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

Luis Rodriguez-Rodriguez,Javier Martín,F David Carmona,Benjamín Fernandez-Gutiérrez,Jose Ivorra-Cortes,Isidoro González-Álvaro,Hanna W Van Steenbergen,Annette H M Van Der Helm-Van Mil,Alejandro Balsa

doi:10.1186/s13075-015-0830-z

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.

Highlights

Prostaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism
The rs6896969 polymorphism showed a significant association with radiological damage in the constant effect pooled analysis of the discovery cohorts, no significant association was observed in the replication cohorts or the overall pooled analysis
Analysis of the PTGER4 region and radiological joint damage Because rs6896969 showed a significant association in the pooled analysis of the Spanish cohorts, and because we considered PTGER4 a good candidate gene to play a part in rheumatoid arthritis (RA) radiological joint damage due to its immune regulation and bone metabolism roles, we decided to carry on and perform a fine-mapping analysis of the region around PTGER4 using available Immunochip data

Summary

Introduction

Prostaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism. Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects between 0.5 % and 1 % of the population in developed countries It is a complex genetic condition with several patterns of progression [1] potentially associated with significant morbidity, disability, and costs to society [2]. This receptor has been implicated both in immune regulation and in bone metabolism Together with another prostaglandin E2 receptor (EP2), it regulates the production of proinflammatory factors [such as interleukin (IL)-6, macrophage colony-stimulating factor, and vascular endothelial growth factor] in response to IL-1β in human synovial fibroblasts [4, 5]. It induces the production of parathyroid hormone-related peptide in RA fibroblasts treated with IL-1α [14]

Objectives

Methods

Results

Discussion

Conclusion