An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis.
Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.
Tokuhiro
Shinya
S
Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.
Yamada
Ryo
R
Chang
Xiaotian
X
Suzuki
Akari
A
Kochi
Yuta
Y
Sawada
Tetsuji
T
Suzuki
Masakatsu
M
Nagasaki
Miyuki
M
Ohtsuki
Masahiko
M
Ono
Mitsuru
M
Furukawa
Hidehiko
H
Nagashima
Masakazu
M
Yoshino
Shinichi
S
Mabuchi
Akihiko
A
Sekine
Akihiro
A
Saito
Susumu
S
Takahashi
Atsushi
A
Tsunoda
Tatsuhiko
T
Nakamura
Yusuke
Y
Yamamoto
Kazuhiko
K
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003094:Collagen / Q000494:pharmacology; D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns / Q000235:genetics*; D019169:Jurkat Cells; D015810:Linkage Disequilibrium; D008156:Luciferases; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D027701:Organic Cation Transport Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D000074058:Solute Carrier Family 22 Member 5; D014157:Transcription Factors / Q000235:genetics*
D002352:Carrier Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D014157:Transcription Factors; D003094:Collagen; D008156:Luciferases