title: PADI4 and HLA-DRB1 are genetic risks for radiographic progression in RA patients, independent of ACPA status: results from the IORRA cohort study.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment. Recently, a large-scaled GWAS meta-analysis using more than 37,000 Japanese samples were conducted and 13 RA susceptibility loci were identified. However, it is not clear whether these loci have significant impact on joint destruction or not. This is the first study focused on the 13 loci to investigate independent genetic risk factors for radiographic progression in the first five years from onset of RA.
  
  
  METHODS
  Sharp/van der Heijde score of hands at 5-year disease duration, which represents joint damage, were measured retrospectively and used as an outcome variable in 865 Japanese RA patients. Genetic factors regarded as putative risk factors were RA-susceptible polymorphisms identified by the Japanese GWAS meta-analysis, including HLA-DRB1 (shared epitope, SE), rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4) and rs2847297 (PTPN2). These putative genetic risk factors were assessed by a stepwise multiple regression analysis adjusted for possible non-genetic risk factors: autoantibody positivity (anti-citrullinated peptide antibody [ACPA] and rheumatoid factor), history of smoking, gender and age at disease onset.
  
  
  RESULTS
  The number of SE alleles (P = 0.002) and risk alleles of peptidyl arginine deiminase type IV gene (PADI4, P = 0.04) had significant impact on progressive joint destruction, as well as following non-genetic factors: ACPA positive (P = 0.0006), female sex (P = 0.006) and younger age of onset (P = 0.02).
  
  
  CONCLUSIONS
  In the present study, we found that PADI4 risk allele and HLA-DRB1 shared epitope are independent genetic risks for radiographic progression in Japanese rheumatoid arthritis patients. The results of this study give important knowledge of the risks on progressive joint damage in RA patients.
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Suzuki
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikari
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yano
authors.forename: Eisuke
authors.initials: E
authors.lastname: Inoue
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Atsuo
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Shigeki
authors.initials: S
authors.lastname: Momohara
mesh_terms: D000906:Antibodies / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology; D001175:Arthrography; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
chemical_list: D000906:Antibodies; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases