Warwickshire Vascular and Endovascular Unit, University Hospital Coventry & Warwickshire, Coventry, UK.
Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Leicester, UK.
Heart. 2014 Jun;100(12):916-22. doi: 10.1136/heartjnl-2013-305130.
Aortic aneurysms are an important cause of cardiovascular death in elderly patients. At present, little is known of the pathobiology of aneurysmal disease and this limits the ability to develop non-surgical treatments to stabilise aneurysms. Both thoracic and abdominal aortic aneurysms (AAA) demonstrate a strong genetic component in their aetiology. Determination of the genetic variants associated with aneurysmal disease is one approach to increasing the understanding the pathways leading to aneurysmal degeneration of the aorta. In this review, we aim to summarise the current knowledge of the genetics underlying the two most common disease phenotypes, thoracic aortic aneurysm (TAA) and AAA. Genetically, AAA represent a multifactorial disease, with the likelihood that there are multiple variants of very low effect sizes contributing to the overall genetic disease risk. Non-syndromic TAA appears to be associated with a smaller number of risk loci with higher individual effect sizes at these loci. Candidate gene and genome-wide approaches have identified robust associations between AAA and variants in/nearby the SORT1, low-density lipoprotein receptor, DAB2IP, LRP1, ELN, CRP, TGFB and various matrix metallo-proteinase genes suggesting that aberrations of lipid metabolism and proteolytic pathways are the key contributors to disease. Some of these associations (eg, LRP1) are not associated with atherosclerosis, suggesting pathways unique to AAA. Genetic variants associated with non-syndromic TAA (ACTA2 and MYH11) are related to the TGFβ pathway, strongly implicated in syndromic TAA, thus suggesting a common pathway between syndromic and non-syndromic TAA.
主动脉瘤是老年患者心血管死亡的一个重要原因。目前，人们对动脉瘤疾病的病理生物学知之甚少，这限制了开发非手术治疗方法来稳定动脉瘤的能力。胸主动脉瘤和腹主动脉瘤（AAA）在其发病机制中都表现出很强的遗传成分。确定与动脉瘤疾病相关的遗传变异是增加对导致主动脉瘤退行性变的途径的理解的一种方法。在这篇综述中，我们旨在总结导致两种最常见疾病表型（胸主动脉瘤（TAA）和 AAA）的遗传学基础的最新知识。从遗传学上讲，AAA 是一种多因素疾病，很可能有多个非常小的效应大小的变体共同导致整体遗传疾病风险。非综合征性 TAA 似乎与较少的风险位点相关，这些位点的个体效应大小较高。候选基因和全基因组方法已经确定了 AAA 与 SORT1、低密度脂蛋白受体、DAB2IP、LRP1、ELN、CRP、TGFB 和各种基质金属蛋白酶基因附近/内的变体之间存在稳健的关联，表明脂质代谢和蛋白水解途径的异常是疾病的关键促成因素。这些关联中的一些（例如 LRP1）与动脉粥样硬化无关，这表明 AAA 有其独特的途径。与非综合征性 TAA 相关的遗传变异（ACTA2 和 MYH11）与 TGFβ 途径有关，该途径强烈暗示了综合征性 TAA，因此表明综合征性和非综合征性 TAA 之间存在共同途径。
