GENETIC BASIS OF ABDOMINAL AORTIC ANEURYSM

腹主动脉瘤(AAA)是指腹主动脉扩张。 腹主动脉的部分。未经治疗的患者的主要并发症 AAA为破裂；破裂致死的风险至少为50%。它 是导致美国老年人死亡的主要原因。 AAA的具体名称尚不清楚。有强有力的证据表明，AAA聚集在 家庭聚集性，但家庭聚集的原因不明。确实有 有迹象表明某些蛋白质和蛋白酶抑制基因可能与此有关 在AAA。有一种主动脉瘤的小鼠模型。因此， 支持AAA的遗传病因的证据是强有力的。有， 然而，几乎没有系统性的努力来确定模式 遗传或识别与致病因素有关的基因 AAA。 本研究旨在探讨腹主动脉瘤的遗传学基础。 我们建议收集通过AAA患者确定的家庭的数据。 将对先证者的成年无症状亲属进行超声筛查 完成以确定其相对于AAA的状态。 将进行分离分析以确认我们的 AAA易感性主效隐性基因的初步证据。 为了了解腹主动脉瘤的病因并定位与腹主动脉瘤有关的基因(S)，我们 应使用蛋白质和基因组DNA RFLP标记进行连锁分析 选定的多重构族的成员。将使用的DNA探针 是基于最新的生化和分子遗传学 有证据表明，胶原基因的突变，特别是COL3Al，可能 易患上主动脉瘤。除 胶原基因、弹性蛋白基因和金属蛋白酶基因 胶原酶和基质分解酶以及丝氨酸蛋白酶弹性酶也是 被认为是AAA易感性的候选基因。特定的测试 将进行遗传异质性研究。基因突变的可能性 已知易患心血管疾病的基因座变异(载脂蛋白B， 载脂蛋白E、脂蛋白(A)和低密度脂蛋白受体)导致AAA的风险也将 调查过了。 这个项目的长期目标是开发方法 复杂疾病的遗传分析。本项目将增加 我们对AAA和AAA病因中的遗传成分的理解 改进症状前检测方法。

Abdominal aortic aneurysm (AAA) is the dilatation of the abdominal portion of the aorta. The major complication of an untreated AAA is rupture; the risk of fatality from rupture is at least 50%. It is a leading cause of death among the elderly in the U.S.A. The etiology of AAA is unclear. There is strong evidence that AAA aggregates in families, but the causes of familial aggregation are unknown. There are indications that some protein and protease inhibitor loci may be involved in AAA. There is a mouse model for aortic aneurysms. Thus, the evidence favoring a genetic etiology for AAA is strong. There has, however, been little systematic effort to determine the mode of inheritance or to identify genes that are involved in the causation of AAA. The present study aims to investigate the genetic basis of AAA. We propose to collect data on families ascertained through AAA patients. Ultrasound screening of adult asymptomatic relatives of probands will be done to determine their status with respect to AAA. Segregation analysis will be performed to confirm our preliminary evidence of a major recessive gene for AAA susceptibility. To understand the etiology and localize the gene(s) involved in AAA, we shall perform linkage analysis using protein and genomic DNA RFLP markers of members of selected multiplex families. The DNA probes to be used were selected on the basis of recent biochemical and molecular genetic evidence that mutations in the collagen genes, particularly COL3Al, may predispose individuals to develop aortic aneurysms. In addition to the collagen genes, the genes for elastin and for the metallo-proteases collagenase and stromelysin and the serine protease elastase are also considered as candidate genes for AAA susceptibility. Specific tests of genetic heterogeneity will be performed. The possibility that genetic variation at loci known to predispose to cardiovascular disease (apoB, apoE, Lp(a) and the LDL-receptor) contributes to AAA risk will also be investigated. The long-term objectives of this project are to develop methods of genetic analysis of complex diseases. The present project will add to our understanding of the genetic component in the etiology of AAA and improve methods of presymptomatic detection.