Protein tyrosine phosphatase non-receptor 22 and C-Src tyrosine kinase genes are down-regulated in patients with rheumatoid arthritis

Several protein tyrosine phosphatase non-receptor 22 (PTPN22) single-nucleotide polymorphisms (SNPs) have been significantly related with rheumatoid arthritis (RA) susceptibility. Nevertheless, its potential influence on PTPN22 expression in RA has not been completely elucidated. Furthermore, PTPN22 binds to C-Src tyrosine kinase (CSK) forming a key complex in autoimmunity. However, the information of CSK gene in RA is scarce. In this study, we analyzed the relative PTPN22 and CSK expression in peripheral blood from 89 RA patients and 43 controls to determine if the most relevant PTPN22 (rs2488457, rs2476601 and rs33996649) and CSK (rs34933034 and rs1378942) polymorphisms may influence on PTPN22 and CSK expression in RA. The association between PTPN22 and CSK expression in RA patients and their clinical characteristics was also evaluated. Our study shows for the first time a marked down-regulation of PTPN22 expression in RA patients carrying the risk alleles of PTPN22 rs2488457 and rs2476601 compared to controls (p?=?0.004 and p?=?0.007, respectively). Furthermore, CSK expression was significantly lower in RA patients than in controls (p?<?0.0001). Interestingly, a reduced PTPN22 expression was disclosed in RA patients with ischemic heart disease (p?=?0.009). The transcriptional suppression of this PTPN22/CSK complex may have a noteworthy clinical relevance in RA patients

Expression of osteoprotegerin and its ligands, RANKL and TRAIL, in rheumatoid arthritis

Osteoprotegerin (OPG), receptor activator of nuclear factor-?B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have been involved in rheumatoid arthritis (RA) pathophysiology. In this study, we assessed messenger RNA (mRNA) expression of these molecules by qPCR in peripheral blood from 26 patients with RA (12 of them with ischemic heart disease -IHD) and 10 healthy controls. Correlation coefficients between OPG, RANKL and TRAIL expression levels in RA patients and their clinical and demographic characteristics were also evaluated. Whereas OPG and OPG/TRAIL ratio expression were significantly increased in RA patients compared to controls (fold change?=?1.79, p?=?0.013 and 2.07, p?=?0.030, respectively), RANKL/OPG ratio was significantly decreased (fold change?=?0.50, p?=?0.020). No significant differences were found between patients and controls in RANKL and TRAIL expression. Interestingly, TRAIL expression was significantly higher in RA patients with IHD compared to those without IHD (fold change?=?1.46, p?=?0.033). Moreover, biologic disease-modifying antirheumatic drugs (DMARDs) significantly decreased RANKL expression in RA patients (p?=?0.016). Our study supports an important role of OPG and TRAIL in RA. Furthermore, it highlights an effect of biologic DMARDs in the modulation of RANKL

The presence of both HLA-DRB1[*]04:01 and HLA-B[*]15:01 increases the susceptibility to cranial and extracranial giant cell arteritis.

Objectives: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. Methods: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. Results: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA. Conclusions: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from ‘‘Instituto de Salud Carlos III’’ (ISCIII) (Spain). However, this research did not receive any specific grant from funding agencies in the commercial or not-for-profit sectors

HLA-DRB1 association with Henoch-Schonlein purpura

Objective: Henoch-Schönlein purpura (HSP) is the most common vasculitis in children but it is not exceptional in adults. Increased familial occurrence supports a genetic predisposition for HSP. In this context, an association with the human leukocyte antigen-HLA-DRB1*01 phenotype has been suggested in Caucasian individuals with HSP. However, data on the potential association of HSP with HLA-DRB1*01 were based on small case series. To further investigate this issue, we performed HLA-DRB1 genotyping of the largest series of HSP patients ever assessed for genetic studies in Caucasians. Methods: 342 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al classification criteria, and 303 sex and ethnically matched controls were assessed. HLA-DRB1 alleles were determined using a PCR-Sequence-Specific-Oligonucleotide Probe (PCR-SSOP) method. Results: A statistically significant increase of HLA-DRB1*01 in HSP patients when compared with controls was found (43% vs 7%, respectively; p<0.001; odds ratio-OR=2.03 [1.43-2.87]). It was due to the increased frequency of HLA-DRB1*0103 phenotype in HSP (14% vs 2%; p<0.001; OR=8.27 [3.46-23.9]). These results remained statistically significant after adjusting for Bonferroni correction. In contrast, a statistically significant decreased frequency of the HLA-DRB1*0301 phenotype was observed in patients compared to controls (5.6% vs 18.1%, respectively; p<0.001, OR=0.26 [0.14-0.47]), even after adjustment for Bonferroni correction. No HLA-DRB1 association with specific features of the disease was found. Conclusion: Our study confirms an association of HSP with HLA-DRB1*01 in Caucasians. Also, a protective effect against the development of HSP appears to exist in Caucasians carrying the HLA-DRB1*03 phenotype

