GENETIC BASIS OF ABDOMINAL AORTIC ANEURYSM

描述：（改编自研究者摘要）腹主动脉 动脉瘤（AAA）是腹主动脉的扩张，如果 未被发现导致破裂 AAA破裂相关死亡率 估计为90%，而选择性修复的死亡风险为 约6%。 AAA破裂是老年人死亡的主要原因 美国人 AAA风险标志物的识别可能导致 预防性干预。 家庭中的AAA聚集和隔离 分析表明，AAA的家族风险最好解释为 分离的主基因与常染色体隐性模式， 传承 该项目的目标是确定遗传（主要基因）和 环境因素导致AAA的显著聚集 受影响的人的亲属。 这一目标将通过 满足以下具体目标：1）收集至少180个 受影响的亲属对（主要是兄弟姐妹对），有AAA，没有 结缔组织疾病家族史的证据，以及 对这些个体进行150个高信息微卫星的基因分型 以20 cM的分辨率标记常染色体基因组的多态性; 2） 为了测试AAA和这些基因座之间的连锁，使用稳健的受影响的 谱系成员方法来鉴定可能含有 使个体易患AAA的基因; 3）确认 易感基因的存在，并使用 明确的检索策略，分辨率不断提高的基因分型， 和重新分析家庭资料;和4）确定易感基因 通过结合饱和度映射和分子分析， 候选基因座;和5）调查AAA与 环境措施，以确定评估风险的方程式， AAA患者的亲属基于环境措施， 基因型 基于以下各项的数量和结构的功效计算： 已经收集的家庭证明了识别的可行性 使用这种策略使AAA易感的基因，即使存在 相关基因座的显著异质性。 在 除了通过连锁来鉴定AAA所必需的基因外， 分析，将进行一系列的关联分析， 识别既不必要也不必要的真正易感基因 足以引起疾病，但改变了个人的风险， 发展AAA。

DESCRIPTION: (Adapted from Investigator's Abstract) Abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta which can, if undetected, lead to rupture. The mortality associated with ruptured AAA is estimated to be 90%, while elective repair has a mortality risk of approximately 6%. Ruptured AAA is a leading cause of death among older Americans. The identification of markers of AAA risk could lead to preventive intervention. AAA aggregates in families, and segregation analysis shows that familial risk of AAA is best explained by the segregation of a major gene with an autosomal recessive mode of inheritance. The goal of this project is to identify the genetic (major genes) and environmental factors responsible for the significant aggregation of AAA among relatives of affected individuals. This goal will be achieved by satisfying the following specific aims: 1) to collect a minimum of 180 affected relative pairs (primarily sibling pairs) with AAA and no evidence of a family history of a connective tissue disorder, and to genotype these individuals for 150 highly informative microsatellite polymorphisms marking the autosomal genome at a resolution of 20 cM; 2) to test for linkage between AAA and these loci using robust affected pedigree member methods to identify genomic regions which may contain genes that predispose individuals to develop AAA; 3) to confirm the existence of predisposing gene(s) and refine their location using a defined search strategy, genotyping at increasing levels of resolution, and re-analysis of family data; and 4) to identify the predisposing gene by a combination of saturation mapping and molecular analysis of candidate loci; and 5) to investigate the association of AAA with environmental measures to determine an equation for estimating risk for relatives of AAA patients based upon environmental measures and genotype. Power calculations based upon the number and structure of families already collected demonstrate the feasibility of identifying genes that predispose to AAA using this strategy, even in presence of significant heterogeneity with respect to the loci involved. In addition to identifying genes that are necessary for AAA by linkage analysis, a series of analyses of association will be undertaken to identify true susceptibility genes that are neither necessary nor sufficient to cause disease, but which modify an individual's risk of developing AAA.