hOGG1基因型、血8-OHdG水平与缺血性心肌病的相关性以及阿托伐他汀对缺血性心肌病患者血8-OHdG水平和病死率的影

发布时间：2018-06-08 02:38

本文选题：缺血性心肌病 + 氧化应激　；参考：《郑州大学》2016年博士论文

【摘要】：目前国内外大量的研究已应用8-羟基脱氧鸟嘌呤(8-OHd G)作为评估氧化应激和DNA氧化损伤指标。在DNA氧化损伤中,8-OHd G是最具代表性的氧化损伤产物和敏感生物标志物,已成为目前医学研究的热点。参与人类脱氧核糖核酸(DNA)损伤修复的基因有130多种,人类8-羟基鸟嘌呤糖苷酶(h OGG1)是其中的一种,h OGG1基因可以对损伤了的DNA进行修复,特异地切除8-OHd G。h OGG1基因第7外显子第1245位碱基的C/G多态,其326位密码子或编码丝氨酸(Ser)或编码半胱氨酸(Cys),表现出不同酶活性,可能与个体氧化损伤相关。多项研究表明,氧化损伤与冠状动脉粥样硬化性心脏病(CAHD)及其并发症明显相关,同时脂质代谢紊乱是造成动脉粥样硬化的主要因素,可造成活性氧产生增多,形成氧化应激,引起血管内皮功能紊乱和心血管并发症的发生。冠状动脉粥样硬化性心脏病,简称冠心病(CHD),缺血性心肌病(ICM)是CHD的一种特殊类型,它是具有一系列临床表现的一组症候群,包括心律失常、心脏扩大、僵硬、心力衰竭等。长期心肌缺血更易诱导心肌弥漫性纤维化,最终损害心脏收缩和(或)舒张功能。随着社会进入人口老龄化阶段,ICM发病率和死亡率呈同步快速增高,500万的美国心力衰竭人群中,至少有350万不同程度伴有ICM病因的心室收缩和舒张功能不全。目前,ICM的发病机制尚未得到确切证实,临床上的治疗手段特异性较差,作为心脏病领域研究的热点被人们熟知。越来越多的证据表明,ICM易受遗传、环境因素干扰。目前DNA修复基因多态性及其表达作用和氧化应激在ICM中的作用越来越受到重视。他汀能明显降低CHD患者心血管事件的发生率,其作为抗动脉粥样硬化药物,已经成为冠心病的二级预防药物。h OGG1基因Ser326Cys多态性和血清8-OHd G水平与ICM发病是否存在关系,他汀类药物是否具有抗氧化作用,不同剂量阿托伐他汀抗氧化作用是否存在差异以及其对ICM患者血清8-OHd G水平和病死率的是否存在影响等,针对上述研究的报道较少。本研究拟分为两部分来探讨:1.h OGG1基因Ser326Cys基因型、血清8-OHd G水平与ICM之间的关系;2.不同剂量阿托伐他汀对ICM患者血清8-OHd G水平和病死率的影响。第一部分h OGG1基因Ser326Cys基因型、血清8-OHd G水平与缺血性心肌病之间的关系目的探讨h OGG1基因Ser326Cys基因型和血清8-OHd G水平与ICM的关系以及ICM的氧化应激机制。方法用病例-对照研究设计,选取ICM病例(病例组)和与之年龄、性别匹配,同期住院的冠状动脉造影示冠状动脉正常的对照各246例,按1:1配对。运用PCR-RFLP技术检测h OGG1基因Ser326Cys单核苷酸多态性,同时检测血8-OHd G水平及相关生化指标。结果两种等位基因频率分布无差异(χ2=2.182 P=0.140),三种基因型频率分布差异有显著性(χ2=12.388 P=0.002),病例组Cys/Cys基因型频率明显高于对照组,相对于Ser/Cys基因型,Cys/Cys基因型是发生ICM的危险因素(OR=2.22,95%CI:1.40~3.28),将Ser/Ser和Ser/Cys基因型合并计算,发现携带Cys/Cys基因型者患ICM的风险增加(OR=1.92,95%CI:1.21~2.88)。病例组血8-OHd G水平明显高于对照组(P0.05),携带Cys/Cys基因型的患者血8-OHd G水平明显增高(P0.05)。结论1.h OGG1基因型与ICM存在相关性,携带Cys/Cys基因型的个体患ICM的风险明显增加。2.ICM患者的血清8-OHd G水平明显增高,携带h OGG1 Cys/Cys基因型的ICM患者,8-OHd G水平增高明显。第二部分不同剂量阿托伐他汀对缺血性心肌病患者血清8-OHd G水平和病死率的影响目的比较40 mg与20 mg阿托伐他汀对ICM患者血清8-OHd G水平及病死率的影响。方法将病例组246例随机分为两组:阿托伐他汀(辉瑞)20 mg/d治疗组124例和40 mg/d治疗组122例。两组患者接受阿托伐他汀治疗的同时,根据病情加用其它药物。随访4年,记录不良反应发生率。记录入选对象的一般临床资料,进行心功能分级分类,测定相关生化指标和血清8-OHd G水平,心脏彩色多普勒检测心功能指标。结果4年内,治疗组246例患者中有144人完成4年随访,其中20 mg治疗组70人,40 mg治疗组74人,6例中断治疗和随访,96例患者随访过程中死亡。随访期间,两组药物应用、药物性肝炎和横纹肌溶解发生和其他不良反应方面比较差异无统计学意义(P0.05)。两治疗组自身治疗前后比较,TC、LDL-C均有明显降低(P0.05)。40 mg治疗组较20 mg治疗组及40 mg治疗组自身治疗前后8-OHd G、hs-CRP和BNP降低明显(P0.05)。研究开始时,两治疗组间心功能各项指标比较无明显差异(P0.05),研究结束时,与20 mg治疗组比较,40 mg治疗组治疗后,E峰和E/A比值水平增高明显,A峰水平降低明显,差异均有显著性(P0.05),自身治疗前后比较,上述指标差异均有显著性(P0.05)。40 mg组总死亡率虽低于20 mg组总死亡率,但两组间差异无统计学意义(P0.05)。同一心功能下,应用不同剂量阿托伐他汀ICM患者的病死率比较无明显差异(P0.05)。结论1.不同剂量阿托伐他汀的抗氧化作用存在差异,40 mg阿托伐他汀治疗组8-OHd G水平降低明显。2.阿托伐他汀治疗ICM安全有效并可改善心脏舒张功能。3.同一心功能下,应用不同剂量阿托伐他汀ICM患者的病死率无明显差别。
[Abstract]:8- hydroxy deoxyguanine (8-OHd G) has been used as an indicator of oxidative stress and DNA oxidative damage at home and abroad. In DNA oxidative damage, 8-OHd G is the most representative oxidation damage product and sensitive biomarker, and has become a hot spot in medical research. It is involved in the damage repair of human deoxyribonucleic acid (DNA). There are more than 130 genes, and the human 8- hydroxyguanosine glucosidase (H OGG1) is one of them. The H OGG1 gene can repair the damaged DNA and specifically remove the C/G polymorphism of the 1245th base base of the seventh exon of the 8-OHd G.h OGG1 gene. The 326 bit codon or the encoded serine (Ser) or the coded cysteine (Cys) shows different