title: PTGER4 gene variant rs76523431 is a candidate risk factor for radiological joint damage in rheumatoid arthritis patients: a genetic study of six cohorts.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The PTGER4 gene is a candidate risk factor for radiological progression in RA.
authors.affiliation: Rheumatology Department and Heath Research Institute (IdISSC), Hospital Clinico San Carlos, c/o Prof. Martin Lagos s/n, 28040, Madrid, Spain. lrrodriguez@salud.madrid.org.
authors.forename: Luis
authors.initials: L
authors.lastname: Rodriguez-Rodriguez
authors.affiliation: Rheumatology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain. ivorra_jos@gva.es.
authors.forename: Jose
authors.initials: J
authors.lastname: Ivorra-Cortes
authors.affiliation: Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, Granada, Spain. dcarmona@ipb.csic.es.
authors.forename: F David
authors.initials: FD
authors.lastname: Carmona
authors.affiliation: Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, Granada, Spain. martin@ipb.csic.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.affiliation: Rheumatology Department and Heath Research Institute (Idipaz), Hospital Universitario de La Paz, Madrid, Spain. alejandro.balsa@salud.madrid.org.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. h.w.van_steenbergen@lumc.nl.
authors.forename: Hanna W
authors.initials: HW
authors.lastname: van Steenbergen
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. a.h.m.van_der_helm@lumc.nl.
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.affiliation: Rheumatology Service and Heath Research Institute (IP), Hospital Universitario de La Princesa, Madrid, Spain. isidoro.ga@ser.es.
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Álvaro
authors.affiliation: Rheumatology Department and Heath Research Institute (IdISSC), Hospital Clinico San Carlos, c/o Prof. Martin Lagos s/n, 28040, Madrid, Spain. benjamin.fernandez@salud.madrid.org.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernandez-Gutiérrez
mesh_terms: D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics*; D012307:Risk Factors
chemical_list: C545650:PTGER4 protein, human; D058309:Receptors, Prostaglandin E, EP4 Subtype