title: Identification of the oxidative stress-related gene MSRA as a rheumatoid arthritis susceptibility locus by genome-wide pathway analysis.
abstract: OBJECTIVE
  Genome-wide association studies carried out in rheumatoid arthritis (RA) have led to the discovery of several genetic associations with this disease. Still, the current associated genetic variations can explain only part of the genetic risk involved in RA, and it is well recognized that these genome-wide association studies are likely underpowered to detect all common disease variants. This study was undertaken to explore the genomic regions showing low-significance associations in previous genome-wide association studies of RA.
  
  
  METHODS
  To reduce the false-positive signal fraction, we exploited pathway analysis to prioritize regions containing genes most likely to be implicated in RA. We hypothesized that true disease genes would be in a similar pathway. Therefore, genes from similar pathways but located in different regions were prioritized for replication using Prioritizer software. A total of 384 genetic variants selected from previous RA genome-wide association studies were tested in a Spanish case-control discovery cohort comprising 376 RA patients and 478 healthy controls for replication. Statistically significant associations were further validated in replication cohorts from Spain and The Netherlands. The study consisted of a total of 1,818 RA patients and 2,498 controls.
  
  
  RESULTS
  We detected a novel genetic association between RA and the MSRA gene (rs10903323) in the Spanish combined population (P = 2.91 × 10(-5) , odds ratio [OR] 1.51). This association was further tested in our independent Dutch replication cohort. Combined analysis showed an overall association of MSRA with RA (P = 3.19 × 10(-4) , OR 1.28).
  
  
  CONCLUSIONS
  Our findings indicate that a novel association in the MSRA gene is related to oxidative stress and support the notion of a major role for this process in RA.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain. cebercoto@ipb.csic.es
authors.forename: Jose-Ezequiel
authors.initials: JE
authors.lastname: Martín
authors.forename: Behrooz Z
authors.initials: BZ
authors.lastname: Alizadeh
authors.forename: Miguel A
authors.initials: MA
authors.lastname: González-Gay
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: Dora
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernández-Gutiérrez
authors.forename: Enrique
authors.initials: E
authors.lastname: Raya
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Ruben
authors.initials: R
authors.lastname: van't Slot
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Piet
authors.initials: P
authors.lastname: van Riel
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D051150:Methionine Sulfoxide Reductases / Q000235:genetics*; D009426:Netherlands; D016017:Odds Ratio; D018384:Oxidative Stress / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013030:Spain
chemical_list: D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase