Do genetic susceptibility variants associate with disease severity in early active rheumatoid arthritis?

Ian C. Scott, Frühling Rijsdijk, Jemma Walker, Jelmar Quist, Sarah L. Spain, Rachael Tan, Sophia Steer, Yukinori Okada, Soumya Raychaudhuri, Andrew P. Cope, Cathryn M. Lewis

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Objective. Genetic variants affect both the development and severity of rheumatoid arthritis (RA). Recent studies have expanded the number of RA susceptibility variants. We tested the hypothesis that these associated with disease severity in a clinical trial cohort of patients with early, active RA. Methods. We evaluated 524 patients with RA enrolled in the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trials. We tested validated susceptibility variants-69 single-nucleotide polymorphisms (SNP), 15 HLA-DRB1 alleles, and amino acid polymorphisms in 6 HLA molecule positions-for their associations with progression in Larsen scoring, 28-joint Disease Activity Scores, and Health Assessment Questionnaire (HAQ) scores over 2 years using linear mixed-effects and latent growth curve models. Results. HLA variants were associated with joint destruction. The 04:01 SNP (rs660895, p = 0.0003),04:01 allele (p = 0.0002), and HLA-DRâ1 amino acids histidine at position 13 (p = 0.0005) and valine at position 11 (p = 0.0012) significantly associated with radiological progression. This association was only significant in anticitrullinated protein antibody (ACPA)-positive patients, suggesting that while their effects were not mediated by ACPA, they only predicted joint damage in ACPA-positive RA. Non-HLA variants did not associate with radiograph damage (assessed individually and cumulatively as a weighted genetic risk score). Two SNP-rs11889341 (STAT4, p = 0.0001) and rs653178 (SH2B3-PTPN11, p = 0.0004)-associated with HAQ scores over 6-24 months. Conclusion. HLA susceptibility variants play an important role in determining radiological progression in early, active ACPA-positive RA. Genome-wide and HLA-wide analyses across large populations are required to better characterize the genetic architecture of radiological progression in RA.

Original languageEnglish
Pages (from-to)1131-1140
Number of pages10
JournalJournal of Rheumatology
Issue number7
StatePublished - 1 Jul 2015
Externally publishedYes


  • Genetics
  • Hla antigens
  • Outcome measures
  • Radiography
  • Rheumatoid arthritis


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