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1.
PLoS One ; 14(2): e0213073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818333

RESUMO

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.

2.
PLoS One ; 13(5): e0196793, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29734345

RESUMO

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Marcadores Genéticos/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
3.
Sci Rep ; 8(1): 8195, 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844438

RESUMO

A rare variant (BAFF-var) of the tumor necrosis factor superfamily 13b (TNFSF13B) gene has been recently associated with multiple sclerosis (MS) and systemic lupus erythematosus (SLE). The aim of this study was to investigate the association between TNFSF13B BAFF-var and susceptibility to rheumatoid arthritis (RA) and replicate that association in SLE. 6,218 RA patients, 2,575 SLE patients and 4,403 healthy controls from three different countries were included in the study. TNFSF13B BAFF-var was genotyped using TaqMan allelic discrimination assay. PLINK software was used for statistical analyses. TNFSF13B BAFF-var was significantly associated with RA (p = 0.015, OR = 1.21, 95% CI = 1.03-1.41) in the Spanish cohort. A trend of association was observed in the Dutch (p = 0.115) and German (p = 0.228) RA cohorts. A meta-analysis of the three RA cohorts included in this study revealed a statistically significant association (p = 0.002, OR = 1.24, 95% CI = 1.10-1.38). In addition, TNFSF13B BAFF-var was significantly associated with SLE in the Spanish (p = 0.001, OR = 1.41, 95% CI = 1.14-1.74) and the German cohorts (p = 0.030, OR = 1.86, 95% CI = 1.05-3.28), with a statistically significant p-value obtained in the meta-analysis (p = 0.0002, OR = 1.46, 95% CI = 1.09-2.32). The results obtained confirm the known association of TNFSF13B BAFF-var with SLE and, for the first time, demonstrate that this variant contributes to susceptibility to RA.

4.
Med. clín (Ed. impr.) ; 147(2): 56-62, jul. 2016. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-154368

RESUMO

Fundamento y objetivo: Evaluar el efecto de los tratamientos anti-TNF sobre la densidad mineral ósea (DMO), los marcadores de remodelado óseo (MRO) y la ratio receptor activator for nuclear factor κB ligand (RANKL, «ligando del receptor activador del factor nuclear κB»)/osteoprotegerina (OPG) en los pacientes con enfermedades inflamatorias articulares crónicas. Métodos: Estudio longitudinal prospectivo en condiciones de práctica clínica sobre 31 pacientes diagnosticados de artritis reumatoide, artropatía psoriásica y espondilitis anquilosante que estuvieron durante un año en tratamiento con fármacos anti-TNF alfa. Al inicio y al final del estudio se evaluaron la DMO, la OPG y la forma soluble de RANKL (sRANKL), y durante el estudio (0, 3, 6, 9 y 12 meses), la actividad de la enfermedad (SDAI, BASDAI y PCR), la capacidad funcional (HAQ, BASFI), los MRO y la vitamina D. Resultados: La DMO no se modificó después de un año de tratamiento. Los pacientes que consumieron corticoides tuvieron una pérdida media de masa ósea del 3% en el raquis lumbar (± 1,6, p = 0,02). En cuanto a los MRO, no experimentaron cambios significativos a lo largo del estudio. Disminuyó la actividad de la enfermedad, tanto SDAI (p = 0,002) como BASDAI (p = 0,002). La OPG se mantuvo sin cambios durante el año de tratamiento, mientras que disminuyeron significativamente tanto el sRANKL (0,28 ± 0,22, p = 0,013) como la ratio sRANKL/OPG (0,04 ± 0,03, p = 0,031). Conclusión: Los pacientes en tratamiento con anti-TNF no presentaron una pérdida de DMO significativa durante el seguimiento (un año), a la vez que experimentaron una mejora de la actividad de la enfermedad. Estos resultados han sido más evidentes en los pacientes respondedores (AU)


Background and objective: To evaluate the effect of anti-TNF treatments on bone mineral density (BMD), bone remodelling markers (BRM) and receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) in patients with chronic inflammatory joint diseases. Methods: A longitudinal prospective study was performed under clinical practice conditions on 31 patients diagnosed of rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis who had received treatment with anti-TNF alpha drugs for one year. BMD, OPG and RANKL soluble form (sRANKL) were studied at the onset and end of the study. During the study (0, 3, 6, 9 and 12 month), disease activity (SDAI, BASDAI and CRP), functional capacity (HAQ, BASFI), BRM and vitamin D were studied. Results: BMD was not modified after one year of treatment. The patients who took corticosteroids had a mean bone mass loss of 3% in the lumbar spine (± 1.6, P = .02). In regards to the BRM, did not experience significant changes over the course of the study. Disease activity, both SDAI (P = .002) and BASDAI (P = .002), decreased. OPG was maintained without changes during the year of treatment while both the sRANKL (0.28 ± 0.22, P = .013) and sRANKL/OPG ratio significantly decreased (0.04 ± 0.03,P = .031). Conclusion: The patients being treated with anti-TNF did not present with a significant loss of DMO during the study (one year), at the same time experiencing an improvement in disease activity. This protection has been clearer in the responding patients (AU)


Assuntos
Humanos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Inflamação/fisiopatologia , Artrite/tratamento farmacológico , Densidade Óssea , Osteoprotegerina , Mediadores da Inflamação/análise , Ligante RANK , Remodelação Óssea
5.
Med Clin (Barc) ; 147(2): 56-62, 2016 Jul 15.
Artigo em Espanhol | MEDLINE | ID: mdl-27209224

RESUMO

BACKGROUND AND OBJECTIVE: To evaluate the effect of anti-TNF treatments on bone mineral density (BMD), bone remodelling markers (BRM) and receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) in patients with chronic inflammatory joint diseases. METHODS: A longitudinal prospective study was performed under clinical practice conditions on 31 patients diagnosed of rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis who had received treatment with anti-TNF alpha drugs for one year. BMD, OPG and RANKL soluble form (sRANKL) were studied at the onset and end of the study. During the study (0, 3, 6, 9 and 12 month), disease activity (SDAI, BASDAI and CRP), functional capacity (HAQ, BASFI), BRM and vitamin D were studied. RESULTS: BMD was not modified after one year of treatment. The patients who took corticosteroids had a mean bone mass loss of 3% in the lumbar spine (±1.6, P=.02). In regards to the BRM, did not experience significant changes over the course of the study. Disease activity, both SDAI (P=.002) and BASDAI (P=.002), decreased. OPG was maintained without changes during the year of treatment while both the sRANKL (0.28±0.22, P=.013) and sRANKL/OPG ratio significantly decreased (0.04±0.03, P=.031). CONCLUSION: The patients being treated with anti-TNF did not present with a significant loss of DMO during the study (one year), at the same time experiencing an improvement in disease activity. This protection has been clearer in the responding patients.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/farmacologia , Adalimumab/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Artrite Psoriásica/metabolismo , Artrite Reumatoide/metabolismo , Biomarcadores/metabolismo , Doença Crônica , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Feminino , Humanos , Infliximab/farmacologia , Infliximab/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Osteoprotegerina/metabolismo , Estudos Prospectivos , Ligante RANK/metabolismo , Espondilite Anquilosante/metabolismo , Resultado do Tratamento
6.
Mod Rheumatol ; : 1-6, 2015 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-26418571

RESUMO

OBJECTIVE: To assess effectiveness and safety of certolizumab PEGol (CZP) in rheumatoid arthritis (RA) patients after 12 months of treatment and to detect predictors of response. METHODS: Observational longitudinal prospective study of RA patients from 35 sites in Spain. Variables (baseline, 3- and 12-month assessment): sociodemographics, previous Disease Modifying Anti-Rheumatic Drug (DMARD) and previous Biological Therapies (BT) use; TJC, SJC, ESR, CRP, DAS28, SDAI. Response variables: TJC, SJC, CRP, ESR, and steroids dose reductions, EULAR Moderate/Good Response, SDAI response and remission, DAS28 remission. Safety variables: discontinuation due to side-effects. Descriptive, comparative and Logistic regression analyses were performed. RESULTS: We included 168 patients: 79.2% women, mean age 54.5 years (±13.2 SD), mean disease duration 7.5 years (±7.3 SD). Mean number of prior DMARD: 1.4 (±1.2 SD), mean number of prior BT was 0.8 (±1.1). Mean time on CZP was 9.8 months (±3.4 SD). A total of 71.4% were receiving CZP at 12-month assessment. Baseline predictors of response: lower prior number DMARD; low number prior BT; higher CRP, ESR, TJC, SJC, DAS28 and SDAI (p < 0.05) scores. A 25/46.4% Moderate/Good Response, a 20% SDAI remission, and a 44% DAS28 remission were observed. We observed 48 discontinuations (28.6%), 31 due to partial or complete ineffectiveness, and 17 due to side-effects. CONCLUSIONS: CZP showed benefit in severe RA patients, with significant reduction of all effectiveness parameters, despite the high prevalence of previous BT exposure in our series. We found CRP, ESR, prior DMARD/BT number, TJC, SJC, DAS28, and SDAI as baseline predictors of response. CZP was mostly well tolerated.

7.
Arthritis Res Ther ; 17: 63, 2015 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-25885039

RESUMO

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA.


Assuntos
Adalimumab/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Imunoglobulina G/genética , Infliximab/genética , Adalimumab/uso terapêutico , Adulto , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Sequência de Bases , Feminino , Genótipo , Humanos , Alótipos de Imunoglobulina , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
8.
Arthritis Res Ther ; 16(2): R66, 2014 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-24612463

RESUMO

INTRODUCTION: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. METHODS: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. RESULTS: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. CONCLUSION: Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
9.
Pharmacogenet Genomics ; 24(1): 1-5, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24253594

