RT Journal Article
SR Electronic
T1 Genetic Factors for the Severity of ACPA-negative Rheumatoid Arthritis in 2 Cohorts of Early Disease: A Genome-wide Study
JF The Journal of Rheumatology
JO J Rheumatol
FD The Journal of Rheumatology
SP 1383
OP 1391
DO 10.3899/jrheum.140741
VO 42
IS 8
A1 Diederik P.C. de Rooy
A1 Roula Tsonaka
A1 Maria L.E. Andersson
A1 Kristina Forslind
A1 Alexandra Zhernakova
A1 Mojca Frank-Bertoncelj
A1 Caroline G.F. de Kovel
A1 Bobby P.C. Koeleman
A1 Désirée M.F.M. van der Heijde
A1 Tom W.J. Huizinga
A1 René E.M. Toes
A1 Jeanine J. Houwing-Duistermaat
A1 Caroline Ospelt
A1 Björn Svensson
A1 Annette H.M. van der Helm-van Mil
YR 2015
UL http://www.jrheum.org/content/42/8/1383.abstract
AB Objective. Rheumatoid arthritis (RA) that is negative for anticitrullinated protein antibodies (ACPA) is a subentity of RA, characterized by less severe disease. At the individual level, however, considerable differences in the severity of joint destruction occur. We performed a study on genetic factors underlying the differences in joint destruction in ACPA-negative patients.Methods. A genome-wide association study was done with 262 ACPA-negative patients with early RA included in the Leiden Early Arthritis Clinic and related to radiographic joint destruction over 7 years. Significant single-nucleotide polymorphisms (SNP) were evaluated for association with progression of radiographic joint destruction in 253 ACPA-negative patients with early RA included in the Better Anti-Rheumatic Farmaco Therapy (BARFOT) study. According to the Bonferroni correction of the number of tested SNP, the threshold for significance was p < 2 × 10−7 in phase 1 and 0.0045 in phase 2. In both cohorts, joint destruction was measured by Sharp/van der Heijde method with good reproducibility.Results. Thirty-three SNP associated with severity of joint destruction (p < 2 × 10−7) in phase 1. In phase 2, rs2833522 (p = 0.0049) showed borderline significance. A combined analysis of both the Leiden and BARFOT datasets of rs2833522 confirmed this association with joint destruction (p = 3.57 × 10−9); the minor allele (A) associated with more severe damage (for instance, after 7 yrs followup, patients carrying AA had 1.22 times more joint damage compared to patients carrying AG and 1.50 times more joint damage than patients carrying GG). In silico analysis using the ENCODE and Ensembl databases showed presence of H3K4me3 histone mark, transcription factors, and long noncoding RNA in the region of rs2833522, an intergenic SNP located between HUNK and SCAF4.Conclusion. Rs2833522 might be associated with the severity of joint destruction in ACPA-negative RA.