A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility
A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility
复制标题
DOI：
10.1038/ng.583
复制
发表时间：
2010-06-01
期刊：
影响因子：
30.8
通讯作者：
Yamamoto, Kazuhiko
中科院分区：
文献类型：
--
作者：
Kochi, Yuta;Okada, Yukinori;Yamamoto, Kazuhiko
类风湿性关节炎是一种常见的自身免疫性疾病，具有复杂的遗传病因。通过对类风湿关节炎的全基因组关联研究，我们在6q27位点发现了编码趋化因子（C-C基序）受体6 （Th17细胞的表面标记）的基因CCR6多态性，该多态性与类风湿关节炎易感性相关，并在来自日本的两个独立复制队列（rs3093024，共7,069例类风湿关节炎患者（病例）和20,727例对照，总体优势比= 1.19,P = 7.7 x 10(19)）中得到验证。我们发现CCR6 （CCR6DNP）在与rs3093024的强连锁不平衡中存在三等位基因二核苷酸多态性，该多态性对基因转录有影响。CCR6DNP基因型与CCR6的表达水平相关，与类风湿关节炎患者血清中白细胞介素-17 （IL-17）的存在相关。此外，CCR6DNP与格雷夫斯病和克罗恩病的易感性有关。这些结果表明，CCR6在人类疾病中il -17驱动的自身免疫中起关键作用。
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 x 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.