Showing papers by "Tomas R. Vazquez-Rodriguez published in 2010"

Insulin resistance in rheumatoid arthritis: the impact of the anti-TNF-α therapy

Abstract: Increased prevalence of insulin resistance has been observed in patients with rheumatoid arthritis (RA). High-grade systemic inflammation is implicated in the development of insulin resistance in these patients. Tumor necrosis factor (TNF)-alpha is a potent proinflammatory cytokine that plays a role in the initiation and progression of inflammation and the mechanisms associated with accelerated atherosclerosis in RA. In assessing data immediately prior to and after intravenous infusion of the anti-TNF-alpha monoclonal antibody-infliximab in RA patients on period treatment with this drug attributable to disease refractory to conventional disease-modifying antirheumatic drugs, a dramatic improvement of insulin resistance and insulin sensitivity was observed. A long-term positive effect of TNF-alpha antagonists infliximab and etanercept on insulin resistance in RA patients with severe disease was also reported. These results highlight the importance of therapies that act blocking TNF-alpha function to reduce the mechanisms implicated in the development of the metabolic syndrome observed in RA.

A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis

Abstract: Introduction: We determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients with RA. Methods: Six hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo and Hospital San Carlos, Madrid, were studied. Patients and controls (n = 865) were genotyped using predesigned TaqMan SNP genotyping assays. Results: No significant differences in allele or genotype frequencies for the MTHFR gene polymorphisms between RA patients and controls were found. Also, no association between the MTHFR 677 C>T polymorphism and CV events or endothelial dysfunction was observed. However, the MTHFR 1298 allele C frequency was increased in patients with CV events after 5 years (38.7% versus 30.3%; odds ratio = 1.45; 95% confidence interval = 1.00 to 2.10; P = 0.04) and 10 years (42.2% versus 31.0%; odds ratio = 1.62; 95% confidence interval = 1.08 to 2.43; P = 0.01) follow up. Moreover, patients carrying the MTHFR 1298 AC and CC genotypes had a significantly decreased flow-mediated endothelium-dependent vasodilatation (4.3 ± 3.9%) compared with those carrying the MTHFR 1298 AA genotype (6.5 ± 4.4%) (P = 0.005). Conclusions: Our results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA.

Visfatin is not associated with inflammation or metabolic syndrome in patients with severe rheumatoid arthritis undergoing anti-TNF-alpha therapy.

Abstract: Background and objective Visfatin is an insulin-mimetic adipokine. In non-rheumatoid arthritis (RA) patients circulating levels of visfatin are correlated with the amount of visceral fat. Recent studies have disclosed an implication of visfatin in inflammation. Chronic systemic inflammation is of major importance in the development of atherosclerosis in RA. In the present study we investigated whether inflammation, obesity or metabolic syndrome are potential determinants of circulating visfatin concentrations in a group of RA patients on periodical treatment with the TNF-alpha blocker infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating visfatin concentrations in patients with severe RA. Methods We investigated 33 non-diabetic patients with RA on periodical treatment with infliximab. Serum visfatin levels were determined immediately prior to and after infliximab infusion. Results There was no correlation between body mass index of RA patients and baseline serum level of visfatin. Also, no significant correlations between baseline visfatin levels and the age at the time of the study or at the onset of the disease, disease duration, ESR and CRP levels, DAS28, lipids, insulin sensitivity, resistin or the cumulative prednisone dose at the time of the study were found. Visfatin levels did not change upon infliximab infusion. Conclusions In RA patients on TNF-alpha blocker treatment, circulating visfatin levels are unrelated to disease activity, adiposity or metabolic syndrome. The beneficial effect of anti-TNF-alpha therapy on cardiovascular mortality in RA does not seem to be mediated by changes in serum levels of visfatin.

Association between IL-18 gene polymorphisms and biopsy-proven giant cell arteritis

