Abstract
IntroductionAlthough susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA.MethodWe performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed.ResultsRs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10−8), followed by rs6986423 in CSMD1 (p = 2.4 × 10−6) and rs17727339 in FCRL3 (p = 1.4 × 10−5). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations.ConclusionMany of the susceptibility loci were shared between ACPA-positive and -negative RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0623-4) contains supplementary material, which is available to authorized users.
Highlights
Susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA
A total of 670 patients with ACPAnegative RA from three independent cohorts (GARNET Consortium detailed in Methods) and 16,891 controls were genome-scanned with different single nucleotide polymorphism (SNP) typing platforms (Table 1) and the data were imputed separately using the same Hapmap phase II East Asian panel as reference and corrected in order to fit meta-analysis as detailed in Methods
When we focused on our results in the GWAS meta-analysis of the genes that had been reported to be associated with ACPA-negative RA in the previous studies, four out of the 13 genes had SNPs with suggestive association (P
Summary
Susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA. Anti-citrullinated peptide/protein antibody (ACPA) is a highly specific autoantibody to RA, which recognizes a broad range of citrullinated peptides and appears in approximately 80% of patients with RA [2,3,4]. Previous studies addressing the genetic difference between RA subsets with or without ACPA have shown that ACPA-negative RA has different susceptibility human leukocyte antigen (HLA) alleles from ACPA-positive RA [5,6,7,8]. A recent study in Europeans confirmed the different susceptibility HLA alleles in the context of susceptibility effects of amino acid residues [9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
