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.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
Many of the susceptibility loci were shared between ACPA-positive and -negative RA.
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. a0001101@kuhp.kyoto-u.ac.jp.
Chikashi
C
Terao
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan. ohmurako@kuhp.kyoto-u.ac.jp.
Koichiro
K
Ohmura
Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan. ykochi@src.riken.jp.
Yuta
Y
Kochi
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. kikari@mac.com.
Katsunori
K
Ikari
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. yokada.brc@tmd.ac.jp.
Yukinori
Y
Okada
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. shimmy@kuhp.kyoto-u.ac.jp.
Masakazu
M
Shimizu
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. nnnmd11@hotmail.com.
Naoshi
N
Nishina
Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan. akaris@src.riken.jp.
Akari
A
Suzuki
Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan. keimyouzen@src.riken.jp.
Keiko
K
Myouzen
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. tkawa@genome.med.kyoto-u.ac.jp.
Takahisa
T
Kawaguchi
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. meiko@genome.med.kyoto-u.ac.jp.
Meiko
M
Takahashi
Dohgo Spa Hospital, Matsuyama, Japan. keetakas@ehime.med.or.jp.
Kiyoshi
K
Takasugi
Department of Rheumatology, Niigata Rheumatic Center, Niigata, Japan. med@ra-center.com.
Akira
A
Murasawa
The Centre for Rheumatic Diseases, Matsuyama Red Cross Hospital, Matsuyama, Japan. smizuki@matsuyama.jrc.or.jp.
Shinichi
S
Mizuki
Higashihiroshima Memorial Hospital, Hiroshima, Japan. ajisu@hotmail.com.
Mitsuhiro
M
Iwahashi
Pharm C, Matsubara Mayflower Hospital, 944-25 Fujita, Kato City, Hyogo, Japan. kansetsusaisei123@cup.ocn.ne.jp.
Keiko
K
Funahashi
Kurashiki Sweet Hospital, Kurashiki, Japan. zaraspook3hook@yahoo.co.jp.
Masamitsu
M
Natsumeda
Department of the Control for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan. morifuru@kuhp.kyoto-u.ac.jp.
Moritoshi
M
Furu
Department of the Control for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan. mohashim@kuhp.kyoto-u.ac.jp.
Motomu
M
Hashimoto
Department of the Control for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan. hiromu@kuhp.kyoto-u.ac.jp.
Hiromu
H
Ito
Department of the Control for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan. takfujii@kuhp.kyoto-u.ac.jp.
Takao
T
Fujii
Kurashiki Sweet Hospital, Kurashiki, Japan. ky-6182@rice.ocn.ne.jp.
Kazuhiko
K
Ezawa
Matsubara Mayflower Hospital, 944-25 Fujita, Kato City, Hyogo, Japan. mats@mayflower-hp.jp.
Tsukasa
T
Matsubara
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. tsutake@z5.keio.jp.
Tsutomu
T
Takeuchi
Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan. mkubo@src.riken.jp.
Michiaki
M
Kubo
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. ryamada@genome.med.kyoto-u.ac.jp.
Ryo
R
Yamada
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. amtanigu@ior.twmu.ac.jp.
Atsuo
A
Taniguchi
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. yamanaka@ior.twmu.ac.jp.
Hisashi
H
Yamanaka
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. smomohara@ior.twmu.ac.jp.
Shigeki
S
Momohara
Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan. yamamoto-tky@umin.ac.jp.
Kazuhiko
K
Yamamoto
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan. mimorit@kuhp.kyoto-u.ac.jp.
Tsuneyo
T
Mimori
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. fumi@genome.med.kyoto-u.ac.jp.|Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto, Japan. fumi@genome.med.kyoto-u.ac.jp.
Fumihiko
F
Matsuda
D001172:Arthritis, Rheumatoid / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D044466:Asian People / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D010456:Peptides, Cyclic / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values
D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide