Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Nat Genet. 2023 Nov;55(11):1831-1842. doi: 10.1038/s41588-023-01510-y. Epub 2023 Oct 16.
Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.
腹主动脉瘤（AAA）是一种具有显著遗传性的常见疾病。在这项研究中，我们对 14 个发现队列进行了全基因组关联荟萃分析，发现了 141 个独立的关联，包括 97 个以前未报道的位点。荟萃分析得出的多基因风险评分解释了 AAA 风险超出临床危险因素的范围。AAA 风险位点的基因表明，脂质代谢、血管发育和重塑、细胞外基质失调和炎症作为 AAA 发病机制的关键机制参与其中。这些基因还表明，AAA 的发展与其他单基因主动脉疾病之间存在重叠，特别是通过转化生长因子 β 信号通路。鉴于脂质代谢在 AAA 中作用的强有力证据，我们使用孟德尔随机化来确定非高密度脂蛋白胆固醇在 AAA 中的核心作用，并确定了重新利用前蛋白转化酶枯草溶菌素/凝血酶 9（PCSK9）抑制剂的机会。这一结果得到了一项研究的支持，该研究表明，PCSK9 功能丧失可防止临床前小鼠模型中 AAA 的发展。