Influence of elevated-CRP level-related polymorphisms in non-rheumatic Caucasians on the risk of subclinical atherosclerosis and cardiovascular disease in rheumatoid arthritis

Association between elevated C-reactive protein (CRP) serum levels and subclinical atherosclerosis and cardiovascular (CV) events was described in rheumatoid arthritis (RA). CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 exert an influence on elevated CRP serum levels in non-rheumatic Caucasians. Consequently, we evaluated the potential role of these genes in the development of CV events and subclinical atherosclerosis in RA patients. Three tag CRP polymorphisms and HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were genotyped in 2,313 Spanish patients by TaqMan. Subclinical atherosclerosis was determined in 1,298 of them by carotid ultrasonography (by assessment of carotid intima-media thickness-cIMT-and presence/absence of carotid plaques). CRP serum levels at diagnosis and at the time of carotid ultrasonography were measured in 1,662 and 1,193 patients, respectively, by immunoturbidimetry. Interestingly, a relationship between CRP and CRP serum levels at diagnosis and at the time of the carotid ultrasonography was disclosed. However, no statistically significant differences were found when CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were evaluated according to the presence/absence of CV events, carotid plaques and cIMT after adjustment. Our results do not confirm an association between these genes and CV disease in RA

Cranial and extracranial giant cell arteritis share similar HLA-DRB1 association

Objective:To determine whether giant cell arteritis (GCA) patients with the typical pattern of cranial ischemicmanifestations and those with the extracranial large-vessel-vasculitis (LVV)-GCA phenotype exhibit differentHLA-DRB1association.Methods:178 biopsy-proven GCA patients who had cranial ischemic features but no LVV manifestations, 100patients with LVV-GCA without cranial ischemic manifestations and 486 ethnically matched healthy controlswere recruited. All patients and controls were Spanish of European ancestry. We comparedHLA-DRB1pheno-type frequencies between the three groups.Results:Both GCA subgroups had well-differentiated clinical features. Patients with LVV-GCA were younger(68.0§10.0 yearsversus74.0§10.4 years;p<0.01) and presented more commonly with polymyalgia rheu-matica symptoms (81%versus39.3%;p<0.01) than those with the classic cranial GCA phenotype.HLA-DRB1*04phenotype frequency was significantly increased in patients with classic cranial GCA compared tocontrols (42.1%versus23.5%, respectively;p<0.01; odds ratio-OR [95% confidence interval-CI] = 2.38[1.623.47]). This association was mainly due to theHLA-DRB1*04:01allele (20.8%versus5.3%, respectively;p<0.01; OR [95% CI] = 4.64 [2.638.26]).HLA-DRB1*04association was also observed in LVV-GCA patientswhen compared to controls (46.0%versus23.5%, respectively;p<0.01; OR [95% CI] = 2.78 [1.734.44])

Influence of IL17A gene on the pathogenesis of immunoglobulin-A vasculitis

OBJECTIVES: Cytokines signaling pathway genes represent a key component of the genetic network implicated in the pathogenesis of immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. Interleukin (IL)17A is described as a genetic risk locus for some autoimmune diseases, such as giant cell arteritis and spondyloarthritis. Accordingly, we aimed to determine the potential influence of IL17A on the pathogenesis of IgAV. METHODS: Five IL17A tag polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909), which cover the major variability of this gene, were genotyped in 360 Caucasian patients with IgAV and 1,003 sex and ethnically matched healthy controls using TaqMan probes. RESULTS: No statistically significant differences between patients with IgAV and healthy controls were observed when each IL17A genetic variant was analysed independently. Similarly, no statistically significant differences between patients with IgAV and healthy controls were found when the five IL17A polymorphisms were evaluated combined conforming haplotypes. In addition, there were no statistically significant differences in genotype, allele and haplotype frequencies of IL17A when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IL17A on the pathogenesis of IgAV