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, 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 & 12 others Takao Fujii, Kazuhiko Ezawa, Tsukasa Matsubara, Tsutomu Takeuchi, Michiaki Kubo, Ryo Yamada, Atsuo Taniguchi, Hisashi Yamanaka, Shigeki Momohara, Kazuhiko Yamamoto, Tsuneyo Mimori, Fumihiko Matsuda

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Article number104
JournalArthritis Research and Therapy
Volume17
Issue number1
DOIs
Publication statusPublished - 18-04-2015

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Rheumatoid Arthritis
Peptides
Antibodies
Population
Proteins
Rheumatoid Factor
Single Nucleotide Polymorphism
HLA Antigens
Odds Ratio

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

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. / 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. In: Arthritis Research and Therapy. 2015 ; Vol. 17, No. 1.
@article{d6e64382ab104871a9629fa22a948b0c,
title = "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",
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.",
author = "Chikashi Terao and Koichiro Ohmura and Yuta Kochi and Katsunori Ikari and Yukinori Okada and Masakazu Shimizu and Naoshi Nishina and Akari Suzuki and Keiko Myouzen and Takahisa Kawaguchi and Meiko Takahashi and Kiyoshi Takasugi and Akira Murasawa and Shinichi Mizuki and Mitsuhiro Iwahashi and Keiko Funahashi and Masamitsu Natsumeda and Moritoshi Furu and Motomu Hashimoto and Hiromu Ito and Takao Fujii and Kazuhiko Ezawa and Tsukasa Matsubara and Tsutomu Takeuchi and Michiaki Kubo and Ryo Yamada and Atsuo Taniguchi and Hisashi Yamanaka and Shigeki Momohara and Kazuhiko Yamamoto and Tsuneyo Mimori and Fumihiko Matsuda",
year = "2015",
month = "4",
day = "18",
doi = "10.1186/s13075-015-0623-4",
language = "English",
volume = "17",
journal = "Arthritis Research and Therapy",
issn = "1478-6354",
publisher = "BioMed Central",
number = "1",

}

Terao, C, Ohmura, K, Kochi, Y, Ikari, K, Okada, Y, Shimizu, M, Nishina, N, Suzuki, A, Myouzen, K, Kawaguchi, T, Takahashi, M, Takasugi, K, Murasawa, A, Mizuki, S, Iwahashi, M, Funahashi, K, Natsumeda, M, Furu, M, Hashimoto, M, Ito, H, Fujii, T, Ezawa, K, Matsubara, T, Takeuchi, T, Kubo, M, Yamada, R, Taniguchi, A, Yamanaka, H, Momohara, S, Yamamoto, K, Mimori, T & Matsuda, F 2015, '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', Arthritis Research and Therapy, vol. 17, no. 1, 104. https://doi.org/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. / 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.

In: Arthritis Research and Therapy, Vol. 17, No. 1, 104, 18.04.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA

T2 - A meta-analysis of genome-wide association study in a Japanese population

AU - Terao, Chikashi

AU - Ohmura, Koichiro

AU - Kochi, Yuta

AU - Ikari, Katsunori

AU - Okada, Yukinori

AU - Shimizu, Masakazu

AU - Nishina, Naoshi

AU - Suzuki, Akari

AU - Myouzen, Keiko

AU - Kawaguchi, Takahisa

AU - Takahashi, Meiko

AU - Takasugi, Kiyoshi

AU - Murasawa, Akira

AU - Mizuki, Shinichi

AU - Iwahashi, Mitsuhiro

AU - Funahashi, Keiko

AU - Natsumeda, Masamitsu

AU - Furu, Moritoshi

AU - Hashimoto, Motomu

AU - Ito, Hiromu

AU - Fujii, Takao

AU - Ezawa, Kazuhiko

AU - Matsubara, Tsukasa

AU - Takeuchi, Tsutomu

AU - Kubo, Michiaki

AU - Yamada, Ryo

AU - Taniguchi, Atsuo

AU - Yamanaka, Hisashi

AU - Momohara, Shigeki

AU - Yamamoto, Kazuhiko

AU - Mimori, Tsuneyo

AU - Matsuda, Fumihiko

PY - 2015/4/18

Y1 - 2015/4/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84929298327&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929298327&partnerID=8YFLogxK

U2 - 10.1186/s13075-015-0623-4

DO - 10.1186/s13075-015-0623-4

M3 - Article

VL - 17

JO - Arthritis Research and Therapy

JF - Arthritis Research and Therapy

SN - 1478-6354

IS - 1

M1 - 104

ER -