Abstract
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.
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Acknowledgements
We thank E. Tatsu, K. Kobayashi, E. Kanno, M. Mito, N. Iwamoto and the other members of the Laboratory for Rheumatic Diseases for technical assistance; H. Kawakami for computer programming; many members of the SNP Research Center for assistance; S. Tsukada, D. Nakai, R. Nakagomi, R. Kawaida and M. Nakayama-Hamada for discussions; and M. Yukioka, S. Tohma, T. Matsubara, S. Wakitani, R. Teshima and Y. Nishioka for clinical sample collection. This work was supported by a grant from the Japanese Millennium Project.
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Tokuhiro, S., Yamada, R., Chang, X. et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 35, 341–348 (2003). https://doi.org/10.1038/ng1267
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DOI: https://doi.org/10.1038/ng1267
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