Genetic Determinants of Coronary Atherosclerosis

描述（由申请人提供）：冠状动脉粥样硬化是西方国家的主要死亡原因，受遗传因素的影响很大。对赋予动脉粥样硬化易感性的特定基因和序列变异的鉴定受到两个主要障碍的阻碍：1)动脉粥样硬化的发病机制极其复杂；2)人类基因组高度多态性，估计包含1000万个DNA序列变异。由于大多数多态性可能对基因功能几乎没有影响，这种巨大的异质性使识别系统影响疾病表型的序列变异的努力变得混乱。为了确定与冠状动脉粥样硬化相关的序列变异，我们进行了一项全基因组关联研究，并验证了在病例和对照的独立样本中通过复制观察到的50种关联。在这项资助中，我们将解决两个关键问题：1)这50个snp中哪一个与冠状动脉粥样硬化可重复相关，以及2)这些snp赋予冠状动脉粥样硬化遗传易感性的机制是什么。这些问题将分三个步骤解决。首先，我们将在第三个独立人群——社区动脉粥样硬化风险（ARIC）研究中验证通过重复观察到的相关性。其次，我们将精细绘制与冠状动脉粥样硬化相关的基因组区域，并筛选相关区间的基因，以寻找功能性snp。第三，为了阐明所观察到的关联背后的机制，我们将在达拉斯心脏研究中测试已确定的snp与心血管危险因素（如血浆脂质和脂蛋白水平、血压、c反应蛋白）之间的关联，这是一项大型、多种族、基于人群的研究，其中进行了心血管危险因素的详细表型分析。我们的初步数据为支持这一方法提供了令人信服的证据：通过两种不同方法分析的不同人群的多个独立病例对照比较，我们确定的两个基因座与冠心病密切相关。其中一个位点确定了一个新基因，该基因与冠状动脉粥样硬化的直接测量相关，但与血胆固醇或血压等中间表型无关。第二个基因座编码蛋白转化酶PCSK9， PCSK9与降低LDL-C水平有关，并对ARIC队列和渥太华队列中流行的冠心病具有实质性保护作用。相关性：与动脉粥样硬化相关的snp的鉴定可能为影响动脉粥样硬化易感性的新途径提供分子处理，并为预防和治疗冠心病提供新的治疗靶点。

DESCRIPTION (provided by applicant): Coronary atherosclerosis, a leading cause of death in Western countries, is strongly influenced by genetic factors. Identification of the specific genes and sequence variants that confer susceptibility to atherosclerosis has been hampered by two major obstacles: 1)the pathogenesis of atherosclerosis is extremely complex, and 2) the human genome is highly polymorphic, containing an estimated 10 million DNA sequence variants. Since most polymorphisms probably have little effect on gene function, this enormous heterogeneity has confounded efforts to identify sequence variants that systematically influence disease phenotypes. To identify sequence variants associated with coronary atherosclerosis we performed a genome-wide association study and validated 50 of the associations observed by replication in independent samples of cases and controls. In this grant we will address two critical questions: 1) Which of these 50 SNPs are reproducibly associated with coronary atherosclerosis, and 2) What is the mechanism by which these SNPs confer genetic susceptibility to coronary atherosclerosis. These questions will be addressed in three sequential steps. First, we will validate the associations observed by replication in a third, independent population, the Atherosclerosis Risk in Communities (ARIC) study. Second, we will fine map the genomic regions confirmed to be associated with coronary atherosclerosis, and screen genes in the associated interval for functional SNPs. Third, to elucidate the mechanisms underlying the associations observed we will test for association between the SNPs identified and cardiovascular risk factors (e.g. plasma lipid and lipoprotein levels, blood pressure, C-reactive protein) in the Dallas Heart Study, a large, multiethnic, population-based study in which detailed phenotyping of cardiovascular risk factors has been performed. Our preliminary data provide compelling evidence to support this approach: two of the loci we have identified are strongly associated with coronary heart disease in multiple independent case-control comparisons from different populations assayed by two different methods. One of these loci identifies a novel gene that is associated with associated with direct measures of coronary atherosclerosis but not with intermediate phenotypes such as blood cholesterol or blood pressure. The second locus encodes the proprotein convertase PCSK9 which is associated with decreased levels of LDL-C and substantial protection against incident CHD in the ARIC cohort and against prevalent CHD in the cohort from Ottawa. Relevance: The identification of SNPs associated with atherosclerosis may provide a molecular handle on novel pathways that influence susceptibility to atherosclerosis, and reveal new therapeutic targets for prevention and treatment of CHD.