Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis.
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.
Suzuki
Akari
A
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.
Yamada
Ryo
R
Chang
Xiaotian
X
Tokuhiro
Shinya
S
Sawada
Tetsuji
T
Suzuki
Masakatsu
M
Nagasaki
Miyuki
M
Nakayama-Hamada
Makiko
M
Kawaida
Reimi
R
Ono
Mitsuru
M
Ohtsuki
Masahiko
M
Furukawa
Hidehiko
H
Yoshino
Shinichi
S
Yukioka
Masao
M
Tohma
Shigeto
S
Matsubara
Tsukasa
T
Wakitani
Shigeyuki
S
Teshima
Ryota
R
Nishioka
Yuichi
Y
Sekine
Akihiro
A
Iida
Aritoshi
A
Takahashi
Atsushi
A
Tsunoda
Tatsuhiko
T
Nakamura
Yusuke
Y
Yamamoto
Kazuhiko
K
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
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