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Objective: Osteoprotegerin (OPG) may contribute to the link between systemic inflammation and increased cardiovascular risk. We investigated the relationship of OPG concentrations with endothelial activation and carotid atherosclerosis in rheumatoid arthritis (RA)., Methods: OPG concentrations and those of endothelial activation molecules were measured by using ELISA in 34 patients who were treated with infliximab (IFX), both immediately before and after an IFX infusion. Carotid intima-media thickness (CIMT) and plaque were determined by ultrasound in 27 of the study participants., Results: Median (interquartile range) OPG concentrations decreased from 4.8 pmol/l (2.8-6.5) to 4.4 pmol/l (2.9-6.1; p = 0.04) upon IFX infusion. Baseline OPG concentrations were inversely associated with those of total and low-density lipoprotein (LDL) cholesterol (partial R = -0.50, p = 0.004, and R = -0.48, p = 0.007, respectively). Prior to IFX administration, OPG concentrations were associated with those of intercellular adhesion molecule (ICAM)-1 (partial R = 0.34, p = 0.05), CIMT (partial R = 0.51 to 0.52, p < 0.009), and plaque (OR = 1.52, 95% CI 1.01-2.29 to OR = 1.61, 95% CI 1.03-2.51; p < 0.04), independent of conventional risk factors and C-reactive protein concentrations or disease activity. Except for the OPG concentrations-plaque association (p = 0.09), these relationships remained significant subsequent to IFX administration (p < 0.05). Reductions in OPG levels related to those in vascular cell adhesion molecule (VCAM)-1 concentrations (partial R = 0.35, p = 0.04) and had borderline significance (p = 0.09) with those in ICAM-1 (partial R = 0.29) concentrations., Conclusion: OPG concentrations are independently associated with endothelial activation and carotid atherosclerosis in RA. Reductions in OPG concentrations upon IFX administration are associated with decreased endothelial activation. OPG may be involved in increased cardiovascular disease risk and may improve its stratification in patients with RA.

Objective: To investigate whether a functional integrin alpha M (ITGAM) variant is involved in susceptibility to and clinical manifestations of giant cell arteritis (GCA)., Methods: A Spanish cohort of 437 white patients with biopsy-proven GCA and 1388 healthy controls were genotyped using the TaqMan allele discrimination technology., Results: No association was observed between ITGAM rs1143679 and GCA (p = 0.80, OR 0.97). Similarly, subphenotype analyses did not yield significant differences between the case subgroups and the control set or between GCA patients with or without the main specific features of GCA., Conclusion: Our results suggest that the ITGAM rs1143679 variant does not play an important role in the pathophysiology of GCA.

Objective: To assess the potential association between the rs1343151 IL23R and the rs3790567 IL12RB2 polymorphisms and giant cell arteritis (GCA). We also studied whether these polymorphisms might influence the phenotypic expression of GCA., Methods: In total, 357 Spanish patients with biopsy-proven GCA and 574 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the rs1343151 IL23R and the rs3790567 IL12RB2 polymorphisms using a predesigned TaqMan allele discrimination assay and by polymerase chain reaction amplification., Results: Regarding the rs1343151 IL23R polymorphism, no significant differences in the genotype or allele frequencies between GCA patients and healthy controls were observed. The frequency of the minor allele A of the rs3790567 IL12RB2 variant was increased in GCA patients compared with controls (30.1% vs 25.7%, respectively; p = 0.039, OR 1.25, 95% CI 1.01-1.54). An increased frequency of subjects carrying the minor allele A (GA+AA genotypes) of the rs3790567 IL12RB2 polymorphism was found among GCA patients compared with controls (52.8% vs 44.4%; p = 0.013, OR 1.40, 95% CI 1.06-1.85). Although a higher frequency of the combination of minor alleles (A-A) in the subgroup of patients with visual ischemic complications compared with the combination of both major alleles (G-G; p = 0.029) or with the other allelic combinations (p = 0.035) was found, logistic regression analysis showed that this association was no longer significant after adjustment for potential confounding factors (A-A vs G-G: OR 2.10, 95% CI 0.88-5.04, p = 0.096)., Conclusion: Our results support a potential influence of the rs3790567 IL12RB2 polymorphism in the pathogenesis of GCA.

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.

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.

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.

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.

Objective: Interferon (IFN) regulatory factors (IRF) are transcriptional mediators of IFN-induced signaling pathways and are involved in immune response. We have analyzed for the first time the association of 2 IRF5 gene variants in the susceptibility to giant cell arteritis (GCA)., Methods: Two hundred twenty patients with biopsy-proven GCA and 520 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the IRF5 rs2004640 and for the IRF5 CGGGG insertion/deletion polymorphism using a predesigned TaqMan allele discrimination assay and by polymerase chain reaction amplification, followed by an ABI3100 sequencer, respectively., Results: A genotyping rate of 96% was achieved in this series of GCA patients. No significant differences were found in the genotype distribution between GCA patients and controls for both IRF5 gene variants. In this regard, similar genotype frequencies were found in GCA patients and controls. No significant differences were observed when GCA patients were stratified according to the presence of specific clinical features of the disease such as polymyalgia rheumatica or severe ischemic complications., Conclusion: Our results showed no association of IRF5 rs2004640 and CGGGG insertion/deletion polymorphisms in the susceptibility to and clinical expression of GCA.

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.

