçet's disease in addition to B*51. Other non-HLA genes, such as IL23R and IL-10, play a role in the susceptibility to the disease.


Assuntos
Síndrome de Behçet/genética , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Adulto , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Genótipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígeno HLA-B35/genética , Antígeno HLA-B51/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Espanha
15.
Arthritis Res Ther ; 15(1): R11, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23320549

RESUMO

INTRODUCTION: AIRE is a transcriptional regulator playing a functional role in thymocyte education and negative selection by controlling the expression of peripheral antigens in the thymus. Recently, the AIRE gene was identified as a genetic risk factor for rheumatoid arthritis (RA) in genome wide association (GWA) studies performed in the Japanese population. According to the available data this association is restricted to the Asian population. However, different facts could influence the lack of association in Caucasian populations. The aim of this study was to further investigate the possible role of the AIRE gene in susceptibility to RA in a Caucasian population. METHODS: A total of 472 Spanish Caucasian RA patients and 475 ethnically matched controls were included in the study. Three single-nucleotide polymorphisms (SNPs) (rs2776377, rs878081 and rs1055311) with a minor allele frequency>0.05 in the Caucasian population which were not included in the high-throughput platforms used in the GWA studies performed in susceptibility to RA, and two SNPs (rs2075876 and rs1800520) associated with RA in the Japanese population, were selected and genotyped using TaqMan assays. RESULTS: No significant differences in the distribution of the alleles of rs2776377, rs2075876, rs1055311 and rs1800520 SNPs between RA patients and controls were observed. Nevertheless, the frequency of the C allele of rs878081 was significantly higher among RA patients (80.5% vs. 74.6% in the control group, pc=0.012, OR=1.41, 95%CI 1.13-1.75). Regarding the distribution of the rs878081 genotypes, a higher frequency of CC homozygous individuals was found in the RA patient group (65.56% vs. 56.47% in the control group, pc=0.013, OR=1.47, 95%CI 1.12-1.93). The in silico analysis predicted lower affinity to the binding-site of a motif of the transcription NF-κB family and lower transcription levels of AIRE gene for the rs878081C risk variant CONCLUSIONS: Our findings suggest that the AIRE gene is associated with susceptibility to RA in the Spanish population. Probably, this association has not been detected in the European population in the GWA studies because the earliest high-throughput platforms did not include SNP suitable markers (e.g. rs878081).


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
16.
J Med Virol ; 84(11): 1727-36, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22997075

RESUMO

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.


Assuntos
Hepatite C/imunologia , Linfócitos/química , Monócitos/química , Receptores de LDL/análise , Receptores Virais/análise , Receptores Depuradores Classe B/análise , Tetraspanina 28/análise , Adulto , Idoso , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real
17.
Clin Vaccine Immunol ; 19(2): 223-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22190394

RESUMO

The hepatitis A virus cellular receptor 1 (HAVCR1) gene is highly polymorphic, and several variants have been associated with susceptibility to allergic and autoimmune diseases. The HAVCR1 gene region was identified as a candidate for hepatitis C virus (HCV) natural clearance in a genotyping study of selected immune response genes in both European-American and African-American populations. The aim of the present study was to explore the influence of HAVCR1 in the outcome of HCV infection in the Spanish population. Three cohorts, consisting of 354 subjects with persistent HCV infection (285 with persistent HCV monoinfection and 69 with natural clearance), 182 coinfected HIV/HCV patients, and 320 controls, were included. Samples were genotyped in several polymorphic positions, insertion/deletion variants in exon 4 and tag single nucleotide polymorphisms (SNPs), in order to define previously described HAVCR1 haplotypes (haplotypes A to D). No statistically significant differences were observed with spontaneous resolution of infection or with viral clearance after treatment. Nevertheless, different rates of infection by viral genotypes (G's) were observed among the HAVCR1 haplotypes. Individuals bearing haplotype C had the highest viral G1 infection rate when compared to individuals bearing other haplotypes (75.82% versus 57.72%, respectively; corrected P value [P(c)], 3.2 × 10(-4); odds ratio [OR], 2.30; 95% confidence interval [CI], 1.51 to 3.47). Thus, HAVCR1 could be involved in susceptibility or resistance to infection by a particular HCV genotype.


