中国汉族人群原发性高血压与14号染色体的连锁分析及与APOB基因、KLK1基因的关联研究

【作者】 赵维艳；

【导师】 顾东风；

【作者基本信息】 中国协和医科大学 ， 流行病与卫生统计学， 2006， 博士

【摘要】 研究背景和目的 目前，探索原发性高血压遗传机制的研究方兴未艾，籍此识别相关的易感基因及基因在高血压发病中的可能作用，并进一步建立基因之间及基因与环境因素的交互作用引发高血压的模型，最终使人们更好的理解高血压发病的病理生理学机制。连锁分析法和候选基因法是探察基因组、描述高血压遗传病因的两种互相补充的方法。连锁分析是利用遗传连锁的原理研究致病基因与遗传标记的关系，通常采用家系分析的方法，在家系的相关个体中将候选基因位点的遗传标记与高血压表型进行连锁分析，以确定该位点是否与高血压连锁。目前已经有很多关于高血压的全基因扫描报道，一些研究认为人14号染色体与原发性高血压或血压性状有关，我们试图在中国人群中验证这一结果。关联研究目前广泛应用于阐述人类复杂疾病的遗传学基础。迄今为止，在人们所研究的与原发性高血压相关的候选基因中，载脂蛋白B(APOB)基因和组织激肽释放酶1(KLK1)基因引起研究人员的格外注意。apoB是低密度脂蛋白(LDL)颗粒的主要蛋白成分，在血浆LDL胆固醇代谢平衡中具有重要作用。研究表明，APOB基因对原发性高血压遗传易感性可能具有一定作用。KLK1基因编码人组织激肽释放酶1，该酶是肾脏合成的一种激肽形成酶，其主要生物学功能是切割激肽原释放血管活性的激肽。动物实验和人群研究都表明，KLK1基因可能与原发性高血压有关，我们基于HapMap计划中国人群(CGB)的数据，采用病例对照研究和标签SNP方法在中国汉族原发性高血压病例—对照人群中分别对APOB基因和KLK1基因多态进行了研究。 材料和方法(连锁分析部分)： 本研究采用平均密度大约为10cM的14个微卫星标记在147个中国高血压核心家系共计799名研究对象中对14号染色体进行连锁扫描。每个高血压核心家系的成员必须满足下列标准：(1)年龄大于15岁；(2)自我确认有4个汉族祖父母；(3)父母任意一方患有高血压；(5)三次测定的静息—坐位血压平均值为收缩压＞140 mmHg，和／或舒张压≥90 mmHg；(6)没有继发性高血压的临床或生物学指征。采用荧光标记PCR—聚丙烯酰胺凝胶电泳方法进行基因分型，通过GENEHUNTER软件进行多点非参数连锁分析和排除作图，使用SOLAR软件对更多还原

【Abstract】 Background: One of the important tasks of hypertension research is the elucidation of the genetic basis of hypertension as a means to identify the genes involved, determine their respective role in causing high blood pressure, and establish how they interact with one another and with non-genetic factors to result in the hypertensive phenotype. This search should untimately lead to a better understanding of the pathophsiological mechanisms underlying hypertension. Linkage and association studies are complementary methods, together, provide the means to probe the genome and describe the genetic etiology of essential hypertension. The goal of linkage studies is to determine whether the two loci tend to cosegregate more often than they should if they were not physically close together on the same chromosome. The assumption is that the genetic marker is linked to the gene causing the specific phenotype. There are now many publications describing the results of genome-wide screens for genes controlling blood pressure. Some studies have linked human chromosome 14 with suggestive evidence of linkage to essential hypertension or blood pressure traits. With a Chinese population, we tried to replicate these findings.Genetic association studies are central efforts to identify and characterize genomic variants underlying susceptibility to multifactorial disease. Among candidate genes thus investigated to data, apolipoprotein B (APOB) and tussue kallikreinl (KLK1) genes have drawn substantial attention. Apo B is the sole component of the low-density lipoprotein (LDL) particles and is thought to play an important role in the homeostasis of LDL cholesterol in plasma. Recent studies suggested the apolipoprotein B (APOB) gene played a role in determining susceptibility to essential hypertension. KLK1 gene codes the human tissue kallikreinl (hKl) which is the major kinin-forming enzyme in the kidney. The main biological function of hKl is to process kininogen substrates and release vasoactive kinin peptides. KLK1 gene had been implicated to be associated with blood pressure regulation through animal model and population research. Based on the data of CHB in the international HapMap Project, we investigated the association of KLK1 gene common polymorphisms with essential hypertension in Chinese Han population by tagging single nucleotide polymorphisms (tSNPs) strategy.Methods (linkage analysis): We recruited 147 randomly ascertained families that containning 799 individuals. To be eligible for our study, the subjects had to meet the更多还原