TY - JOUR
T1 - Genetic Factors for the Severity of ACPA-negative Rheumatoid Arthritis in 2 Cohorts of Early Disease
T2 - A Genome-wide Study
AU - de Rooy, Diederik P. C.
AU - Tsonaka, Roula
AU - Andersson, Maria L. E.
AU - Forslind, Kristina
AU - Zhernakova, Alexandra
AU - Frank-Bertoncelj, Mojca
AU - de Kovel, Caroline G. F.
AU - Koeleman, Bobby P. C.
AU - van der Heijde, Desiree M. F. M.
AU - Huizinga, Tom W. J.
AU - Toes, Rene E. M.
AU - Houwing-Duistermaat, Jeanine J.
AU - Ospelt, Caroline
AU - Svensson, Bjorn
AU - van der Helm-van Mil, Annette H. M.
PY - 2015/8
Y1 - 2015/8
N2 - 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 x 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 x 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 x 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.
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 x 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 x 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 x 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.
KW - RHEUMATOID ARTHRITIS
KW - AUTOANTIBODIES
KW - GENETIC STUDIES
KW - JOINT EROSIONS
KW - JOINT DESTRUCTION
KW - CITRULLINATED PROTEINS
KW - SUSCEPTIBILITY LOCI
KW - ASSOCIATION
KW - PREDICTION
KW - ANTIBODIES
KW - RISK
KW - METAANALYSIS
KW - PROGRESSION
KW - ANNOTATION
U2 - 10.3899/jrheum.140741
DO - 10.3899/jrheum.140741
M3 - Article
SN - 0315-162X
VL - 42
SP - 1383
EP - 1391
JO - Journal of Rheumatology
JF - Journal of Rheumatology
IS - 8
ER -