Rodriguez-Rodriguez Luis, Ivorra-Cortes Jose, Carmona F David, Martín Javier, Balsa Alejandro, van Steenbergen Hanna W, van der Helm-van Mil Annette H M, González-Álvaro Isidoro, Fernandez-Gutiérrez Benjamín
Rheumatology Department and Heath Research Institute (IdISSC), Hospital Clinico San Carlos, c/o Prof. Martin Lagos s/n, 28040, Madrid, Spain.
Rheumatology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
Arthritis Res Ther. 2015 Nov 5;17:306. doi: 10.1186/s13075-015-0830-z.
Prostaglandin 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).
Six 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.
The 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.
The PTGER4 gene is a candidate risk factor for radiological progression in RA.
前列腺素E受体4（PTGER4）与免疫调节和骨代谢有关。本研究旨在分析其在类风湿关节炎（RA）放射学关节损伤中的作用。
纳入了6个欧洲或北美血统的RA患者独立队列，包括1789例患者及5083组X线片。将圣卡洛斯临床医院类风湿关节炎队列、公主早期关节炎登记纵向研究队列以及拉巴斯大学医院早期关节炎（西班牙）队列作为发现队列，将莱顿早期关节炎诊所（荷兰）、威奇托（美国）以及风湿病国家数据库（美国和加拿大）队列作为验证队列。首先，使用TaqMan分析和可用的Illumina免疫芯片数据对PTGER4 rs6896969单核苷酸多态性（SNP）进行基因分型，并在发现队列和验证队列中进行研究。其次，在发现队列中使用免疫芯片基因分型数据对PTGER4基因及其邻近区域进行分析。基于合并的p值、该区域的连锁不平衡结构以及转录特性区域的位置，选择SNP进行验证。使用逆方差加权荟萃分析汇总发现队列、验证队列和总体队列的结果。分析多态性对总体放射学损伤（固定效应）和随时间的损伤进展（时间变化效应）的影响。
在发现队列的固定效应合并分析中，rs6896969多态性与放射学损伤存在显著关联，尽管在验证队列或总体合并分析中未观察到显著关联。关于PTGER4区域的分析，在发现队列中分析了976个变异。从固定效应和时间变化效应分析中，分别选择了12个和20个SNP进行验证。仅rs76523431变异在发现队列、验证队列和总体队列的时间变化效应合并分析中与放射学进展存在显著关联。总体合并效应大小为1.10（95%置信区间1.05 - 1.14，p = 2.10×10⁻⁵），这意味着每个次要等位基因拷贝的放射学年度进展要高10%。
PTGER4基因是RA放射学进展的候选风险因素。