Abstract: Introduction: The objective was to investigate the potential implication of the IL18 gene promoter polymorphisms in the susceptibility to giant-cell arteritis (GCA). Methods: In total, 212 patients diagnosed with biopsy-proven GCA were included in this study. DNA from patients and matched controls was obtained from peripheral blood. Samples were genotyped for the IL18-137 G>C (rs187238), the IL18-607 C>A (rs1946518), and the IL18-1297 T>C (rs360719) gene polymorphisms with polymerase chain reaction, by using a predesigned TaqMan allele discrimination assay. Results: No significant association between the IL18-137 G>C polymorphism and GCA was found. However, the IL18 -607 allele A was significantly increased in GCA patients compared with controls (47.8% versus 40.9% in patients and controls respectively; P = 0.02; OR, 1.32; 95% CI, 1.04 to 1.69). It was due to an increased frequency of homozygosity for the IL18 -607 A/A genotype in patients with GCA (20.4%) compared with controls (13.4%) (IL18 -607 A/A versus IL18 607 A/C plus IL18 -607 C/C genotypes: P = 0.04; OR, 1.59; 95% CI, 1.02 to 2.46). Also, the IL18-1297 allele C was significantly increased in GCA patients (30.7%) compared with controls (23.0%) (P = 0.003; OR, 1.48; 95% CI, 1.13 to 1.95). In this regard, an increased susceptibility to GCA was observed in individuals carrying the IL18-1297 C/C or the IL18-1297 C/T genotypes compared with those carrying the IL18-1297 T/T genotype (IL18-1297 C/C plus IL18-1297 T/C versus IL181297 T/T genotype in GCA patients compared with controls: P = 0.005; OR, 1.61; 95% CI, 1.15 to 2.25). We also found an additive effect of the IL18 -1297 and -607 polymorphisms with TLR4 Asp299Gly polymorphism. The OR for GCA was 1.95 for combinations of genotypes with one or two risk alleles, whereas carriers of three or more risk alleles have an OR of 3.7. Conclusions: Our results show for the first time an implication of IL18 gene-promoter polymorphisms in the susceptibility to biopsy-proven GCA. In addition, an additive effect between the associated IL18 and TLR4 genetic variants was observed.

Lack of association of PTPN22, STAT4 and TRAF1/C5 gene polymorphisms with cardiovascular risk in rheumatoid arthritis.

Abstract: Objectives To determine whether the PTPN22, STAT4 and TRAF1/C5 gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction or inereased carotid intima-media thickness (IMT) in a series of Spanish patients with rheumatoid arthritis (RA) Methods Six hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo, and Hospital San Carlos, Madrid, were studied Patients were genotyped using predesigned TaqMan single nucleotide polymorphism genotyping assays Moreover, between March and December 2007, a subgroup of unselected RA patients with no history of CV events was studied for the presence of subclinical atherosclerosis by the assessment of the endothelial function (n= 126) and the carotid artery IMT (n= 110) by ultrasonography studies Results No significant differences in the allele or genotype frequencies for the PTPN22, STAT4 and TRAF1/CS gene polymorphisms between RA patients with or without CV events were found It was also the case when we analysed the potential influence of the genotypes in the presence of endothelial dysfunction or increased carotid artery IMT of patients with RA Conclusion Our results do not show that the PTPN22, STAT4 and TRAF1/CS gene polymorphisms may confer a direct risk of CV disease in patients with RA

Influence of CD40 rs1883832 polymorphism in susceptibility to and clinical manifestations of biopsy-proven giant cell arteritis.

Abstract: Objective. To assess the potential association between CD40 rs1883832 polymorphism and biopsy-proven giant cell arteritis (GCA). We also studied the influence of the polymorphism on phenotypic expression of this vasculitis, in particular the development of visual ischemic manifestations. Methods. Three hundred five Spanish patients with biopsy-proven GCA and 788 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the CD40 rs1883832 C/T polymorphism using a predesigned TaqMan allele discrimination assay and by polymerase chain reaction amplification. Results. Patients with GCA showed a trend toward a higher frequency of the minor allele homozygote of rs1883832 (TT) compared to healthy controls (12.1% vs 8.3%, respectively; p = 0.05, OR 1.54, 95% CI 0.98–2.40). Also, a marginally significant increased frequency of the minor allele T was observed in patients with GCA who had visual ischemic manifestations (36.9%) compared to those without visual ischemic manifestations (27.7%; p = 0.04, OR 1.53, 95% CI 0.99–2.34). In this regard, patients with GCA carrying the minor allele T (either TT or TC) experienced visual ischemic manifestations more commonly than those carrying the CC genotype (58.5% vs 44.2%; p = 0.04, OR 1.78, 95% CI 0.99–3.22). Conclusion. Our results suggest a potential implication of the CD40 rs1883832 C/T polymorphism in susceptibility to visual ischemic manifestations in individuals with biopsy-proven GCA.

Lack of association between macrophage migration inhibitory factor-173 gene polymorphism with disease susceptibility and cardiovascular risk in rheumatoid arthritis patients from northwestern Spain.

