Regulatory polymorphisms in extracellular matrix protease genes and susceptibility to rheumatoid arthritis: a case-control study

Many extracellular matrix (ECM) proteases seem to be important in rheumatoid arthritis (RA) and regulation of their transcription levels is a critical mechanism for controlling their activity. We have investigated, therefore, whether the best-characterized single nucleotide polymorphisms (SNPs) affecting transcription of the ECM proteases that have been related with joint pathology are associated with RA susceptibility. Nine SNPs in eight genes were selected by bibliographic search, including SNPs in the genes encoding matrix metalloproteinase (MMP)1, MMP2, MMP3, MMP7, MMP9, MMP13, plasminogen activator, tissue type (PLAT) and PAI-1. They were studied in a case-control setting that included 550 RA patients and 652 controls of Spanish ancestry from a single center. Genotyping was performed by single-base extension. Only two of the nine SNPs showed significant association with RA susceptibility. RA patients showed increased frequencies of the -7351 T allele of the gene encoding PLAT (36.4% versus 32.1% in controls, p = 0.026) and the -1306 T allele of the gene encoding MMP2 (24.5% versus 20.3% in controls, p = 0.013). These two alleles seemed to cooperate according to an additive model with respect to increased RA susceptibility (p = 0.004), and they were the low-expression alleles of the respective SNPs in a PLAT enhancer and the MMP2 promoter. These findings are in agreement with previous data suggesting that these two ECM proteases have a protective role in RA pathology. Confirmation of these associations will be needed to support these hypotheses. The remaining SNPs did not show association, either individually or collectively. Therefore, although regulatory SNPs in ECM proteases did not show any major effect on RA susceptibility, it was possible to find modest associations that, if replicated, will have interesting implications in the understanding of RA pathology

Lack of association of a variable number of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case-control studies in Spanish Caucasians

A recent genetic association study has identified a microsatellite in the coding sequence of the asporin gene as a susceptibility factor for osteoarthritis (OA). Alleles of this microsatellite determine the variable number of aspartic acid residues in the amino-terminal end of the asporin protein. Asporin binds directly to the growth factor transforming growth factor beta and inhibits its anabolic effects in cartilage, which include stimulation of collagen and aggrecan synthesis. The OA-associated allele, with 14 aspartic acid residues, inhibits the anabolic effects of transforming growth factor beta more strongly than other asporin alleles, leading to increased OA liability. We have explored whether the association found in several cohorts of Japanese hip OA and knee OA patients was also present in Spanish Caucasians. We studied patients that had undergone total joint replacement for primary OA in the hip (n = 303) or the knee (n = 188) and patients with hand OA (n = 233), and we compared their results with controls (n = 294) lacking overt OA clinical symptoms. No significant differences were observed in any of the multiple comparisons performed, which included global tests of allele frequency distributions and specific comparisons as well as stratification by affected joint and by sex. Our results, together with reports from the United Kingdom and Greece, indicate that the stretch of aspartic acid residues in asporin is not an important factor in OA susceptibility among European Caucasians. It remains possible that lifestyle, environmental or genetic differences allow for an important effect of asporin variants in other ethnic groups as has been reported in the Japanese, but this should be supported by additional studies

Cis-regulation of IRF5 expression is unable to fully account for systemic lupus erythematosus association: analysis of multiple experiments with lymphoblastoid cell lines

INTRODUCTION: Interferon regulatory factor 5 gene (IRF5) polymorphisms are strongly associated with several diseases, including systemic lupus erythematosus (SLE). The association includes risk and protective components. They could be due to combinations of functional polymorphisms and related to cis-regulation of IRF5 expression, but their mechanisms are still uncertain. We hypothesised that thorough testing of the relationships between IRF5 polymorphisms, expression data from multiple experiments and SLE-associated haplotypes might provide useful new information. METHODS: Expression data from four published microarray hybridisation experiments with lymphoblastoid cell lines (57 to 181 cell lines) were retrieved. Genotypes of 109 IRF5 polymorphisms, including four known functional polymorphisms, were considered. The best linear regression models accounting for the IRF5 expression data were selected by using a forward entry procedure. SLE-associated IRF5 haplotypes were correlated with the expression data and with the best cis-regulatory models. RESULTS: A large fraction of variability in IRF5 expression was accounted for by linear regression models with IRF5 polymorphisms, but at a different level in each expression data set. Also, the best models from each expression data set were different, although there was overlap between them. The SNP introducing an early polyadenylation signal, rs10954213, was included in the best models for two of the expression data sets and in good models for the other two data sets. The SLE risk haplotype was associated with high IRF5 expression in the four expression data sets. However, there was also a trend towards high IRF5 expression with some protective and neutral haplotypes, and the protective haplotypes were not associated with IRF5 expression. As a consequence, correlation between the cis-regulatory best models and SLE-associated haplotypes, regarding either the risk or protective component, was poor. CONCLUSIONS: Our analysis indicates that although the SLE risk haplotype of IRF5 is associated with high expression of the gene, cis-regulation of IRF5 expression is not enough to fully account for IRF5 association with SLE susceptibility, which indicates the need to identify additional functional changes in this gene

Long-Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials.

OBJECTIVE: Psoriatic arthritis (PsA) requires long-term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3-year apremilast safety and tolerability in PsA. METHODS: Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg twice daily, or apremilast 20 mg twice daily. Placebo patients were re-randomized to apremilast 30 mg twice daily or 20 mg twice daily at week 16 (early escape) or 24. Double-blind treatment continued to week 52; patients could continue apremilast during an open-label, long-term treatment phase. RESULTS: In total, 1493 patients received at least one dose of study medication and were included in the safety population (placebo: n = 495; apremilast 30 mg: n = 497; apremilast 20 mg: n = 501). Among patients receiving apremilast, 53.2% (767/1441) completed 3 years of treatment. Greater rates of adverse events (AEs) were reported with apremilast (61.1%; exposure-adjusted incidence rate [EAIR]/100 patient-years, 265.1) versus placebo (47.5%; EAIR/100 patient-years, 200.7) in the placebo-controlled period. During weeks 0 to ≤52, the most common AEs occurring in apremilast-exposed patients were diarrhea (13.9%; EAIR/100 patient-years, 18.6), nausea (12.3%; EAIR/100 patient-years, 16.0), headache (9.4%; EAIR/100 patient-years, 12.1), upper respiratory tract infection (9.1%; EAIR/100 patient-years, 11.5), and nasopharyngitis (6.2%; EAIR/100 patient-years, 7.7). Most AEs were mild/moderate with apremilast exposure ≤156 weeks. Rates of depression remained low (EAIR/100 patient-years, 1.8). Major adverse cardiac events (EAIR/100 patient-years, 0.5), malignancies (EAIR/100 patient-years, 0.9), and serious opportunistic infections (EAIR/100 patient-years, 0.0) were infrequent over the 3-year exposure period. Discontinuation rates due to AEs were low ( CONCLUSION: Apremilast demonstrated a favorable safety profile and was well tolerated up to 156 weeks

High sodium intake is associated with self-reported rheumatoid arthritis: a cross sectional and case control analysis within the SUN cohort

Sodium intake is a potential environmental factor for immune-mediated inflammatory diseases. The aim of this study is to investigate the association of sodium intake with rheumatoid arthritis. We performed a cross-sectional study nested in a highly educated cohort investigating dietary habits as determinants of disease. Daily sodium intake in grams per day was estimated from a validated food frequency questionnaire. We identified prevalent self-reported cases of rheumatoid arthritis. Logistic regressionmodelswere used to estimate the odds ratio for rheumatoid arthritis by sodium intake adjusting for confounders. Linear trend tests and interactions between variables were explored. Sensitivity analyses included age- and sex-matched case–control study, logistic multivariate model adjusted by residuals, and analysis excluding individuals with prevalent diabetes or cardiovascular disease. The effective sample size was 18,555 individuals (mean age 38-years old, 60% women) including 392 self-reported rheumatoid arthritis. Median daily sodium intake (estimated from foods plus added salt) was 3.47 (P25–75: 2.63–4.55) grams. Total sodium intake in the fourth quartile showed a significant association with rheumatoid arthritis (fully adjusted odds ratio 1.5; 95% CI 1.1–2.1, P for trend¼0.02). Never smokers with high sodium intake had higher association than ever smokers with high sodium intake (P for interaction¼0.007). Dosedependent association was replicated in the case–control study. High sodiumintakemay be associated with a diagnosis of rheumatoid arthritis. This confirms previous clinical and experimental research

Analysis of TNFAIP3, a feedback inhibitor of nuclear factor-κB and the neighbor intergenic 6q23 region in rheumatoid arthritis susceptibility

Introduction Genome-wide association studies of rheumatoid arthritis (RA) have identified an association of the disease with a 6q23 region devoid of genes. TNFAIP3, an RA candidate gene, flanks this region, and polymorphisms in both the TNFAIP3 gene and the intergenic region are associated with systemic lupus erythematosus. We hypothesized that there is a similar association with RA, including polymorphisms in TNFAIP3 and the intergenic region. Methods To test this hypothesis, we selected tag-single nucleotide polymorphisms (SNPs) in both loci. They were analyzed in 1,651 patients with RA and 1,619 control individuals of Spanish ancestry. Results Weak evidence of association was found both in the 6q23 intergenic region and in the TNFAIP3 locus. The rs582757 SNP and a common haplotype in the TNFAIP3 locus exhibited association with RA. In the intergenic region, two SNPs were associated, namely rs609438 and rs13207033. The latter was only associated in patients with anti-citrullinated peptide antibodies. Overall, statistical association was best explained by the interdependent contribution of SNPs from the two loci TNFAIP3 and the 6q23 intergenic region. Conclusions Our data are consistent with the hypothesis that several RA genetic factors exist in the 6q23 region, including polymorphisms in the TNFAIP3 gene, like that previously described for systemic lupus erythematosus

Lack of replication of interactions between polymorphisms in rheumatoid arthritis susceptibility: case-control study

Introduction: Approximately 100 loci have been definitively associated with rheumatoid arthritis (RA) susceptibility. However, they explain only a fraction of RA heritability. Interactions between polymorphisms could explain part of the remaining heritability. Multiple interactions have been reported, but only the shared epitope (SE) × protein tyrosine phosphatase nonreceptor type 22 (PTPN22) interaction has been replicated convincingly. Two recent studies deserve attention because of their quality, including their replication in a second sample collection. In one of them, researchers identified interactions between PTPN22 and seven single-nucleotide polymorphisms (SNPs). The other showed interactions between the SE and the null genotype of glutathione S-transferase Mu 1 (GSTM1) in the anti-cyclic citrullinated peptide-positive (anti-CCP+) patients. In the present study, we aimed to replicate association with RA susceptibility of interactions described in these two high-quality studies. Methods: A total of 1,744 patients with RA and 1,650 healthy controls of Spanish ancestry were studied. Polymorphisms were genotyped by single-base extension. SE genotypes of 736 patients were available from previous studies. Interaction analysis was done using multiple methods, including those originally reported and the most powerful methods described. Results: Genotypes of one of the SNPs (rs4695888) failed quality control tests. The call rate for the other eight polymorphisms was 99.9%. The frequencies of the polymorphisms were similar in RA patients and controls, except for PTPN22 SNP. None of the interactions between PTPN22 SNPs and the six SNPs that met quality control tests was replicated as a significant interaction term the originally reported finding or with any of the other methods. Nor was the interaction between GSTM1 and the SE replicated as a departure from additivity in anti-CCP+ patients or with any of the other methods. Conclusions: None of the interactions tested were replicated in spite of sufficient power and assessment with different assays. These negative results indicate that whether interactions are significant contributors to RA susceptibility remains unknown and that strict standards need to be applied to claim that an interaction exists

New Sequence Variants in HLA Class II/III Region Associated with Susceptibility to Knee Osteoarthritis Identified by Genome-Wide Association Study

Osteoarthritis (OA) is a common disease that has a definite genetic component. Only a few OA susceptibility genes that have definite functional evidence and replication of association have been reported, however. Through a genome-wide association study and a replication using a total of ∼4,800 Japanese subjects, we identified two single nucleotide polymorphisms (SNPs) (rs7775228 and rs10947262) associated with susceptibility to knee OA. The two SNPs were in a region containing HLA class II/III genes and their association reached genome-wide significance (combined P = 2.43×10−8 for rs7775228 and 6.73×10−8 for rs10947262). Our results suggest that immunologic mechanism is implicated in the etiology of OA