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Review
. 2015 Apr 18;17(1):104.
doi: 10.1186/s13075-015-0623-4.

Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population

Chikashi Terao  1 , Koichiro Ohmura  2 , Yuta Kochi  3 , Katsunori Ikari  4 , Yukinori Okada  5 , Masakazu Shimizu  6 , Naoshi Nishina  7 , Akari Suzuki  8 , Keiko Myouzen  9 , Takahisa Kawaguchi  10 , Meiko Takahashi  11 , Kiyoshi Takasugi  12 , Akira Murasawa  13 , Shinichi Mizuki  14 , Mitsuhiro Iwahashi  15 , Keiko Funahashi  16 , Masamitsu Natsumeda  17 , Moritoshi Furu  18 , Motomu Hashimoto  19 , Hiromu Ito  20 , Takao Fujii  21 , Kazuhiko Ezawa  22 , Tsukasa Matsubara  23 , Tsutomu Takeuchi  24 , Michiaki Kubo  25 , Ryo Yamada  26 , Atsuo Taniguchi  27 , Hisashi Yamanaka  28 , Shigeki Momohara  29 , Kazuhiko Yamamoto  30 , Tsuneyo Mimori  31 , Fumihiko Matsuda  32   33
Affiliations
Review

Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population

Chikashi Terao et al. Arthritis Res Ther. .

Abstract

Introduction: Although 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.

Method: We 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.

Results: Rs6904716 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.

Conclusion: Many of the susceptibility loci were shared between ACPA-positive and -negative RA.

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Figures

Figure 1
Figure 1
Manhattan plot of meta-analysis of three genome-wide association studies (GWAS) for anti-citrullinated peptide/protein antibody-negative rheumatoid arthritis. The horizontal line indicates the GWAS significance level (P = 5 × 10−8).
Figure 2
Figure 2
Correlation of odds ratios (ORs) of rheumatoid arthritis (RA) susceptibility single nucleotide polymorphisms (SNPs) for anti-citrullinated peptide/protein antibody (ACPA)-positive RA and those for ACPA-negative RA. (A) Correlations of ORs regarding the 21 susceptibility SNPs to RA for ACPA-positive and -negative RA. The upper panel shows the results in the genome-wide association studies (GWAS) meta-analysis and the lower panel shows the results in the replication study. (B) ORs of the 21 SNPs in RA-susceptibility loci for ACPA-negative RA in the combined analysis (blue line) and ACPA-positive RA (red line) are plotted. Mean +/− 95% CI are shown. (C) Correlation coefficient of ORs between ACPA-positive and -negative RA in terms of SNPs stratified by P-values for ACPA-positive RA. *P-values <1.0 × 10−7. SNPs in the HLA locus were excluded from this analysis.
Figure 3
Figure 3
Correlations of odds ratios (ORs) in sets of non-human leukocyte antigen (HLA) single nucleotide polymorphisms (SNPs) among anti-citrullinated peptide/protein antibody (ACPA)-positive rheumatoid arthritis (RA) and the two subsets of ACPA-negative RA. Correlation coefficient of ORs between ACPA-positive RA and ACPA-negative RF-positive RA (A), between ACPA-positive RA and ACPA-negative RF-negative RA (B), and between ACPA-negative RF-positive RA and ACPA-negative RF-negative RA (C), in terms of SNPs stratified by p-values of ACPA-positive RA (A, B) or each study (C). *Positive correlation with P-values <1.0 × 10−7. SNPs in the HLA locus were excluded from this analysis.
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