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

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

来源：Arthritis Research and Therapy, 2015, 17(1): 104.

DOI：10.1186/s13075-015-0623-4

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 x 10(-8)), followed by rs6986423 in CSMD1 (p = 2.4 x 10(-6)) and rs17727339 in FCRL3 (p = 1.4 x 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.

• 出版日期2015-4-18
• 单位RIKEN