title: Identification of IRX1 as a Risk Locus for Rheumatoid Factor Positivity in Rheumatoid Arthritis in a Genome-Wide Association Study.
abstract: Rheumatoid factor (RF) is a well-established diagnostic and prognostic biomarker in rheumatoid arthritis (RA). However, ∼20% of RA patients are negative for this anti-IgG antibody. To date, only variation at the HLA-DRB1 gene has been associated with the presence of RF. This study was undertaken to identify additional genetic variants associated with RF positivity.
  
  
  
  A genome-wide association study (GWAS) for RF positivity was performed using an Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RA patients were genotyped for >550,000 single-nucleotide polymorphisms (SNPs). Association testing was performed using an allelic chi-square test implemented in Plink software. An independent cohort of 472 RF-positive and 190 RF-negative RA patients was used to validate the most significant findings.
  
  
  
  In the discovery stage, a SNP in the IRX1 locus on chromosome 5p15.3 (SNP rs1502644) showed a genome-wide significant association with RF positivity (P = 4.13 × 10(-8) , odds ratio [OR] 0.37 [95% confidence interval (95% CI) 0.26-0.53]). In the validation stage, the association of IRX1 with RF was replicated in an independent group of RA patients (P = 0.034, OR 0.58 [95% CI 0.35-0.97] and combined P = 1.14 × 10(-8) , OR 0.43 [95% CI 0.32-0.58]).
  
  
  
  To our knowledge, this is the first GWAS of RF positivity in RA. Variation at the IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. Our findings indicate that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA.
authors.affiliation: Vall d'Hebron Hospital Research Institute, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Julià
authors.affiliation: Instituto de Investigación Biomédica de A Coruña-Hospital Universitario A Coruña, A Coruña, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco
authors.affiliation: Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernández-Gutierrez
authors.affiliation: Instituto de Investigación Sanitaria and Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: Antonio
authors.identifier: 0000-0002-2624-0606
authors.initials: A
authors.lastname: González
authors.affiliation: Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Cañete
authors.affiliation: Hospital del Mar, Barcelona, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Maymó
authors.affiliation: Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alperi-López
authors.affiliation: Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Olivè
authors.affiliation: Hospital Moisès Broggi, Barcelona, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Corominas
authors.affiliation: Hospital Universitario Marqués de Valdecilla, Santander, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Martínez-Taboada
authors.affiliation: Hospital Universitario La Princesa, IIS Princesa, Madrid, Spain.
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Álvaro
authors.affiliation: Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, and Universidad de Málaga, Málaga, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernandez-Nebro
authors.affiliation: Hospital Sant Rafael, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Erra
authors.affiliation: Hospital General La Mancha Centro, Ciudad Real, Spain.
authors.forename: Simón
authors.initials: S
authors.lastname: Sánchez-Fernández
authors.affiliation: Vall d'Hebron Hospital Research Institute, Barcelona, Spain.
authors.forename: Arnald
authors.initials: A
authors.lastname: Alonso
authors.affiliation: Vall d'Hebron Hospital Research Institute, Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: López-Lasanta
authors.affiliation: Vall d'Hebron Hospital Research Institute, Barcelona, Spain.
authors.forename: Raül
authors.initials: R
authors.lastname: Tortosa
authors.affiliation: Barcelona Supercomputing Center, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Codó
authors.affiliation: Barcelona Supercomputing Center, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Lluis Gelpi
authors.affiliation: National DNA Bank Carlos III and University of Salamanca, Salamanca, Spain.
authors.forename: Andrés C
authors.initials: AC
authors.lastname: García-Montero
authors.affiliation: National Genotyping Center and Pompeu Fabra University, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Bertranpetit
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Hospital Universitario de Guadalajara, Guadalajara, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Tornero
authors.affiliation: Vall d'Hebron Hospital Research Institute, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Marsal
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D056426:Genetic Loci; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012217:Rheumatoid Factor / Q000235:genetics*; D012306:Risk; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C501591:IRX1 protein, human; D014157:Transcription Factors; D012217:Rheumatoid Factor