孟德尔随机化
表达数量性状基因座
单核苷酸多态性
全基因组关联研究
医学
腹主动脉瘤
生物信息学
肿瘤科
遗传学
生物
基因
动脉瘤
遗传变异
外科
基因型
作者
Yanghui Chen,Xin Xu,Linlin Wang,Ké Li,Yang Sun,Lei Xiao,Jing Dai,Man Huang,Yan Wang,Dao Wen Wang
出处
期刊:EBioMedicine
[Elsevier]
日期:2022-09-01
卷期号:83: 104199-104199
被引量:7
标识
DOI:10.1016/j.ebiom.2022.104199
摘要
BackgroundAs aortic aneurysms (AAs) enlarge, they can become life-threatening if left undiagnosed or neglected. At present, there is a lack of radical treatments for preventing disease progression. Therefore, we aimed to identify effective drug targets that slow the progression of AAs.MethodsA Mendelian randomization (MR) analysis was conducted to identify therapeutic targets which are associated with AAs. Summary statistics for AAs were obtained from two datasets: the UK Biobank (2228 cases and 408,565 controls) and the FinnGen study (3658 cases and 244,907 controls). Cis-expression quantitative trait loci (cis-eQTL) for druggable genes were retrieved from the eQTLGen Consortium and used as genetic instrumental variables. Colocalization analysis was performed to determine the probability that single nucleotide polymorphisms (SNPs) associated with AAs and eQTL shared causal genetic variants.FindingsFour drug targets (BTN3A1, FASN, PLAU, and PSMA4) showed significant MR results in two independent datasets. Proteasome 20S subunit alpha 4 (PSMA4) and plasminogen activator, urokinase (PLAU) in particular, were found to have strong evidence for colocalization with AAs, and abdominal aortic aneurysm in particular. Additionally, except for the association between PSMA4 and intracranial aneurysms, no association between genetically proxied inhibition of PLAU and PSMA4 was detected in increasing the risk of other cardiometabolic risks and diseases.InterpretationThis study supports that drug-targeting PLAU and PSMA4 inhibition may reduce the risk of AAs.FundingThis work was supported by National Key R&D Program of China (NO. 2017YFC0909400), Nature Science Foundation of China (No. 91839302, 81790624), Project supported by Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01), and Tongji Hospital Clinical Research Flagship Program (no. 2019CR207).
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