Zhao Wenfeng, Zhang Qing, Wang Jiawen, Yu Huan, Zhen Xiaoyuan, Li Lijuan, Qu Yan, He Yan, Zhang Jianhua, Li Chengtao, Zhang Suhua, Luo Bin, Huang Jiang, Gao Yuzhen
Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
Institute of Forensic Medicine, Guizhou Medical University, Guiyang, China.
Front Genet. 2022 Apr 11;13:869859. doi: 10.3389/fgene.2022.869859. eCollection 2022.
Sudden cardiac death (SCD) was defined as an unexpected death from cardiac causes during a very short duration. It has been reported that Niemann-Pick type C1 () gene mutations might be related to cardiovascular diseases. The purpose of the study is to investigate whether common genetic variants of is involved in SCD susceptibility. Based on a candidate-gene-based approach and systematic screening strategy, this study analyzed an 8-bp insertion/deletion polymorphism (rs150703258) within downstream of for the association with SCD risk in Chinese populations using 158 SCD cases and 524 controls. The association of rs150703258 and SCD susceptibility was analyzed using logistic regression. Genotype-phenotype correlation analysis was performed using public database including 1000G, expression quantitative trait loci (eQTL), and further validated by human heart tissues using PCR. Dual-luciferase assay was used to explore the potential regulatory role of rs150703258. Gene expression profiling interactive analysis and transcription factors prediction were performed. Logistic regression analysis exhibited that the deletion allele of rs150703258 significantly increased the risk of SCD [odds ratio (OR) = 1.329; 95% confidence interval (95%CI):1.03-1.72; = 0.0289]. Genotype-phenotype correlation analysis showed that the risk allele was significantly associated with higher expression of NPC1 at mRNA and protein expressions level in human heart tissues. eQTL analysis showed NPC1 and C18orf8 (an adjacent gene to NPC1) are both related to rs150703258 and have higher expression level in the samples with deletion allele. Dual-luciferase activity assays indicate a significant regulatory role for rs150703258. Gene expression profiling interactive analysis revealed that NPC1 and C18orf8 seemed to be co-regulated in human blood, arteries and heart tissues. analysis showed that the rs150703258 deletion variant may create transcription factor binding sites. In addition, a rare 12-bp allele (4-bp longer than the insertion allele) of rs150703258 was discovered in the current cohort. In summary, our study revealed that rs150703258 might contribute to SCD susceptibility by regulating NPC1 and C18orf8 expression. This indel may be a potential marker for risk stratification and molecular diagnosis of SCD. Validations in different ethnic groups with larger sample size and mechanism explorations are warranted to confirm our findings.
心源性猝死（SCD）被定义为在极短时间内由心脏原因导致的意外死亡。据报道，尼曼-匹克C1型（NPC1）基因突变可能与心血管疾病有关。本研究的目的是调查NPC1常见基因变异是否与SCD易感性有关。基于候选基因方法和系统筛选策略，本研究使用158例SCD病例和524例对照，分析了NPC1下游的一个8碱基对插入/缺失多态性（rs150703258）与中国人群SCD风险的关联。使用逻辑回归分析rs150703258与SCD易感性的关联。使用包括千人基因组计划（1000G）、表达数量性状位点（eQTL）的公共数据库进行基因型-表型相关性分析，并通过人心脏组织的聚合酶链反应（PCR）进一步验证。使用双荧光素酶测定法探索rs150703258的潜在调控作用。进行基因表达谱交互分析和转录因子预测。逻辑回归分析显示，rs150703258的缺失等位基因显著增加了SCD风险[比值比（OR）=1.329；95%置信区间（95%CI）：1.03 - 1.72；P = 0.0289]。基因型-表型相关性分析表明，风险等位基因在人心脏组织的mRNA和蛋白质表达水平上与NPC1的较高表达显著相关。eQTL分析表明，NPC1和C18orf8（NPC1的相邻基因）均与rs150703258相关，并且在具有缺失等位基因的样本中具有较高的表达水平。双荧光素酶活性测定表明rs150703258具有显著的调控作用。基因表达谱交互分析显示，NPC1和C18orf8在人血液、动脉和心脏组织中似乎受到共同调控。分析表明，rs150703258缺失变异可能会产生转录因子结合位点。此外，在当前队列中发现了rs150703258的一个罕见的12碱基对等位基因（比插入等位基因长4个碱基对）。总之，我们的研究表明，rs150703258可能通过调节NPC1和C18orf8的表达而导致SCD易感性。这种插入/缺失可能是SCD风险分层和分子诊断的潜在标志物。有必要在不同种族的更大样本中进行验证并探索其机制，以证实我们研究结果。