RESUMO

BACKGROUND: The IL-6 -174G/C genetic variant has recently been associated with the clinical response to etanercept therapy in rheumatoid arthritis (RA) patients. Considering previous results, the aim of our study was to validate the role of this polymorphism as a predictor of the antitumor necrosis factor (anti-TNF) treatment outcome in RA. MATERIALS AND METHODS: Our study population was composed of 199 Spanish patients with RA receiving anti-TNF therapy. The IL-6 -174G/C (rs1800795) genetic variant was genotyped using the TaqMan allelic discrimination technology. Patients were classified, according to the European League Against Rheumatism (EULAR) criteria, as responders (good and moderate response) and nonresponders at 6, 12, 18, and 24 months after the first infusion. RESULTS: The -174*G allele was significantly associated with a good or moderate EULAR response at 12 [P=0.015, odds ratio (OR)=2.93, 95% confidence interval (CI) 1.29-6.70], 18 (P=4.54E-03, OR=5.17, 95% CI 1.80-14.85), and 24 months (P=4.54E-03, OR=14.86, 95% CI 2.91-75.91). A meta-analysis combining these data with the results from a previous study confirmed this association (P=1.89E-02, OR=1.80, 95% CI 1.13-2.87, at 12 months). CONCLUSION: Our results support the role of the -174G/C IL-6 polymorphism as a genetic marker of responsiveness to anti-TNF therapy.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Interleucina-6/genética , Regiões Promotoras Genéticas , Receptores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/administração & dosagem , Artrite Reumatoide/genética , Citosina , Etanercepte , Feminino , Marcadores Genéticos , Genótipo , Guanina , Humanos , Imunoglobulina G/administração & dosagem , Infliximab , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores do Fator de Necrose Tumoral/administração & dosagem , Reprodutibilidade dos Testes , Resultado do Tratamento
10.
Arthritis Res Ther ; 14(6): R273, 2012 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-23270786

RESUMO

INTRODUCTION: Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. METHODS: The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. RESULTS: Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. CONCLUSIONS: Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.


Assuntos
Predisposição Genética para Doença/genética , Hipertensão Pulmonar/genética , Canal de Potássio Kv1.5/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/etnologia , Itália , Desequilíbrio de Ligação , Países Baixos , Razão de Chances , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/etnologia , Espanha , Suécia , Reino Unido
11.
J Rheumatol ; 39(12): 2294-302, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23027890

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan(®) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.


Assuntos
Predisposição Genética para Doença , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Progressão da Doença , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Escleroderma Sistêmico/etnologia
12.
Arthritis Res Ther ; 14(3): R154, 2012 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-22731751

RESUMO

INTRODUCTION: The aim of the present study was to investigate the possible role of CD40 and CD40 ligand (CD40LG) genes in the susceptibility and phenotype expression of systemic sclerosis (SSc). METHODS: In total, 2,670 SSc patients and 3,245 healthy individuals from four European populations (Spain, Germany, The Netherlands, and Italy) were included in the study. Five single-nucleotide polymorphisms (SNPs) of CD40 (rs1883832, rs4810485, rs1535045) and CD40LG (rs3092952, rs3092920) were genotyped by using a predesigned TaqMan allele-discrimination assay technology. Meta-analysis was assessed to determine whether an association exists between the genetic variants and SSc or its main clinical subtypes. RESULTS: No evidence of association between CD40 and CD40LG genes variants and susceptibility to SSc was observed. Similarly, no significant statistical differences were observed when SSc patients were stratified by the clinical subtypes, the serologic features, and pulmonary fibrosis. CONCLUSIONS: Our results do not suggest an important role of CD40 and CD40LG gene polymorphisms in the susceptibility to or clinical expression of SSc.


Assuntos
Antígenos CD40/genética , Ligante de CD40/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Genótipo , Humanos
14.
Ann Rheum Dis ; 70(4): 638-41, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21187296

RESUMO

OBJECTIVES: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. METHODS: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. RESULTS: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). CONCLUSIONS: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.


Assuntos
Ligante OX40/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Regiões Promotoras Genéticas/genética
15.
BMC Med Genet ; 7: 48, 2006 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-16719905

RESUMO

BACKGROUND: Several lines of evidence suggest that chemokines and cytokines play an important role in the inflammatory development and progression of systemic lupus erythematosus. The aim of this study was to evaluate the relevance of functional genetic variations of RANTES, IL-8, IL-1alpha, and MCP-1 for systemic lupus erythematosus. METHODS: The study was conducted on 500 SLE patients and 481 ethnically matched healthy controls. Genotyping of polymorphisms in the RANTES, IL-8, IL-1alpha, and MCP-1 genes were performed using a real-time polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. RESULTS: No significant differences between SLE patients and healthy controls were observed when comparing genotype, allele or haplotype frequencies of the RANTES, IL-8, IL-1alpha, and MCP-1 polymorphisms. In addition, no evidence for association with clinical sub-features of SLE was found. CONCLUSION: These results suggest that the tested functional variation of RANTES, IL-8, IL-1alpha, and MCP-1 genes do not confer a relevant role in the susceptibility or severity of SLE in the Spanish population.


Assuntos
Quimiocinas/genética , Interleucinas/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Adulto , Quimiocina CCL2/genética , Quimiocina CCL5/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Inflamação/genética , Interleucina-1/genética , Interleucina-8/genética , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino
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