title: Phenome-Wide Association Study of Autoantibodies to Citrullinated and Noncitrullinated Epitopes in Rheumatoid Arthritis.
abstract: Patients with rheumatoid arthritis (RA) develop autoantibodies against a spectrum of antigens, but the clinical significance of these autoantibodies is unclear. Using a phenome-wide association study (PheWAS) approach, we examined the association between autoantibodies and clinical subphenotypes of RA.
  
  
  
  This study was conducted in a cohort of RA patients identified from the electronic medical records (EMRs) of 2 tertiary care centers. Using a published multiplex bead assay, we measured 36 autoantibodies targeting epitopes implicated in RA. We extracted all International Classification of Diseases, Ninth Revision (ICD-9) codes for each subject and grouped them into disease categories (PheWAS codes), using a published method. We tested for the association of each autoantibody (grouped by the targeted protein) with PheWAS codes. To determine significant associations (at a false discovery rate [FDR] of ≤0.1), we reviewed the medical records of 50 patients with each PheWAS code to determine positive predictive values (PPVs).
  
  
  
  We studied 1,006 RA patients; the mean ± SD age of the patients was 61.0 ± 12.9 years, and 79.0% were female. A total of 3,568 unique ICD-9 codes were grouped into 625 PheWAS codes; the 206 PheWAS codes with a prevalence of ≥3% were studied. Using the PheWAS method, we identified 24 significant associations of autoantibodies to epitopes at an FDR of ≤0.1. The associations that were strongest and had the highest PPV for the PheWAS code were autoantibodies against fibronectin and obesity (P = 6.1 × 10-4, PPV 100%), and that between fibrinogen and pneumonopathy (P = 2.7 × 10-4, PPV 96%). Pneumonopathy codes included diagnoses for cryptogenic organizing pneumonia and obliterative bronchiolitis.
  
  
  
  We demonstrated application of a bioinformatics method, the PheWAS, to screen for the clinical significance of RA-related autoantibodies. Using the PheWAS approach, we identified potentially significant links between variations in the levels of autoantibodies and comorbidities of interest in RA.
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Katherine P
authors: KP
authors: Liao
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Jeffrey A
authors: 0000-0002-5556-4618
authors: JA
authors: Sparks
authors: Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors: Boris P
authors: BP
authors: Hejblum
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and Biogen, Cambridge, Massachusetts.
authors: I-Hsin
authors: IH
authors: Kuo
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Jing
authors: J
authors: Cui
authors: VA Palo Alto Healthcare System and Stanford University School of Medicine, Palo Alto, California.
authors: Lauren J
authors: LJ
authors: Lahey
authors: Partners Healthcare, Charlestown, Massachusetts.
authors: Andrew
authors: A
authors: Cagan
authors: Partners Healthcare, Charlestown, Massachusetts.
authors: Vivian S
authors: VS
authors: Gainer
authors: Shanghai Jiao Tong University, Shanghai, China.
authors: Weidong
authors: W
authors: Liu
authors: The Wharton School, University of Pennsylvania, Philadelphia.
authors: T Tony
authors: TT
authors: Cai
authors: VA Palo Alto Healthcare System and Stanford University School of Medicine, Palo Alto, California.
authors: Jeremy
authors: J
authors: Sokolove
authors: Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors: Tianxi
authors: T
authors: Cai
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000235:genetics*; D000939:Epitopes; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D010641:Phenotype
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide