Khodursky Samuel, Yuan Shuai, Spin Joshua M, Tsao Philip S, Levin Michael G, Damrauer Scott M
Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
medRxiv. 2024 Sep 23:2024.09.20.24314065. doi: 10.1101/2024.09.20.24314065.
Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. Genetic studies have identified numerous associated loci, many potentially encoding plasma proteins. However, the causal effects of plasma proteins on AAA have not been thoroughly studied. We used genetic causal inference approaches to identify plasma proteins that have a potential causal impact on AAA.
Causal inference was performed using two-sample Mendelian randomization (MR). For AAA, we utilized recently published summary statistics from a multi-population genome-wide association (GWAS) meta-analysis including 39,221 individuals with, and 1,086,107 individuals without AAA from 14 cohorts. We used protein quantitative trait loci (pQTLs) identified in two large-scale plasma-proteomics studies (deCODE and UKB-PPP) to generate genetic instruments. We tested 2,783 plasma proteins for possible causal effects on AAA using two-sample MR with inverse variance weighting and common sensitivity analyses to evaluate the MR assumptions. Bayesian colocalization and gene ontology (GO) enrichment analyses provided additional insights.
MR identified 90 plasma proteins associated with AAA at FDR<0.05, with 25 supported by colocalization analysis. Among those supported by both MR and colocalization were previously experimentally validated proteins such as PCSK9 (OR 1.3; 95%CI 1.2-1.4; P<1e-10), LTBP4 (OR 3.4; 95%CI 2.6-4.6; P<1e-10) and COL6A3 (OR 0.6; 95%CI 0.5-0.7; P<1e-6). GO analysis revealed enrichment of proteins found in extracellular matrix (ECM, OR 7.8; P<1e-4), some with maximal mRNA levels in aortic tissue. Bi-directional MR suggested plasma level changes were not caused by liability to AAA itself. We then investigated whether variants responsible for expression changes in the aorta also influenced plasma levels and AAA risk. Colocalization analysis showed that an aortic expression quantitative trait locus (eQTL) for COL6A3, and a splicing quantitative trait locus (sQTL) for LTBP4 colocalized with their respective plasma pQTLs and AAA signals (posterior probabilities 0.84 and 0.89, respectively).
Our results highlight proteins and pathways with potential causal effects on AAA, providing a foundation for future functional experiments. These findings suggest a possible causal pathway whereby genetic variation affecting ECM proteins expressed in the aortic wall cause their levels to change in blood plasma, influencing development of AAA.
腹主动脉瘤（AAA）是一种常见且危及生命的血管疾病。基因研究已确定了众多相关基因座，其中许多可能编码血浆蛋白。然而，血浆蛋白对AAA的因果效应尚未得到充分研究。我们使用基因因果推断方法来识别对AAA有潜在因果影响的血浆蛋白。
使用两样本孟德尔随机化（MR）进行因果推断。对于AAA，我们利用了最近发表的多群体全基因组关联（GWAS）荟萃分析的汇总统计数据，该分析包括来自14个队列的39221例患有AAA的个体和1086107例未患AAA的个体。我们使用在两项大规模血浆蛋白质组学研究（deCODE和UKB-PPP）中确定的蛋白质定量性状位点（pQTL）来生成基因工具。我们使用具有逆方差加权的两样本MR和常见敏感性分析来测试2783种血浆蛋白对AAA的可能因果效应，以评估MR假设。贝叶斯共定位和基因本体（GO）富集分析提供了更多见解。
MR确定了90种血浆蛋白与AAA相关，错误发现率（FDR）<0.05，其中25种得到共定位分析的支持。在MR和共定位均支持的蛋白中，有一些先前已通过实验验证的蛋白，如前蛋白转化酶枯草溶菌素9（PCSK9）（比值比[OR] 1.3；95%置信区间[CI] 1.2 - 1.4；P<1e-10）、潜伏性转化生长因子β结合蛋白4（LTBP4）（OR 3.4；95%CI 2.6 - 4.6；P<1e-10）和胶原蛋白VIα3链（COL6A3）（OR 0.6；95%CI 0.5 - 0.7；P<1e-6）。GO分析显示细胞外基质（ECM）中发现的蛋白富集（OR 7.8；P<1e-4），其中一些在主动脉组织中的mRNA水平最高。双向MR表明血浆水平变化不是由AAA本身的易感性引起的。然后，我们研究了负责主动脉表达变化的变体是否也影响血浆水平和AAA风险。共定位分析表明，COL6A3的主动脉表达定量性状位点（eQTL）和LTBP4的剪接定量性状位点（sQTL）与其各自的血浆pQTL和AAA信号共定位（后验概率分别为0.84和0.89）。
我们的结果突出了对AAA有潜在因果影响的蛋白质和途径，为未来的功能实验奠定了基础。这些发现提示了一种可能的因果途径，即影响主动脉壁中表达的ECM蛋白的基因变异导致其在血浆中的水平发生变化，从而影响AAA的发展。