Assuntos
Haplótipos , Hepacivirus/genética , Hepatite C/genética , Glicoproteínas de Membrana/genética , Receptores Virais/genética , Feminino , Genótipo , Hepacivirus/classificação , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Espanha
18.
Hum Genet ; 128(2): 221-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20549518

RESUMO

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.


Assuntos
Haplótipos , RNA Mensageiro/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Doenças Autoimunes/complicações , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Fenômenos Bioquímicos , Suscetibilidade a Doenças/complicações , Suscetibilidade a Doenças/imunologia , Éxons , Genótipo , Humanos , Testes Imunológicos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fenômenos Fisiológicos , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/imunologia
19.
Hepatology ; 52(1): 33-7, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20578254

RESUMO

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.


Assuntos
Hepacivirus/genética , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Interleucinas/genética , Estudos de Coortes , Feminino , Loci Gênicos , Variação Genética , Genótipo , Humanos , Masculino , Espanha
20.
Reumatol. clín. (Barc.) ; 4(4): 136-139, jul.-ago. 2008. tab
Artigo em Inglês | IBECS | ID: ibc-78044

RESUMO

Objective: To establish the influence of cytokines on anxious-depressive manifestations in fibromyalgia (FM) patients. Material and method: The study comprised 56 women (50.5 ± 7.8 years) with FM and 32 healthy female controls (39.65 ± 9.24 years). Psychiatric symptoms were analyzed using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS), while pain was assessed by means of a Visual Analog Scale (VAS). Proinflammatory cytokines IL-6, IL-8, IL-10, and TNFwere assayed in serum using the Luminex-xMAP method. The statistical analysis was carried out using the SSPS statistical package. Results: IL-8 values were significantly lower (p = .013) in patients than in controls. No differences were observed among IL-6, IL-10, and TNFlevels. When comparing cytokine levels with patient age, we observed a significant reduction in IL-6, IL-8, and TNFin older patients. The values of these cytokines showed no relationship to the anxious-depressive symptoms. Conclusions: In our series no differences in serum cytokines were seen between patients with FM and controls, with the exception of a reduction in IL-8 among patients with FM, and which could be attributed to the older age of these patients (AU)


Objetivo: Determinar la influencia de las citocinas en las manifestaciones ansioso-depresivas de pacientes con fibromialgia. Material y método: En el estudio se incluyó a 56 mujeres con fibromialgia (50,5 ± 7,8 años) y 32 mujeres sanas como controles (39,65 ± 9,24 años). Los síntomas psiquiátricos fueron analizados con la Hamilton Depression Rating Scale (HDRS) y la Hamilton Anxiety Rating Scale (HARS), mientras que el dolor fue valorado por medio de una escala visual analógica. Las concentraciones de citocinas proinflamatorias de interleucina (IL)-6, IL-8, IL-10 y factor de necrosis tumoral alfa (TNF) se midieron en suero mediante Luminex-xMAP. El análisis estadístico se realizó con el programa estadístico SSPS. Resultados: Las concentraciones de IL-8 fueron estadísticamente más bajas en pacientes que en controles (p = 0,013). No se observaron diferencias con respecto a las concentraciones de IL-6, IL-10 y TNF. Al comparar los valores de citocinas con la edad de los pacientes, se observó una reducción significativa de IL-6, IL-8 y TNFen los pacientes de mayor edad. No se observó relación entre los valores de estas citocinas y los síntomas ansioso-depresivos. Conclusiones: En nuestra serie no hay diferencias en las concentraciones séricas de citocinas entre pacientes con fibromialgia y controles, con la excepción de una reducción de IL-8 en los pacientes con fibromialgia que podría ser debida a la mayor edad de los pacientes con respecto a los controles (AU)


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Fibromialgia/tratamento farmacológico , Ansiedade/fisiopatologia , Depressão/fisiopatologia , Estudos de Casos e Controles , Citocinas , Distribuição por Idade
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