A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility

• Published in: Nature genetics Vol. 42; no. 6; pp. 515 - 519
• Main Authors: Kochi, Yuta, Okada, Yukinori, Suzuki, Akari, Ikari, Katsunori, Terao, Chikashi, Takahashi, Atsushi, Yamazaki, Keiko, Hosono, Naoya, Myouzen, Keiko, Tsunoda, Tatsuhiko, Kamatani, Naoyuki, Furuichi, Tatsuya, Ikegawa, Shiro, Ohmura, Koichiro, Mimori, Tsuneyo, Matsuda, Fumihiko, Iwamoto, Takuji, Momohara, Shigeki, Yamanaka, Hisashi, Yamada, Ryo, Kubo, Michiaki, Nakamura, Yusuke, Yamamoto, Kazuhiko
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2010; Nature Publishing Group
• Subjects: 631/208/200; 631/208/205/2138; 631/208/727/2000; 692/699/249/1313/498; Agriculture; Animal Genetics and Genomics; Arthritis; Arthritis, Rheumatoid - genetics; Autoimmune diseases; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Disease susceptibility; Diseases of the osteoarticular system; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Function; Genetic aspects; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Human Genetics; Humans; Inflammatory joint diseases; Interleukin-17 - blood; letter; Medical sciences; Pathogenesis; Polymorphism, Genetic; Receptors, CCR6 - genetics; Receptors, CCR6 - metabolism; Regulatory Elements, Transcriptional; Rheumatism; Rheumatoid arthritis; Risk factors; Single nucleotide polymorphisms; Studies; Japan; Variant; Immunopathology; Chronic; Rheumatoid arthritis; Diseases of the osteoarticular system; Autoimmune disease; Inflammatory joint disease
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.583

Yuta Kochi and colleagues identify a regulatory variant in CCR6 associated with susceptibility to rheumatoid arthritis. CCR6 encodes a chemokine receptor expressed on a subset of helper T cells known as Th17 cells, suggesting a possible role for CCR6 in Th17-driven autoimmunity. 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.