Genes of the CYP450-Derived Eicosanoids Pathway in Subclinical Atherosclerosis

描述(申请人提供)：动脉粥样硬化是冠心病的主要原因，在美国，每5例死亡中就有1例是由动脉粥样硬化引起的，每年造成的经济损失超过2000亿美元。虽然在动脉粥样硬化的病因学中已经认识到了基因型和表型之间的复杂关系，但遗传学研究主要集中在“逐个位点”的策略上。当多个基因在功能上相关时--例如，通过一个共同的生物途径--该途径中几个基因中的任何一个的突变都可能导致疾病风险。对一组功能相关的候选基因进行集体或联合测试可能会极大地提高复杂疾病的遗传关联研究的能力。细胞色素P450衍生的二十烷酸类化合物在心血管功能中发挥重要作用，可能与动脉粥样硬化的发病密切相关。在这项应用中，我们将使用来自国际HapMap项目和其他公共或私人努力的基因组序列变异的新信息，以及来自青年冠状动脉风险发展(CARDIA)研究的资源，以评估在年轻的非裔美国人和白人中，由CYP450衍生的二十烷酸类化合物途径基因的常见变异模式与亚临床动脉粥样硬化及其风险因素的相关性。对于每个种族群体，将在20个候选基因中的每一个中对一组信息量最大的单核苷酸多态进行基因分型，这些基因涉及到由CYP450衍生的二十烷基类化合物的生物合成代谢。然后将评估这些基因的常见变异模式(多位点基因型和单倍型)与两种亚临床动脉粥样硬化的非侵入性指标的相关性：冠状动脉钙化斑块(CAC)和颈动脉内膜中层增厚(IMT)。膳食多不饱和脂肪酸(PUFAs)是细胞色素P450酶的有效底物，可调节内源性二十烷酸类化合物的产生。这项拟议的研究提供了有效评估可改变的环境因素-饮食多不饱和脂肪酸-对新候选基因变异模式与亚临床动脉粥样硬化风险之间关系的影响的机会。这项拟议的研究的意义在于它可能识别与动脉粥样硬化发展有关的新机制，有助于更好地了解疾病病因，并为开发新的治疗靶点和营养干预开辟新的途径。

DESCRIPTION (provided by applicant): Atherosclerosis is the primary cause of coronary heart disease, which contributes to 1 of every 5 deaths and exacts a financial toll of over $200 billion annually in the US. Although complex relationships between genotype and phenotype have been recognized in the etiology of atherosclerosis, genetic studies have largely focused on a "locus-by-locus" strategy. When multiple genes are functionally related - for example, through a common biologic pathway - mutations at any of several genes of that pathway may contribute to disease risk. Collective or joint testing of a set of functionally related candidate genes may dramatically improve the power of genetic association studies of complex disease. CYP450-derived eicosanoids play an important role in cardiovascular function and may be intimately involved in pathogenesis of atherosclerosis. In this application, we will use new information on genome sequence variation derived from the International HapMap project and other public or private efforts, and resources from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study to evaluate the associations of common patterns of variation in genes of the CYP450-derived eicosanoids pathway with subclinical atherosclerosis and its risk/actors in young African-Americans and Whites. For each racial group, a set of maximally informative single nucleotide polymorphisms will be genotyped in each of 20 candidate genes involved in the biosynthesis metabolism of CYP450-derived eicosanoids. Common patterns of variation (multi-locus genotypes and haplotypes) in these genes will then be assessed for their associations with 2 non-invasive measures of subclinical atherosclerosis: presence of coronary calcified plaque (CAC) and carotid intima media thickening (IMT). Dietary polyunsaturated fatty acids (PUFAs) are efficient substrates of the CYP450 enzymes and may modulate the production of endogenous CYP450-derived eicosanoids. The proposed study provides the opportunity to efficiently evaluate the effects of modifiable environmental factors - dietary PUFAs - on the relationships between patterns of variation in novel candidate genes and risk for subclinical atherosclerosis. The significance of the proposed research lies in its potential to identify new mechanisms implicated in the development of atherosclerosis, contributing to a better understanding of disease etiology and opening new avenues for the development of novel therapeutic targets and nutritional interventions.