SCN4B基因变异与心房颤动的遗传学研究

发布时间：2018-07-25 06:31

【摘要】：心房颤动（Atrial fibrillation，AF）是以心房快速不规则的电活动为主要特征的一类临床常见心律失常疾病，发病率约为总人群的0.4%-1%，并且随年龄的增长发病率增加。AF会增加缺血性脑卒中和心力衰竭的患病风险，降低病人的生活质量，增加了致死率和致残率，加重了社会经济的负担。 AF是一种受遗传与环境因素共同作用的复杂疾病，除少数家族性AF属于单基因遗传外，大部分AF的发生有着复杂的遗传模式。研究与AF发生和维持有关的基因对理解其发病机制有重要的作用。目前研究AF的主要遗传学方法包括家系连锁分析、候选基因研究和全基因组关联分析（genome wide association study，GWAS）。通过这些方法已发现了一些与AF相关的基因和遗传位点，其中已发现的大部分致病基因与离子通道有关，主要涉及钾离子、钙离子和钠离子通道。心脏钠离子通道主要是由构成孔道的α亚单位和辅助的β亚单位构成，选择性允许钠离子跨膜通过，对心肌细胞动作电位形成起到重要作用。近几年，在编码钠离子通道的相关基因SCN5A、SCN1B、SCN2B、SCN3B中发现了与AF相关的突变，因此，，我们推测SCN4B也可能参与了与AF的发生，并在中国汉族人群AF患者中进行了相关分子遗传学研究。本研究首先应用高分辨率熔解曲线（high resolution melt analysis，HRM）与测序相结合的方法，对480例中国汉族AF患者SCN4B的五个外显子进行突变筛查。结果显示，在一例患者SCN4B第五外显子处发现一个同义突变（C798T），在4例患者第一外显子处发现AG杂合的一个新的罕见单核苷酸多态位点（single nucleotidepolymorphism，SNP）-rs149868494（MAF＜0.005），其对应的氨基酸由甘氨酸变为丝氨酸。随后，我们在944例AF患者和981例正常对照人群中对这一罕见SNPrs149868494基因多态性进行了分析，结果显示rs149868494的小等位A可显著增加中国汉族人群AF的发病风险（P=0.014，OR=3.663），在显性和加性遗传模式下P值为0.001，OR=3.676。本研究的结果显示位于SCN4B的编码区的一个罕见SNP rs149868494与中国汉族人群AF显著关联，提示SCN4B可能是参与中国汉族人群AF发生的易感基因，这为深入了解AF的发生机制提供了新的思路。
[Abstract]:Atrial fibrillation (Atrial fibrillation AF) is a common clinical arrhythmia disease characterized by rapid and irregular atrial electrical activity. The incidence rate is about 0.4-1 of the total population, and with the increase of age, the incidence of .AF increases the risk of ischemic stroke and heart failure, reduces the patient's quality of life, and increases the mortality and disability rate. AF is a complex disease affected by genetic and environmental factors. Except for a few familial AF belong to single gene inheritance, most of AF has a complex genetic pattern. The study of the genes involved in the occurrence and maintenance of AF plays an important role in understanding the pathogenesis of AF. At present, the main genetic methods of AF include pedigree linkage analysis, candidate gene analysis and genome-wide association analysis (genome wide association studyGwas). Through these methods, some genes and genetic sites related to AF have been found, and most of the pathogenic genes have been found to be related to ion channels, mainly involving potassium ions, calcium ions and sodium channels. Cardiac sodium channel is mainly composed of 伪 subunits and auxiliary 尾 subunits, which selectively allow sodium ions to cross the membrane and play an important role in the formation of action potential in cardiomyocytes. In recent years, mutations associated with AF have been found in the gene SCN5An1B, SCN2BN3B, which encodes sodium channel. Therefore, we speculate that SCN4B may also be involved in the pathogenesis of AF, and have carried out molecular genetic studies in AF patients of Han nationality in China. In this study, the mutation of five exons of SCN4B in 480 Chinese Han patients with AF was screened by high resolution fusion curve (high resolution melt analysis HRM) combined with sequencing. The results show that A synonymous mutation (C798T) was found at exon 5 of SCN4B in one patient and a new rare single nucleotide polymorphismSNPs (MAF < 0.005) of AG heterozygosity was found at exon 1 of AG in 4 patients. The corresponding amino acid of C798T was changed from glycine to serine. Subsequently, we analyzed this rare SNPrs149868494 gene polymorphism in 944 AF patients and 981 normal controls. The results showed that the small allele A of rs149868494 could significantly increase the risk of AF in Chinese Han population (P0. 014 ORA 3.663), P value was 0. 001 ORA 3.676 in dominant and additive genetic models. The results of this study suggest that a rare SNP rs149868494 located in the coding region of SCN4B is significantly associated with AF in Chinese Han population, suggesting that SCN4B may be a susceptible gene involved in the development of AF in Chinese Han population. This provides a new idea for further understanding the mechanism of AF.
【学位授予单位】：华中科技大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R541.75;R394

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