RT Journal Article
SR Electronic
T1 Do Genetic Susceptibility Variants Associate with Disease Severity in Early Active Rheumatoid Arthritis?
JF The Journal of Rheumatology
JO J Rheumatol
FD The Journal of Rheumatology
SP 1131
OP 1140
DO 10.3899/jrheum.141211
VO 42
IS 7
A1 Ian C. Scott
A1 Frühling Rijsdijk
A1 Jemma Walker
A1 Jelmar Quist
A1 Sarah L. Spain
A1 Rachael Tan
A1 Sophia Steer
A1 Yukinori Okada
A1 Soumya Raychaudhuri
A1 Andrew P. Cope
A1 Cathryn M. Lewis
YR 2015
UL http://www.jrheum.org/content/42/7/1131.abstract
AB 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-DRβ1 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.