PTGER4 gene variant rs76523431 is a candidate risk factor for radiological joint damage in rheumatoid arthritis patients: a genetic study of six cohorts

Abstract

IntroductionProstaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism. The aim of this study was to analyze its role in radiological joint damage in rheumatoid arthritis (RA).MethodsSix independent cohorts of patients with RA of European or North American descent were included, comprising 1789 patients with 5083 sets of X-rays. The Hospital Clínico San Carlos Rheumatoid Arthritis, Princesa Early Arthritis Register Longitudinal study, and Hospital Universitario de La Paz early arthritis (Spain) cohorts were used as discovery cohorts, and the Leiden Early Arthritis Clinic (The Netherlands), Wichita (United States), and National Databank for Rheumatic Diseases (United States and Canada) cohorts as replication cohorts. First, the PTGER4 rs6896969 single-nucleotide polymorphism (SNP) was genotyped using TaqMan assays and available Illumina Immunochip data and studied in the discovery and replication cohorts. Second, the PTGER4 gene and adjacent regions were analyzed using Immunochip genotyping data in the discovery cohorts. On the basis of pooled p values, linkage disequilibrium structure of the region, and location in regions with transcriptional properties, SNPs were selected for replication. The results from discovery, replication, and overall cohorts were pooled using inverse-variance–weighted meta-analysis. Influence of the polymorphisms on the overall radiological damage (constant effect) and on damage progression over time (time-varying effect) was analyzed.ResultsThe rs6896969 polymorphism showed a significant association with radiological damage in the constant effect pooled analysis of the discovery cohorts, although no significant association was observed in the replication cohorts or the overall pooled analysis. Regarding the analysis of the PTGER4 region, 976 variants were analyzed in the discovery cohorts. From the constant and time-varying effect analyses, 12 and 20 SNPs, respectively, were selected for replication. Only the rs76523431 variant showed a significant association with radiographic progression in the time-varying effect pooled analysis of the discovery, replication, and overall cohorts. The overall pooled effect size was 1.10 (95 % confidence interval 1.05–1.14, p = 2.10 × 10−5), meaning that radiographic yearly progression was 10 % greater for each copy of the minor allele.ConclusionsThe PTGER4 gene is a candidate risk factor for radiological progression in RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0830-z) contains supplementary material, which is available to authorized users.

mPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production

“…Sensing of PGE 2 in T cells is paramount, as efficient T cell priming and activation require EP receptors (9). EP4 ( ptger4 ) variants have been described as candidate risk factors in joint damage in RA patients (39) and in inflammatory bowel disease patients (40). CD4 + T cell conditional EP4 knock-out mice are protected from EAE (26), and EP2 and EP4 antagonists suppress the differentiation of Th1 and Th17 cells in vivo (31).…”

Prostaglandin‐cytokine crosstalk in chronic inflammation

“…Interestingly, polymorphisms in PTGER4 gene (rs12186979 and rs13354346) were related to susceptibility of AS in Europeans and East Asians respectively (International Genetics of Ankylosing Spondylitis Consortium et al ., ). In addition, rs76523431 in PTGER4 was also suggested as a risk factor for RA (Rodriguez‐Rodriguez et al ., ). PTGER4 gene polymorphisms (rs7720838 and rs1494558) were associated with allergy and asthma (Kurz et al ., ; Hinds et al ., ), while rs4613763 was suggested as a psoriasis susceptible locus (Tsoi et al ., ).…”

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…Since EP2 and EP4 mRNA were abundantly expressed in human synovial fibroblasts, PGE 2 has been shown to stimulate IL-6 release from fibroblasts and to downregulate IFN- γ– induced anti-inflammatory actions, presumably via the EP2/EP4 receptors ( Mathieu et al, 2008 ). An important role for EP4 receptor could be suggested since polymorphisms in PTGER4 loci are associated with increased PTGER4 gene expression in synovial biopsy samples from patients with spondyloarthritis, and PTGER4 is a susceptibility gene for ankylosing spondylitis and RA ( Evans et al, 2011 ; Rodriguez-Rodriguez et al, 2015 ).…”