Journal Article 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

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  ,  Momohara, Shigeki  ,  Yamamoto, Kazuhiko  ,  Mimori, Tsuneyo  ,  Matsuda, Fumihiko

172015-04-18 , BioMed Central Ltd.
ISSN:1478-6362
Description
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<sup>-8</sup>), followed by rs6986423 in CSMD1 (p = 2.4 × 10<sup>-6</sup>) and rs17727339 in FCRL3 (p = 1.4 × 10<sup>-5</sup>). 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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http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/210408/1/s13075-015-0623-4.pdf

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