An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis
An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis
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DOI：
10.1038/ng1267
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发表时间：
2003-12-01
期刊：
影响因子：
30.8
通讯作者：
Yamamoto, K
中科院分区：
文献类型：
--
作者：
Tokuhiro, S;Yamada, R;Yamamoto, K
类风湿关节炎是一种常见的炎症性疾病，具有复杂的遗传成分。我们利用单核苷酸多态性（SNPs）进行病例对照连锁不平衡（LD）定位，研究了日本人群中5q31染色体细胞因子基因簇对类风湿关节炎易感性的遗传贡献。在这里，我们报道类风湿关节炎与有机阳离子转运基因SLC22A4之间存在显著关联（P=0.000034）。我们发现SLC22A4的表达对血液和免疫组织具有特异性，并且SLC22A4在胶原诱导关节炎小鼠的炎症关节中也有高表达。一个SNP影响SLC22A4在体外的转录效率，这是由于与造血系统中的转录调节因子RUNX1 （RUNX1）的亲和力存在等位基因差异。RUNX1中的SNP也与类风湿关节炎密切相关（P=0.00035）。我们的数据表明，RUNX1对SLC22A4表达的调控与类风湿关节炎的易感性有关，这可能是两个基因对这种疾病的上位性作用的一个例子。
Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P=0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P=0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.