Abstract: Objective To assess whether the polymorphism of the macrophage migration inhibitory factor (MIF) gene at the position -173 is implicated in the disease susceptibility, risk of cardiovascular (CV) events and presence of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Patients and methods A series of 293 unselected patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo, Spain and 526 matched controls were studied for differences in the MIF-173 G/C gene biallelic polymorphism. A total of 182 consecutive patients that had been periodically followed between March 1996 and September 1996 until patient's death or January 1, 2008 were assessed for the presence of CV events. Moreover, between March and December 2007, a subgroup of unselected RA patients with no history of CV events was studied for the presence of subclinical atherosclerosis by the assessment of the endothelial function (n=107) and the carotid artery intima-media thickness (IMT) (n=91 ) by ultrasonography studies. Patients and controls were genotyped for the MIF-173 G/C gene polymorphism using a PCR system with pre-developed TaqMan allelic discrimination assay. Results No significant differences in allele or genotype frequencies for the MIF-173 gene polymorphism between RA patients and controls were found. Forty four of the 182 patients followed between 1996 and January 2008 experienced CV events. Although the frequency of MIF-173 GG homozygous was increased in those who had CV events (88.6%) compared to those who did not suffer these complication (73.2%), the difference was not statistically significant. It was also the case when we analyzed the potential influence of MIF-173 genotypes in the presence of endothelial dysfunction or increased carotid IMT of patients with RA. Conclusions Our results do not show that MIF-173 gene polymorphism may infer a direct risk for disease susceptibility or CV disease in patients with RA.

Lack of association between hypoxia inducible factor-1 alpha gene polymorphisms and biopsy-proven giant cell arteritis.

Abstract: OBJECTIVES Since the transcription factor hypoxia-inducible factor 1 (HIF-1) is a key early mediator of the response to ischemia and giant cell arteritis (GCA) is a polygenic disease leading to severe ischemic complications, in the present study we analysed for first time the implication of two HIF-1alpha gene polymorphisms in the susceptibility to and clinical expression of GCA. METHODS Two hundred and fifteen biopsy-proven GCA patients and 470 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for two single nucleotide polymorphisms, rs11549465 (C/T) and rs11549467 (G/A), using a pre-designed TaqMan allele discrimination assay. Post PCR, the genotype of each sample was attributed automatically by measuring the allelic specific fluorescence on the ABI PRIM 7900 sequence. RESULTS The HIF-1alpha, rs11549465 TT genotype was extremely uncommon in both GCA patients (2.3%) and controls (2.1%). Although the frequency of individuals carrying the CT or TT genotypes was increased in GCA patients (25.1%) compared to controls (20.4%) the difference was not statistically significant (OR 1.30 [95% CI: 0.89- 1.91]; p=0.17). Also, all GCA patients and most controls (98.9%) were homozygous for the rs11549467 GG genotype. GCA patients carrying the rs11549465 CT or TT genotypes had a slight increased risk of developing visual ischemic complications (33.1%) compared to the remaining GCA patients (22.8%); OR 1.60 (95% CI: 0.81- 3.16); p=0.18. CONCLUSIONS Our results do not confirm an implication of HIF-1alpha gene polymorphisms in the susceptibility to and clinical expression of GCA.

Lack of Association Between IRF5 Gene Polymorphisms and Biopsy-proven Giant Cell Arteritis

Abstract: Objective. A novel association with a 100-kb region on chromosome 9 that contains the tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 genes has been observed in some autoimmune rheumatic diseases, in particular in rheumatoid arthritis. We analyzed the influence of 2 single-nucleotide polymorphisms (SNP) from the TRAF1/C5 region in susceptibility to giant cell arteritis (GCA). Methods. We assessed 220 patients with biopsy-proven GCA and 410 matched controls. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the rs10818488 and rs2900180 TRAF1/C5 gene polymorphisms by polymerase chain reaction, using a predesigned TaqMan allele discrimination assay. Results. A genotyping rate of 95% was achieved in this series of GCA. No significant differences in the genotype distribution between GCA patients and controls were found for the 2 SNP. GCA patients exhibited a reduced frequency of TRAF1/C5 AA homozygosity (7.6%) compared to controls (12.7%) but the difference was only marginally significant (OR 0.58, 95% CI 0.30–1.11, p = 0.07). The frequency of minor allele T of TRAF1/C5 rs2900180 was also slightly reduced in patients (24.3%) compared to controls (27.8%) (p = 0.19). No significant differences were observed when patients were stratified according to the presence of specific clinical disease features. Conclusion. Our results showed no influence of rs10818488 and rs2900180 TRAF1/C5 gene polymorphisms in susceptibility to and clinical expression of GCA.

