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Abstract：
Definitive diagnosis to sudden cardiac death (SCD) is often challenging since the postmortem examination on SCD victims could hardly demonstrate an adequate cause of death. It is therefore important to uncover the inherited risk component to SCD. Signal transducer and activators of transcription 5 A (STAT5A) is a member of the STAT family and a transcription factor that is activated by many cell ligands and associated with various cardiovascular processes. In this study, we performed a systematic variant screening on the STAT5A to filter potential functional genetic variations. Based on the screening results, an insertion/deletion polymorphism (rs3833144) in 3\'UTR of STAT5A was selected as the candidate variant. A total of 159 SCD cases and 668 SCD matched healthy controls was enrolled to perform a case-control study and evaluate the association between rs3833144 and SCD susceptibility in Chinese populations. Logistic regression analysis showed that the deletion allele of rs3833144 had significantly increased the SCD risk (odds ratio (OR) = 1.54; 95% confidence interval (CI) = 1.18-2.01; P = 0.000955). Further genotype-expression eQTL analysis showed that samples with deletion allele appeared to lower expression of STAT5A, and in silico prediction suggested the local 3 D structure changes of STAT5A mRNA caused by the variant. On the other hand, the bioinformatic analysis presented that promoters of RARA and PTGES3L-AARSD1 could interact with rs3833144, and eQTL analysis showed the higher expression of both genes in samples with deletion allele. Dual-luciferase activity assays also suggested the significant regulatory role of rs3833144 in gene transcription. Our current data thus suggested a possible involvement of rs3833144 to SCD predisposition in Chinese populations and rs3833144 with potential function roles may become a candidate marker for SCD diagnosis and prevention.
摘要：
对心源性猝死（SCD）的明确诊断通常具有挑战性，因为对SCD受害者的验尸几乎无法证明足够的死亡原因。因此，重要的是发现SCD的遗传风险成分。信号转导和转录激活因子5A（STAT5A）是STAT家族的成员，是一种被许多细胞配体激活并与各种心血管过程相关的转录因子。在这项研究中,我们对STAT5A进行了系统变异筛选,以筛选潜在的功能性遗传变异.根据筛选结果,选择STAT5A的3UTR中的插入/缺失多态性（rs3833144）作为候选变体。共纳入159例SCD病例和668例SCD匹配的健康对照进行病例对照研究，并评估rs3833144与中国人群SCD易感性之间的关联。Logistic回归分析显示rs3833144缺失等位基因显著增加SCD风险(比值比(OR)=1.54；95%置信区间(CI)=1.18~2.01；P=0.000955)。进一步的基因型表达eQTL分析显示,等位基因缺失的样本出现STAT5A表达降低,计算机预测提示了该变体引起的STAT5AmRNA的局部三维结构变化。另一方面,生物信息学分析表明，RARA和PTGES3L-AARSD1的启动子可以与rs3833144相互作用，eQTL分析显示这两个基因在等位基因缺失的样品中的表达更高。双荧光素酶活性测定还表明rs3833144在基因转录中的重要调节作用。因此，我们目前的数据表明rs3833144可能参与中国人群的SCD易感性，具有潜在功能作用的rs3833144可能成为SCD诊断和预防的候选标志物。