enzyme activities. A number of studies have shown that oxidative damage is associated with coronary atherosclerotic heart disease (CAHD) and its complications, and the disorder of lipid metabolism is the main cause of atherosclerosis, which can cause increased activity of reactive oxygen species, form oxidative stress, cause vascular endothelial dysfunction and cardiovascular disease. The occurrence of complications. Coronary atherosclerotic heart disease (CHD), ischemic cardiomyopathy (ICM) is a special type of CHD. It is a set of syndromes with a series of clinical manifestations, including arrhythmia, heart enlargement, stiffness, heart failure and so on. Long term myocardial ischemia is more likely to induce myocardial diffuse fibrosis and ultimately damage Cardiac contraction and (or) diastolic function. As society enters the aging stage of the population, the incidence and mortality of ICM increase synchronously and rapidly. In 5 million of the people with heart failure in the United States, there are at least 3 million 500 thousand different degrees of ventricular systolic and diastolic dysfunction with the cause of ICM. At present, the pathogenesis of ICM has not been confirmed, clinically. There is a growing number of evidence that ICM is vulnerable to genetic and environmental factors. The role of DNA repair gene polymorphism and its expression and oxidative stress in ICM is becoming more and more important. Statins can significantly reduce the cardiovascular events in patients with CHD. Incidence, as an antiatherosclerotic drug, has become a two level prophylactic drug for coronary heart disease (.H OGG1 gene Ser326Cys polymorphism) and the relationship between serum 8-OHd G level and ICM, statins are antioxidation, different doses of atorvastatin have a difference in oxidation resistance and their effects on ICM patients The effect of serum 8-OHd G level and mortality is less reported. This study is divided into two parts: the 1.h OGG1 gene Ser326Cys genotype, the relationship between serum 8-OHd G level and ICM; 2. the effect of atorvastatin on 8-OHd G level and mortality in ICM patients. The relationship between the Ser326Cys genotype of G1 gene, serum level of 8-OHd G and ischemic cardiomyopathy in order to explore the relationship between the Ser326Cys genotypes of the H OGG1 gene, the relationship between the serum 8-OHd G level and ICM, and the oxidative stress mechanism of ICM. Methods a case control study was designed to select the ICM cases (case group) and the age, sex matching and hospitalization in the same period. Coronary arteriography showed 246 cases of coronary artery normal control, matched by 1:1. The single nucleotide polymorphism of H OGG1 gene Ser326Cys was detected by PCR-RFLP technique, and the serum 8-OHd G level and related biochemical indexes were detected. The frequency distribution of the two alleles was not different (x 2=2.182 P= 0.140), and the difference of frequency distribution of the three genotypes was significant Sex (x 2=12.388 P=0.002), the frequency of Cys/Cys genotype in the case group was significantly higher than that in the control group. Compared with the Ser/Cys genotype, the Cys/Cys genotype was a risk factor for ICM (OR=2.22,95%CI:1.40~3.28). The combined calculation of Ser/Ser and Ser/Cys genotypes showed that the risk of ICM was increased (OR=1.92,95%CI:1.21~2.88) with the Cys/Cys based genotype (OR=1.92,95%CI:1.21~2.88). The level of 8-OHd G in group blood was significantly higher than that in the control group (P0.05), and the level of 8-OHd G in the patients carrying Cys/Cys genotype was significantly higher (P0.05). Conclusion the OGG1 genotype of 1.h is related to ICM, and the risk of ICM is significantly increased in individuals carrying Cys/Cys genotype. The level of 8-OHd G increased significantly in M patients. Second the effect of different doses of atorvastatin on serum 8-OHd G level and mortality in patients with ischemic cardiomyopathy compared the effect of 40 mg and 20 mg atorvastatin on the serum 8-OHd G level and fatality rate of ICM patients. Methods 246 cases of case group were randomly divided into two groups: atorvastatin (Pfizer) 20 mg/d treatment group 124 cases and 122 cases of 40 mg/d treatment group. The two groups were treated with atorvastatin at the same time with other drugs. Follow up for 4 years, record the incidence of adverse reactions. Record the general clinical data of the selected subjects, classify the heart function classification, determine the related biochemical indexes and serum 8-OHd G level, color of heart is more color. In 4 years, 144 of the 246 patients in the treatment group were followed up for 4 years, including 70 in the 20 mg treatment group, 74 in the 40 mg treatment group, 6 with interruption treatment and follow-up, and 96 patients died during the follow-up period. During the follow-up period, the use of drugs, drug-induced liver inflammation and rhabdomyolysis and other adverse reactions were compared during the follow-up period. There was no statistically significant difference (P0.05). Two in the treatment group, before and after the treatment, the TC and LDL-C were significantly decreased (P0.05) in the.40 mg treatment group, the 8-OHd G, hs-CRP and BNP decreased before and after the treatment of the 20 mg group and the 40 mg treatment group. At the end, compared with the 20 mg treatment group, the level of the E peak and the E/A ratio increased significantly after the treatment in the 40 mg treatment group, and the A peak level decreased significantly (P0.05). The differences in the above indexes were significant (P0.05) the total mortality rate of the.40 mg group was lower than the total mortality of the 20 mg group, but there was no statistical difference between the two groups (P) 0.05). Under the same cardiac function, there was no significant difference in the mortality rate of the patients with different doses of atorvastatin ICM (P0.05). Conclusion 1. different doses of atorvastatin had different antioxidative effects, and the level of 8-OHd G in the 40 mg atrovastatin group was significantly lower than that of.2. atrovastatin in the treatment of ICM safe and effective and improved cardiac diastolic function.3 Under the same heart function, there was no significant difference in mortality between different doses of atorvastatin ICM.
【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R542.2

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