title: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis.
abstract: Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of the peptidylarginine deiminases citrullinating enzymes (encoded by PADI genes) in rheumatoid arthritis. Previous linkage studies have shown that a susceptibility locus for rheumatoid arthritis includes four PADI genes but did not establish which PADI gene confers susceptibility to rheumatoid arthritis. We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008). PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues. We also identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis. Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease.
authors.affiliation: Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22, Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Chang
authors.forename: Shinya
authors.initials: S
authors.lastname: Tokuhiro
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sawada
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Suzuki
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nagasaki
authors.forename: Makiko
authors.initials: M
authors.lastname: Nakayama-Hamada
authors.forename: Reimi
authors.initials: R
authors.lastname: Kawaida
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ono
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ohtsuki
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Furukawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yoshino
authors.forename: Masao
authors.initials: M
authors.lastname: Yukioka
authors.forename: Shigeto
authors.initials: S
authors.lastname: Tohma
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Matsubara
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Wakitani
authors.forename: Ryota
authors.initials: R
authors.lastname: Teshima
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nishioka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sekine
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000737:chemistry / Q000378:metabolism; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002956:Citrulline / Q000737:chemistry / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D006239:Haplotypes; D006801:Humans; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D010455:Peptides; D012333:RNA, Messenger; D002956:Citrulline; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases