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Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population

Abstract

Rheumatoid arthritis is a chronic autoimmune inflammatory disease with a complex genetic etiology. Members of the signaling lymphocyte activation molecule (SLAM) family carry out pivotal functions in innate immunity and in conventional lymphocytes. We identified a linkage disequilibrium block associated with rheumatoid arthritis in the chromosome 1q region containing multiple SLAM family genes. In this block, the association peaked at two functional SNPs (rs3766379 and rs6682654) in CD244 in two independent rheumatoid arthritis cohorts from Japan (P = 3.23 × 10−8 and P = 7.45 × 10−8). We also identified a Japanese cohort with systemic lupus erythematosus that had a similar genotype distribution as the rheumatoid arthritis cohorts. We demonstrated that the rheumatoid arthritis–susceptible alleles of rs3766379 and rs6682654 and their haplotype increased their expression in luciferase and allele-specific transcript quantification assays. CD244 is a genetic risk factor for rheumatoid arthritis and may have a role in the autoimmune process shared by rheumatoid arthritis and systemic lupus erythematosus.

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Figure 1: LD block and allelic association around CD244.
Figure 2: Association between CD244 expression and SNPs in CD244 and neighboring genes from ref. 22.
Figure 3: Functional assessment of CD244 SNPs using Jurkat E6-1 cells.
Figure 4: Allelic imbalance of gene expression of CD244 in an EBV-transformed lymphoblastoid cell line with the heterozygous genotypes.

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Gene Expression Omnibus

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Acknowledgements

We thank K. Kobayashi, M. Ohtake-Yamanaka, E. Kanno and all members of the rheumatoid arthritis team for their advice and technical assistance; H. Kawakami and T. Kawaguchi for their expertise in computer programming; and members of the Center for Genomic Medicine of RIKEN and the Biomedical Research Laboratories of Sankyo Co. Ltd. for helpful discussions and assistance in various aspects of this study. We are also grateful to members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan, the Pharma SNP Consortium in Japan and the BioBank Japan Project for supporting our study. This work was supported by grants from the Japanese Millennium Project and the Japanese Ministry of Health, Labor and Welfare.

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Authors

Contributions

A.S. performed most of the experiments and wrote the manuscript; R.Y. and Y.O. performed the data analysis and managed DNA samples and clinical information; Y. Kochi and M.M. summarized clinical data and performed SNP genotyping; T.S. and A.M. managed DNA samples and clinical information; K.S., K.M. and Y. Kamatani performed the SLE association study; Y.H. managed SLE samples; T.T., A.T. and N.K. performed the data analysis; M.K. contributed to SNP genotyping and managed DNA samples; Y.N. managed DNA samples and the project; and K.Y. planned and supervised the whole project.

Corresponding author

Correspondence to Kazuhiko Yamamoto.

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Supplementary Figure 1, Supplementary Tables 1 and 2 (PDF 165 kb)

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Suzuki, A., Yamada, R., Kochi, Y. et al. Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population. Nat Genet 40, 1224–1229 (2008). https://doi.org/10.1038/ng.205

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