Lee Paul C, Jung In-Hyuk, Thussu Shreeya, Patel Ved, Wagoner Ryan, Burks Kendall H, Amrute Junedh, Elenbaas Jared S, Kang Chul Joo, Young Erica P, Scherer Philipp E, Stitziel Nathan O
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO 63108, USA.
iScience. 2024 May 24;27(7):110104. doi: 10.1016/j.isci.2024.110104. eCollection 2024 Jul 19.
Coronary artery disease (CAD) remains a leading cause of disease burden globally, and there is a persistent need for new therapeutic targets. Instrumental variable (IV) and genetic colocalization analyses can help identify novel therapeutic targets for human disease by nominating causal genes in genome-wide association study (GWAS) loci. We conducted cis-IV analyses for 20,125 genes and 1,746 plasma proteins with CAD using molecular trait quantitative trait loci variant (QTLs) data from three different studies. 19 proteins and 119 genes were significantly associated with CAD risk by IV analyses and demonstrated evidence of genetic colocalization. Notably, our analyses validated well-established targets such as PCSK9 and ANGPTL4 while also identifying HTRA1 and endotrophin (a cleavage product of COL6A3) as proteins whose levels are causally associated with CAD risk. Further experimental studies are needed to confirm the causal role of the genes and proteins identified through our multiomic cis-IV analyses on human disease.
冠状动脉疾病（CAD）仍然是全球疾病负担的主要原因，并且一直需要新的治疗靶点。工具变量（IV）和基因共定位分析可以通过在全基因组关联研究（GWAS）位点中指定因果基因，帮助识别人类疾病的新型治疗靶点。我们使用来自三项不同研究的分子性状数量性状位点变异（QTL）数据，对20125个基因和1746种血浆蛋白与CAD进行了顺式IV分析。通过IV分析，19种蛋白质和119个基因与CAD风险显著相关，并显示出基因共定位的证据。值得注意的是，我们的分析验证了如PCSK9和ANGPTL4等已确立的靶点，同时还将HTRA1和内毒素（COL6A3的裂解产物）鉴定为其水平与CAD风险存在因果关联的蛋白质。需要进一步的实验研究来证实通过我们的多组学顺式IV分析鉴定出的基因和蛋白质对人类疾病的因果作用。
