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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Cornelis, F. et al. New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc. Natl. Acad. Sci. USA 95, 10746–10750 (1998).
Shiozawa, S. et al. Identification of the gene loci that predispose to rheumatoid arthritis. Int. Immunol. 10, 1891–1895 (1998).
MacKay, K. et al. Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. Arthritis Rheum. 46, 632–639 (2002).
Jawaheer, D. et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am. J. Hum. Genet. 68, 927–936 (2001).
Seldin, M.F., Amos, C.I., Ward, R. & Gregersen, P.K. The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum. 42, 1071–1079 (1999).
Begovich, A.B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).
Suzuki, A. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).
Remmers, E.F. et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986 (2007).
Kochi, Y. et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat. Genet. 37, 478–485 (2005).
Tokuhiro, S. 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).
Plenge, R.M. et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am. J. Hum. Genet. 77, 1044–1060 (2005).
Iwamoto, T. et al. Association between PADI4 and rheumatoid arthritis: a meta-analysis. Rheumatology (Oxford) 45, 804–807 (2006).
Lee, Y.H. et al. The PTPN22 C1858T functional polymorphism and autoimmune diseases–a meta-analysis. Rheumatology (Oxford) 46, 49–56 (2007).
Yamada, R. & Yamamoto, K. Recent findings on genes associated with inflammatory disease. Mutat. Res. 573, 136–151 (2005).
Mori, M., Yamada, R., Kobayashi, K., Kawaida, R. & Yamamoto, K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J. Hum. Genet. 50, 264–266 (2005).
Thomson, W. et al. Rheumatoid arthritis association at 6q23. Nat. Genet. 39, 1431–1433 (2007).
Scofield, R.H. et al. Thrombocytopenia identifies a severe familial phenotype of systemic lupus erythematosus and reveals genetic linkages at 1q22 and 11p13. Blood 101, 992–997 (2003).
de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).
Graham, D.S. et al. Association of LY9 in UK and Canadian SLE families. Genes Immun. 9, 93–102 (2008).
Balding, D.J. A tutorial on statistical methods for population association studies. Nat. Rev. Genet. 7, 781–791 (2006).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
Stranger, B.E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).
Tregouet, D.A. & Garelle, V. A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies. Bioinformatics 23, 1038–1039 (2007).
Cordell, H.J. & Clayton, D.G. A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am. J. Hum. Genet. 70, 124–141 (2002).
Pajukanta, P. et al. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat. Genet. 36, 371–376 (2004).
Nakajima, H. & Colonna, M. 2B4: an NK cell activating receptor with unique specificity and signal transduction mechanism. Hum. Immunol. 61, 39–43 (2000).
Claus, M., Meinke, S., Bhat, R. & Watzl, C. Regulation of NK cell activity by 2B4, NTB-A and CRACC. Front. Biosci. 13, 956–965 (2008).
Yamamoto, K. & Yamada, R. Lessons from a genomewide association study of rheumatoid arthritis. N. Engl. J. Med. 357, 1250–1251 (2007).
The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
Hochberg, M.C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997).
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.
Author information
Authors and Affiliations
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
Supplementary information
Supplementary Text and Figures
Supplementary Figure 1, Supplementary Tables 1 and 2 (PDF 165 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.205
This article is cited by
-
Genetics of rheumatoid arthritis
Seminars in Immunopathology (2022)
-
Brief report: Decreased expression of CD244 (SLAMF4) on monocytes and platelets in patients with systemic lupus erythematosus
Clinical Rheumatology (2018)
-
T‐cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases
Immunology & Cell Biology (2016)
-
Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population
Arthritis Research & Therapy (2015)
-
Single nucleotide polymorphisms in TNFAIP3 were associated with the risks of rheumatoid arthritis in northern Chinese Han population
BMC Medical Genetics (2014)