A Graves' disease-associated Kozak sequence single-nucleotide polymorphism enhances the efficiency of CD40 gene translation:: A case for translational pathophysiology
A Graves' disease-associated Kozak sequence single-nucleotide polymorphism enhances the efficiency of CD40 gene translation:: A case for translational pathophysiology
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DOI：
10.1210/en.2004-1617
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发表时间：
2005-06-01
期刊：
影响因子：
4.8
通讯作者：
Tomer, Y
中科院分区：
文献类型：
--
作者：
Jacobson, EM;Concepcion, E;Tomer, Y
我们分析了CD40 Kozak序列中与Graves病相关的C/T多态影响CD40表达的机制。CT型和TT型患者B细胞表面CD40CD40表达水平较CC型患者分别降低13.3%和39.4%(P=0.012)。与C等位基因相比，转导T等位基因的大鼠成纤维细胞表达的CD40量减少32.2%(P=0.004)。此外，体外转录/翻译系统显示，T等位基因产生的CD40比C等位基因少15.5%(P<；0.001)，这表明单核苷酸多态对CD40表达的影响是在翻译水平上的。然而，SNP不影响转录，因为定量RT-PCR检测的CD40的mRNA水平不受基因型的影响。因此，我们的结果可能提示与Graves病相关的CD40Kozak SNP的C等位基因可能通过提高CD40mRNA的翻译效率而易患疾病。
We analyzed the mechanism by which a Graves' disease-associated C/T polymorphism in the Kozak sequence of CD40 affects CD40 expression. CD40 expression levels on B cells in individuals with CT and TT genotypes were decreased by 13.3 and 39.4%, respectively, compared with the levels in CC genotypes ( P = 0.012). Similarly, Rat-2 fibroblasts transfected with T-allele cDNA expressed 32.2% less CD40 compared with their C-allele-transfected counterparts ( P = 0.004). Additionally, an in vitro transcription/translation system showed that the T-allele makes 15.5% less CD40 than the C-allele ( P< 0.001), demonstrating that the effect of the single-nucleotide polymorphism ( SNP) on CD40 expression is at the level of translation. However, the SNP did not affect transcription, because the mRNA levels of CD40, as measured by quantitative RTPCR, were independent of genotype. Therefore, our results may suggest that the C allele of the CD40 Kozak SNP, which is associated with Graves' disease, could predispose to disease by increasing the efficiency of translation of CD40 mRNA.