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
N1 - Funding Information:
The authors acknowledge the essential role of the GARNET consortium in developing the study. In this study, the following GARNET members are included: CGM of RIKEN, University of Tokyo, the BioBank Japan Project, Kyoto University and IORRA. We would like to thank all the doctors and staffs who participated in sample collection for the RIKEN cohort and the BioBank Japan Project. We thank K Kobayashi and M Kitazato for their technical assistance. We thank M Kokubo for DNA extraction, GWAS genotyping and secretarial assistance. We would also like to thank H Yoshifuji, N Yukawa, D Kawabata, T Nojima, and T Usui for collecting DNA samples. We thank Y Katagiri for her technical efforts. We also appreciate the contribution of E Inoue and other members of the Institute of Rheumatology, Tokyo Women’s Medical University, for their efforts on the IORRA cohort. This study was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan, the Ministry of Health, Labor and Welfare (MHLW) in Japan, the Japan Society for the Promotion of Science (JSPS), Solution-Oriented Research for Science and Technology (SORST), the Okawa Foundation for Information and Telecommunications.
Publisher Copyright:
© Terao et al.; licensee BioMed Central.
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.
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U2 - 10.1186/s13075-015-0623-4
DO - 10.1186/s13075-015-0623-4
M3 - Article
C2 - 25927497
AN - SCOPUS:84929298327
SN - 1478-6354
VL - 17
JO - Arthritis Research and Therapy
JF - Arthritis Research and Therapy
IS - 1
M1 - 104
ER -