title: PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population.
abstract: OBJECTIVE
  Systemic sclerosis (SSc) is an autoimmune disease for which multiple susceptibility genes have been reported. Genome-wide association studies have shown that large numbers of susceptibility genes are shared among autoimmune diseases. Recently, our group identified 9 novel susceptibility genes associated with rheumatoid arthritis (RA) in a Japanese population. The aim of this study was to elucidate whether the 18 genes that displayed associations or suggestive associations for RA in our previous study are associated with SSc in Japanese.
  
  
  METHODS
  We performed an association study that included 415 patients with SSc and 16,891 control subjects, followed by a replication study that included 315 patients and 21,054 control subjects. The 18 markers reported to display association with RA were analyzed for their associations with SSc in the first study, and 5 markers were further analyzed in the replication study. The inverse variance method was used to evaluate the associations of these markers with SSc in a combined study.
  
  
  RESULTS
  In the phospholipase D4 gene (PLD4), rs2841277 displayed a significant association with SSc in Japanese patients (P = 0.00017). We observed that rs2841280 in exon 2 of PLD4 was in strong linkage disequilibrium with rs2841277 and introduced an amino acid alteration. We also observed associations between SSc and rs6932056 in TNFAIP3 and rs2280381 in IRF8 (P = 0.0000095 and P = 0.0030, respectively), both of which displayed associations with SSc in a European population.
  
  
  CONCLUSIONS
  We determined that PLD4 is a novel susceptibility gene for SSc in Japanese, thus confirming the involvement of PLD4 in autoimmunity. Associations between SSc and TNFAIP3 or IRF8 were also detected in our Japanese population. SSc and RA appear to share relatively large proportions of their genetic backgrounds.
authors.affiliation: Kyoto University, Kyoto, Japan. a0001101@kuhp.kyotou.ac.jp
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nishimoto
authors.forename: Aya
authors.initials: A
authors.lastname: Kawasaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ota
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikari
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
authors.forename: Shigeto
authors.initials: S
authors.lastname: Tohma
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Masataka
authors.initials: M
authors.lastname: Kuwana
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D005092:Exonucleases; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007564:Japan; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D010739:Phospholipase D / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000099185:Interferon Regulatory Factor-8; D005090:Exodeoxyribonucleases
chemical_list: D004268:DNA-Binding Proteins; D005092:Exonucleases; D050835:Interferon Regulatory Factors; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010739:Phospholipase D; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000099185:Interferon Regulatory Factor-8; C579637:PLD4 protein, human; D005090:Exodeoxyribonucleases; C076529:TNFAIP3 protein, human