Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept

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 nonredundant 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 metaanalysis 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 SNPsThis work was supported by the Instituto de Salud Carlos III (ISCIII, Spain) through grants PI14/01651, PI17/01606 and RD16/0012/0014 to AG and PI12/01909 to JJG-R. These grants are partially financed by the European Regional Development Fund of the EU (FEDER

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept

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 SNP

Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

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

Prevalence of RA bone erosions in anti-CCP and anti-CarP defined subgroups.

<p>Error bars represent 95% CI. P value from logistic regression analysis adjusted for gender, age of diagnosis and time of follow-up.</p

Stratified analysis of RA risk factors according to the anti-CarP and anti-CCP status.

<p>Frequency of the A) <i>HLA-DRB1</i> SE and B) <i>PTPN22</i> R620W genotypes in the different strata. White fraction = heterozygotes, grey fraction = homozygotes. C) Frequency of ever smokers. Error bars represent 95% CI. Crl. = controls, NA = not available. P values were obtained with logistic regression analysis adjusted for gender, age of diagnosis and time of follow-up.</p

Characteristics of the patients with RA included in the study.

<p>Characteristics of the patients with RA included in the study.</p

Distribution of patients with RA positive for the different autoantibodies.

<p>We observed that anti-CarP antibodies were not associated with the SE alleles (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161141#pone.0161141.g002" target="_blank">Fig 2A</a>). This lack of association was found in all analyses performed, which included either all the SE alleles together (OR = 1.1, P = 0.6), or only the <i>HLA-DRB1*01</i> alleles (OR = 0.9, P = 0.7), or the *<i>04</i> alleles (OR = 1.0, P = 0.9), or the *<i>1001</i> allele (OR = 1.2, P = 0.7). In addition, we did not observe association in analyses conditional on the anti-CCP status (OR = 0.8, P = 0.4), the RF status (OR = 0.9, P = 0.6) or both (OR = 0.8, P = 0.3). In a similar way, there was no association of the anti-CarP status with the <i>PTPN22</i> R620W polymorphism (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161141#pone.0161141.g002" target="_blank">Fig 2B</a>). Again, this result was consistent in the direct analysis (OR = 0.9, P = 0.7), and in the conditional on other autoantibodies (OR = 0.8, P = 0.5 conditional on anti-CCP; OR = 1.0, P = 0.8 conditional on RF; and OR = 0.9, P = 0.7 conditional in the two other autoantibodies). Finally, we did not observe association of the anti-CarP antibodies with smoking (OR = 1.0, P = 0.9; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161141#pone.0161141.g002" target="_blank">Fig 2C</a>). We should note that the anti-CCP positive status was associated with the SE alleles (P = 2.4 x 10⁻⁷), showed a stronger association than the anti-CCP negative status with the <i>PTPN22</i> R620W polymorphism (P = 0.002 for anti-CCP positive and P = 0.13 for anti-CCP negative patients), but it was not associated with smoking (P = 0.65) in our patients, as we already have noted previously [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161141#pone.0161141.ref016" target="_blank">16</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161141#pone.0161141.ref017" target="_blank">17</a>]. All these analyses were adjusted for gender, age at disease onset and time of follow-up.</p

The use of imaging in new transcatheter interventions: an EACVI review paper.

Transcatheter therapies for the treatment of valve heart diseases have expanded dramatically over the last years. The new developments and improvements in devices and techniques, along with the increasing expertise of operators, have turned the catheter-based approaches for valvular disease into an established treatment option. Various imaging techniques are used during these procedures, but echocardiography plays an essential role during patient selection, intra-procedural monitoring, and post-procedure follow-up. The echocardiographic assessment of patients undergoing transcatheter interventions places demands on echocardiographers that differ from those of the routine evaluation of patients with valve disease, and there is a need for specific expertise for those working in the cath lab. In the context of the current rapid developments and growing use of transcatheter valve therapies, this document intends to update the previous recommendations and address new advancements in imaging, particularly for those involved in any stage of the treatment of patients with valvular heart diseases

Anti-carbamylated protein autoantibodies associated with mortality in Spanish rheumatoid arthritis patients

<div><p>Patients with rheumatoid arthritis (RA) have an increased mortality rate that is associated with the presence of RA-specific autoantibodies in many studies. However, the relative role of rheumatoid factor (RF), anti-CCP antibodies and the most recently established RA-autoantibodies, directed against carbamylated proteins (anti-CarP antibodies), is unclear. Here, we have assessed the role of these three antibodies in 331 patients with established RA recruited from 2001 to 2009 and followed until November 2015. During this time, 124 patients died (37.5%). This death rate corresponds to a mortality rate 1.53 (95% CI 1.26 to 1.80) folds the observed in the reference population. We used for analysis of all-cause mortality the Cox proportional hazard regression model with adjustment for age, sex and smoking. It showed a trend for association with increased mortality of each of the three RA autoantibodies in antibody-specific analysis (hazards ratio (HR) from 1.37 to 1.79), but only the HR of the anti-CarP antibodies was significant (HR = 1.79, 95% CI 1.23 to 2.61, p = 0.002). In addition, the multivariate analysis that included all autoantibodies showed a marked decrease in the HR of RF and of anti-CCP antibodies, whereas the HR of anti-CarP remained significant. This increase was specific of respiratory system causes of death (HR = 3.19, 95% CI 1.52 to 6.69, p = 0.002). Therefore, our results suggest a specific relation of anti-CarP antibodies with the increased mortality in RA, and drive attention to their possible connection with respiratory diseases.</p></div