A functional SNP in the NKX2.5-binding site of ITPR3 promoter is associated with susceptibility to systemic lupus erythematosus in Japanese population
A functional SNP in the NKX2.5-binding site of ITPR3 promoter is associated with susceptibility to systemic lupus erythematosus in Japanese population
复制标题
DOI：
10.1007/s10038-007-0233-3
复制
发表时间：
2008-02-01
影响因子：
3.5
通讯作者：
Matsuda, Koichi
中科院分区：
文献类型：
--
作者：
Oishi, Tetsuya;Iida, Aritoshi;Matsuda, Koichi
系统性红斑狼疮(SLE)是常见的自身免疫性疾病之一，具有复杂的遗传成分。为了确定系统性红斑狼疮的易感基因(S)，我们在日本人群中进行了一项基于全基因组基因的单核苷酸多态性(SNPs)的病例对照关联研究。在此，我们报告了位于染色体6p21上的三磷酸肌醇受体3基因启动子区域的一个SNP(Rs3748079)与系统性红斑狼疮显著相关[P=0.0000000178，优势比为1.88，95%可信区间为1.51-2.35]。该SNP与类风湿关节炎(RA)和Graves病(GD)也有关联(P=0.0084，OR=1.23，95%CI为1.05~1.43)和(P=0.00036，OR=1.57，95%CI为1.22~2.02)。我们发现NKX2.5在包括该SNP在内的区域与非易感T等位基因特异结合。此外，NKX2.5SNP与系统性红斑狼疮有关联(P=0.0037，优势比为1.74，95%CI为1.19~2.55)。同时携带ITPR3和NKX2.5基因座风险基因的个体患SLE的风险较高(优势比=5.77)。我们的数据表明，ITPR3和NKX2.5的遗传和功能相互作用在SLE的发病机制中起着至关重要的作用。
Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases with complex genetic components. To identify a gene(s) susceptible to SLE, we performed a case-control association study using genome-wide gene-based single nucleotide polymorphisms (SNPs) in Japanese population. Here we report that an SNP (rs3748079) located in a promoter region of the inositol 1,4,5-triphosphate receptor type 3 (ITPR3) gene on chromosome 6p21 was significantly associated with SLE in two independent Japanese case-control samples [P = 0.0000000178 with odds ratio of 1.88, 95% confidence interval (CI) of 1.51-2.35]. This particular SNP also revealed associations with rheumatoid arthritis (RA) (P = 0.0084 with odds ratio of 1.23, 95% CI of 1.05-1.43) and with Graves' disease (GD) (P = 0.00036 with odds ratio of 1.57, 95% CI of 1.22-2.02). We found the binding of NKX2.5 specific to the non-susceptible T allele in the region including this SNP. Furthermore, an SNP in NKX2.5 also revealed an association with SLE (P = 0.0037 with odds ratio of 1.74, 95% CI of 1.19-2.55). Individuals with risk genotype of both ITPR3 and NKX2.5 loci have higher risk for SLE (odds ratio = 5.77). Our data demonstrate that genetic and functional interactions of ITPR3 and NKX2.5 play a crucial role in the pathogenesis of SLE.