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…

Chikashi Terao, Koichiro Ohmura, Yuta Kochi, Katsunori Ikari, Yukinori Okada, Masakazu Shimizu, Naoshi Nishina, Akari Suzuki, Keiko Myouzen, Takahisa Kawaguchi, Meiko Takahashi, Kiyoshi Takasugi, Akira Murasawa, Shinichi Mizuki, Mitsuhiro Iwahashi, Keiko Funahashi, Masamitsu Natsumeda, Moritoshi Furu, Motomu Hashimoto, Hiromu Ito, Takao Fujii, Kazuhiko Ezawa, Tsukasa Matsubara, Tsutomu Takeuchi, Michiaki Kubo, Ryo Yamada, Atsuo Taniguchi, Hisashi Yamanaka, Shigeki Momohara, Kazuhiko Yamamoto, Tsuneyo Mimori, Fumihiko Matsuda

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