Objective: Dendritic cells localized at the adventitia-media border of the normal medium-sized arteries play a pivotal role in the initiation of giant cell arteritis (GCA). These cells express a singular surface receptor profile, including a series of Toll-like receptors (TLR). Ligands of TLR-4 promote activation and differentiation of adventitial dendritic cells and are directly implicated in the pathogenesis of GCA. We aimed to assess the potential implication of the TLR4-(+896 A/G) gene polymorphism in the susceptibility to GCA., Methods: A total of 210 patients diagnosed with biopsy-proven GCA and 678 matched controls were included in our study. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the TLR4-(+896 A/G) (rs4986790) gene polymorphism by polymerase chain reaction, using a predesigned TaqMan allele discrimination assay., Results: The TLR4 +896 G allele was significantly increased in biopsy-proven GCA patients compared to controls [p = 0.01; odds ratio (OR) 1.65; 95% confidence interval (CI) 1.08-2.52]. The increase was due to a significantly increased frequency of heterozygosity for the TLR4 -896 A/G genotype in the group of patients with biopsy-proven GCA compared to controls (TLR4 -896 A/G heterozygous in patients with GCA 18.1% compared to 11.4% in controls: p = 0.01; OR 1.72; 95% CI 1.10-2.69). However, no significant differences were observed when patients with GCA were stratified according to the presence of specific clinical features of the disease., Conclusion: Our results show for the first time an association of TLR4-(+896 A/G) gene polymorphism with susceptibility to biopsy-proven GCA.

Objective: To investigate the potential implication of the STAT4 gene polymorphism rs7574865 in the predisposition to or the clinical expression of giant cell arteritis (GCA)., Methods: A total of 212 patients diagnosed with biopsy-proven GCA were studied. DNA from patients and controls matched by age, sex, and ethnicity was obtained from peripheral blood. Samples were genotyped for STAT4 rs7574865 polymorphism., Results: No statistically significant differences in the allele frequencies for the STAT4 rs7574865 polymorphism were observed between patients and controls. Although we observed an increased frequency of the T/T genotype in GCA patients (6.0%) compared to healthy controls (3.9%), this difference did not achieve statistical significance (OR 1.57, 95% CI 0.72-3.41). No statistically significant differences in allele or genotype frequencies were observed when patients were stratified according to the presence of typical disease features such as polymyalgia rheumatica, severe ischemic manifestations, and visual ischemic complications in the setting of this vasculitis., Conclusion: Our results do not support a major role of the STAT4 rs7574865 gene polymorphism in susceptibility to or clinical manifestations of GCA.

Objective: To investigate the potential implication of several polymorphisms of the C-reactive protein (CRP) gene in the predisposition to or clinical expression of giant cell arteritis (GCA)., Methods: A total of 125 patients diagnosed with biopsy-proven GCA and 234 ethnically matched controls from the Lugo region of Northwestern Spain were included in our study. Four functional gene polymorphisms for CRP rs1417938, rs1800947, rs1205, and rs3093059 variants were assessed using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay., Results: Although we observed a significant increase in the frequency of heterozygotes for rs1417938 A/T [odds ratio (OR) = 1.70; 95% confidence interval (CI) 1.04-2.80; p = 0.03] and rs1205 C/T (OR 1.73; 95% CI 1.07-2.78; p = 0.02) in patients with GCA, no statistically significant differences in the allelic frequencies of these 2 polymorphisms were found between patients with GCA and controls. A marginal significant increase in the frequency of rs3093059 allele T in patients with GCA compared to controls was observed (OR 1.81; 95% CI 0.97-3.39; p = 0.04). However, the increased frequency of patients with GCA homozygous for rs3093059 T/T in patients with GCA compared to controls was out of the range of significance (OR 1.77; 95% CI 0.92-3.40; p = 0.07). No significant differences were found when we stratified patients with GCA according to the presence of polymyalgia rheumatica or severe ischemic complications of the disease., Conclusion: The functional CRP gene polymorphisms assessed in our study do not seem to play a major role in the pathogenesis of GCA in individuals from Northwestern Spain.

Objective: Giant cell arteritis (GCA) is a vasculitis preferentially involving large and middle-sized arteries in the elderly. The nuclear factor of k-light polypeptide gene enhancer in B cells (NF-kB) is a family of 5 proteins expressed in most cells that function to regulate gene transcription. NFKB1 gene plays a critical role in the coordination of the immune system by regulating the transcription of a broad variety of genes implicated in the immune response. A NFKB1 promoter polymorphism consisting of a common insertion/deletion (-94ins/delATTG) located between 2 putative key promoter regulatory elements and showing functional effects on the transcription of the NFKB1 gene has been described. Since GCA is a polygenic disease, we sought to assess the potential role of the -94ins/delATTG NFKB1 promoter polymorphism in susceptibility to GCA and to determine if this polymorphism is implicated in the clinical expression of this vasculitis., Methods: Ninety-six patients with biopsy-proven GCA and 204 ethnically matched Caucasian controls from the Lugo region (Northwest Spain) were studied. Genotyping of the -94ins/delATTG NFKB1 promoter polymorphism was performed by fluorescent polymerase chain reaction (PCR)., Results: No significant differences in allele or genotype frequencies for this NFKB1 promoter polymorphism were observed between patients with GCA and controls even when patients were stratified according to gender, presence of polymyalgia rheumatica (n = 38), severe ischemic manifestations (n = 49), or other clinical manifestations of GCA., Conclusion: Our results do not support a role for -94ins/delATTG NFKB1 promoter polymorphism in susceptibility and clinical expression of GCA in a Northwestern Spanish population.