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A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility

Abstract

Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here, through a genome-wide association study of rheumatoid arthritis, we identified a polymorphism in CCR6, the gene encoding chemokine (C-C motif) receptor 6 (a surface marker for Th17 cells) at 6q27, that was associated with rheumatoid arthritis susceptibility and was validated in two independent replication cohorts from Japan (rs3093024, a total of 7,069 individuals with rheumatoid arthritis (cases) and 20,727 controls, overall odds ratio = 1.19, P = 7.7 × 10−19). We identified a triallelic dinucleotide polymorphism of CCR6 (CCR6DNP) in strong linkage disequilibrium with rs3093024 that showed effects on gene transcription. The CCR6DNP genotype was correlated with the expression level of CCR6 and was associated with the presence of interleukin-17 (IL-17) in the sera of subjects with rheumatoid arthritis. Moreover, CCR6DNP was associated with susceptibility to Graves' and Crohn's diseases. These results suggest that CCR6 is critically involved in IL-17–driven autoimmunity in human diseases.

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Figure 1: Results of GWAS and expression analysis around CCR6.
Figure 2: CCR6DNP genotype is correlated with the expression level of CCR6 and IL-17 status of rheumatoid arthritis cases.

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NCBI Reference Sequence

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Acknowledgements

We thank K. Shimada, Y. Hayashi, K. Kobayashi, M. Kitazato and other members of the Laboratory for Autoimmune Diseases, RIKEN and Y. Katagiri at Tokyo Women's Medical University, for their technical assistance. We also thank the members of BioBank Japan and the Rotary Club of Osaka-Midosuji District 2660 Rotary International for supporting our study. This work was conducted as a part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. The replication study of rheumatoid arthritis was performed under the support of Genetics and Allied research in Rheumatoid Arthritis Networking (GARNET) consortium.

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Authors and Affiliations

Authors

Contributions

Y.K., Y.O. and K. Yamamoto. designed the study and drafted the manuscript. Y.O., A.T., T.T. and R.Y. analyzed the GWAS data. N.H. and M.K. performed the genotyping for the GWAS. Y.K. performed expression analysis of CCR6 and functional analysis of CCR6 polymorphisms. Y.K. and K.M. established the genotyping method for CCR6DNP. K.I., S.M. and H.Y. analyzed data for the first replication cohort of rheumatoid arthritis. C.T., K.O., T.M., R.Y. and F.M. analyzed the data for the second replication cohort of rheumatoid arthritis. Y.K. analyzed the data for the Graves' disease cohort. K. Yamazaki analyzed the data for the Crohn's disease cohort. T.F. and S.I. analyzed the data for the fourth control cohort. T.I. and K.I. analyzed CCR6 expression in the synovial tissues. Y.K. and A.S. analyzed the sera of subjects with rheumatoid arthritis. M.K., N.K. and Y.N. contributed to overall GWAS study design.

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Correspondence to Yuta Kochi.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–6 (PDF 803 kb)

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Kochi, Y., Okada, Y., Suzuki, A. et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat Genet 42, 515–519 (2010). https://doi.org/10.1038/ng.583

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