Zhou Wei, Yang Qi, Yu Huan, Zhang Qing, Zou Yan, Chen Xuekun, Yang Zhenzhen, Qu Yiling, Tan Rui, Li Lijuan, Zhu Shaohua, He Yan, Luo Bin, Gao Yuzhen
Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
Department of Epidemiology, Medical College of Soochow University, Suzhou, China.
Leg Med (Tokyo). 2020 Sep;46:101736. doi: 10.1016/j.legalmed.2020.101736. Epub 2020 Jun 13.
Individuals harbouring specific genetic variations might trend towards suffering sudden cardiac death. Cystathionine-γ-lyase is one of the key enzymes of endogenous hydrogen sulfide production, and a key factor on the expression regulation of hydrogen sulfide in human heart. Compelling studies have suggested the cardioprotective effects of hydrogen sulfide, while it remains controversial whether cystathionine-γ-lyase and hydrogen sulfide are beneficial to cardiovascular diseases. In this study, we performed a candidate-gene-based study to evaluate the association of the Indel polymorphism rs113044851 within the 3' untranslated region of Cystathionine-γ-lyase gene and risk of sudden cardiac death in a Chinese Han population. Logistic regression analysis showed that the insertion allele of rs113044851 significantly decreased the risk of sudden cardiac death [odds ratio = 0.58; 95% confidence interval:0.38-0.88; P = 0.0076]. Further genotype-phenotype association analysis indicated that the insertion allele was significantly associated with lower expression of cystathionine-γ-lyase in myocardium tissues. The subsequently in-silico predication revealed that compared with the deletion allele, the binding of the insertion allele with miR-1324 matched better. Finally, dual-luciferase activity assay validated the prediction that the gene transcriptional activity indicated by firefly luciferase activity with ins/ins genotype was lower than that with del/del genotype. In summary, our data suggested that rs113044851 might contribute to susceptibility of sudden cardiac death via regulating gene expression at post-transcriptional level. This indel has the potential to become a molecular diagnosis marker and genetic counseling of sudden cardiac death.
携带特定基因变异的个体可能更容易发生心源性猝死。胱硫醚-γ-裂解酶是内源性硫化氢生成的关键酶之一，也是人类心脏中硫化氢表达调控的关键因素。有说服力的研究表明硫化氢具有心脏保护作用，而胱硫醚-γ-裂解酶和硫化氢是否对心血管疾病有益仍存在争议。在本研究中，我们进行了一项基于候选基因的研究，以评估胱硫醚-γ-裂解酶基因3'非翻译区内插入/缺失多态性rs113044851与中国汉族人群心源性猝死风险的关联。逻辑回归分析表明，rs113044851的插入等位基因显著降低了心源性猝死的风险[比值比=0.58；95%置信区间：0.38 - 0.88；P = 0.0076]。进一步的基因型-表型关联分析表明，插入等位基因与心肌组织中胱硫醚-γ-裂解酶的低表达显著相关。随后的电子预测显示，与缺失等位基因相比，插入等位基因与miR-1324的结合更好。最后，双荧光素酶活性测定验证了萤火虫荧光素酶活性所指示的基因转录活性，ins/ins基因型低于del/del基因型的预测。总之，我们的数据表明，rs113044851可能通过在转录后水平调节基因表达来影响心源性猝死的易感性。这种插入/缺失有可能成为心源性猝死的分子诊断标志物和遗传咨询指标。
