Genetic Determinants of Coronary Atherosclerosis

冠状动脉粥样硬化的遗传决定因素

• 批准号: 7568797
• 负责人: JONATHAN Charles COHEN
• 金额: $ 39.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568797
• 关键词: Address; Atherosclerosis; Biological Assay; Blood; Blood Pressure; C-reactive protein; Cause of Death; Cholesterol; Classification; Communities; Complex; Coronary Arteriosclerosis; Coronary heart disease; Country; DNA Sequence; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Elderly; Family history of; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Goals; Grant; Heart; Heterogeneity; Human Genome; Hypertension; Insulin Resistance; Lipids; Lipoproteins; Maps; Measures; Methods; Molecular; Morbidity - disease rate; Pathogenesis; Pathway interactions; Phenotype; Plasma; Population; Predisposition; Prevention; Proprotein Convertases; Research Personnel; Risk; Risk Factors; Sampling; Screening procedure; Single Nucleotide Polymorphism Map; Smoking; Testing; Variant; cardiovascular risk factor; case control; cohort; density; disease phenotype; gene function; genome wide association study; meetings; mortality; new therapeutic target; novel; population based; premature; programs

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.

描述（由申请人提供）：西方国家的主要死亡原因冠状动脉粥样硬化受到遗传因素的强烈影响。两个主要障碍阻碍了赋予动脉粥样硬化易感性的特定基因和序列变体的鉴定：1）动脉粥样硬化的发病机理非常复杂，而2）人类基因组具有高度多态性，含有估计的1000万个DNA序列变体。由于大多数多态性可能对基因功能影响很小，因此这种巨大的异质性使识别系统影响疾病表型的序列变体的努力混淆了。为了识别与冠状动脉粥样硬化相关的序列变体，我们进行了全基因组关联研究，并验证了在独立病例和对照组中复制观察到的50个关联。在这笔赠款中，我们将解决两个关键问题：1）这50个SNP中的哪一个与冠状动脉粥样硬化相关，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。这些问题将通过三个顺序解决。首先，我们将验证在第三个独立人群中通过复制观察到的关联，社区中的动脉粥样硬化风险（ARIC）研究。其次，我们将细图被确认与冠状动脉粥样硬化有关的基因组区域以及功能性SNP的相关间隔中的筛选基因。第三，为了阐明观察到的关联的基础机制，我们将测试确定的SNP和心血管危险因素（例如，血压脂质和脂蛋白水平，血压，C-反应蛋白）在达拉斯心脏研究中，一项大型，基于人群的研究，以详细措施表现出了Cardiovascastiumper cardiovascastipart cardiovascastival of Cardiovascastipart cardiovascastival cardiovascastival cardiovascastival cardiovascastival cardiovascastiumper。我们的初步数据提供了支持这种方法的令人信服的证据：我们确定的两个基因座与多种不同种群的多种独立病例对照比较中的冠状动脉疾病密切相关，并通过两种不同的方法测定。这些基因座之一确定了与冠状动脉粥样硬化直接测量有关的新基因，而与中间表型（如血液胆固醇或血压）无关。第二个基因座编码了普洛蛋白转化酶PCSK9，这与ARIC队列中的LDL-C水平降低以及针对入射CHD的实质性保护以及对来自渥太华队列中普遍存在的CHD的实质性保护有关。相关性：与动脉粥样硬化相关的SNP的鉴定可以为影响动脉粥样硬化易感性的新途径提供分子处理，并揭示了预防和治疗CHD的新治疗靶标。