Role of BANK1 gene polymorphisms in biopsy-proven giant cell arteritis.

Abstract: Objective. Giant cell arteritis (GCA) is a complex polygenic disease in which more than 1 genetic locus is likely to contribute to disease susceptibility and clinical expression. BANK, an adaptor molecule, has been suggested to participate in the B cell antigen receptors-mediated calcium homeostasis. We assessed for the first time the implication of BANK1 functional variants in susceptibility to GCA. Methods. Two hundred twenty-two patients with biopsy-proven GCA and 534 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for 3 putative functional BANK1 gene polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) using a TaqMan allele discrimination assay. Results. No significant differences were observed in genotype distribution between patients with biopsy-proven GCA and controls for these 3 gene polymorphisms. A trend for a decreased risk of having GCA was observed in individuals carrying the BANK1 rs3733197 GG genotype (patients with GCA 43.9% compared to 51.6% in controls; p = 0.06, OR 0.73, 95% CI 0.53–1.02). The frequency of BANK1 rs3733197 allele G was marginally decreased in patients with biopsy-proven GCA compared to controls (p = 0.09, OR 0.82, 95% CI 0.64–1.04). Haplotype analysis of 3-single-nucleotide polymorphisms found no statistically significant differences between patients with GCA and controls. No significant differences for the BANK1 gene polymorphisms were found when patients were stratified according to specific clinical features of the disease. Conclusion. Our results do not support a major implication of the BANK1 locus in susceptibility to GCA.

Influence of IL2RA rs2104286 Polymorphism in the Risk of Biopsy-proven Giant Cell Arteritis

Abstract: Objective. To assess the influence of the IL2RA rs2104286 A>G polymorphism on susceptibility to and clinical spectrum of manifestations of biopsy-proven giant cell arteritis (GCA). Methods. Our study included 318 patients with biopsy-proven GCA. DNA from patients and healthy controls was obtained from peripheral blood. Samples were genotyped for the IL2RA rs2104286 A>G polymorphism using a predesigned TaqMan allele discrimination assay and by PCR amplification. Results. Although GCA patients showed a higher frequency of the minor allele homozygote of IL2RA rs2104286 (GG) compared to controls (5.1% vs 2.8%, respectively; p = 0.06, odds ratio 1.84, 95% confidence interval 0.91–3.70), the allele distribution showed no significant differences between GCA patients and controls. Stratification of GCA patients according to sex or polymyalgia rheumatica, jaw claudication, visual ischemic manifestations, or other severe ischemic complications did not yield significant differences in the allele or genotype frequencies of the IL2RA rs2104286 polymorphism. Conclusion. IL2RA rs2104286 polymorphism does not appear to be a genetic risk factor for susceptibility to biopsy-proven GCA. Also, this polymorphism does not seem to be implicated in the clinical expression of this vasculitis.

Lack of association between the rs6920220 (G/A) polymorphism of the 6q23 region and biopsy-proven giant cell arteritis.

Abstract: Objective. Recently, 2 independent studies have identified an association between several single-nucleotide polymorphisms (SNP) located in the 6q23 chromosomal region and rheumatoid arthritis (RA). Like RA, giant cell arteritis (GCA) is also a complex polygenic disease in which more than 1 genetic locus is likely to contribute to disease susceptibility and clinical expression. We analyzed the involvement of the rs6920220 (G/A) polymorphism from the 6q23/TNFAIP3 gene region in susceptibility to GCA. Methods. Two hundred twenty patients with biopsy-proven GCA and 490 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were geno-typed for the 6q23 region rs6920220 using a TaqMan allele discrimination assay and by polymerase chain reaction (PCR) amplification. After PCR, the genotype of each sample was attributed automatically by allelic-specific fluorescence using the ABI Prism 7900 sequence detection system. Results. No significant differences in the genotype distribution between patients with GCA and controls for the rs6920220 (G/A) polymorphism were found. No significant differences were observed when patients with GCA were stratified according to the presence of specific clinical features of the disease such as polymyalgia rheumatica or severe ischemic manifestations or specific visual ischemic complications. Conclusion. Our results show no involvement of this 6q23/TNFAIP3 gene region SNP in the susceptibility to or clinical expression of GCA.