目的:主动脉瘤(AA)缺乏有效的药物治疗是一个持续的临床挑战。脂质代谢在AA中起着至关重要的作用。然而,降脂药对AA的影响仍存在争议。本研究旨在探讨降脂药与AA之间的遗传关联。
方法:我们的研究使用了关于全基因组关联研究(GWAS)和表达数量性状基因座(eQTL)研究的公开数据。遗传仪器,特别是与药物靶基因相关的eQTL和位于与低密度脂蛋白胆固醇(LDL-C)相关的药物靶基因座附近或内部的SNP(单核苷酸多态性),已被用作降脂药物的代理。药物靶向孟德尔随机化(MR)研究用于确定降脂药物与不同类型AA之间的因果关系。
结果:MR分析显示HMGCR(3-羟基-3-甲基戊二酰辅酶A还原酶)的高表达与AA的风险增加有关(OR=1.58,95%CI=1.20-2.09,p=1.20×10-03)和较大的管腔大小(主动脉最大面积:OR=1.28,95%CI=1.13-1.04,p=1.48×10CI=PCSK9(前蛋白转化酶枯草杆菌蛋白酶/kexin9型)和CETP(胆固醇酯转移蛋白)与AA有提示关系(PCSK9:OR=1.34,95%CI=1.10-1.63,p=3.07×10-03;CETP:OR=1.38,95%CI=1.06-1.80,p=1.47×10-02)。没有证据支持遗传介导的NPC1L1(Niemann-PickC1-Like1)和LDLR(低密度脂蛋白胆固醇受体)与AA相关。
结论:这项研究为降脂药物与主动脉瘤之间的遗传关联提供了因果证据。HMGCR的较高基因表达,PCSK9和CETP增加AA风险。此外,HMGCR抑制剂可能与较小的主动脉腔大小有关。
这项孟德尔随机化研究使用了涉及100多万人的公开数据,以证明降低LDL-C药物的五个靶基因与主动脉瘤风险之间的因果关系。并暗示一种降脂药可能与主动脉瘤的管腔大小有关。关键发现HMGCR的高表达,PCSK9、CETP与主动脉瘤风险呈正相关,强调相应的降脂药可能是预防高危血脂异常个体动脉瘤的首选药物。我们发现基因预测的HMGCR抑制剂与较小的主动脉腔大小呈正相关。这是首次支持基因HMGCR与主动脉瘤管腔大小的因果关系。
OBJECTIVE: The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The
study aimed to investigate the genetic association between lipid-lowering drugs and AA.
RESULTS: Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR)
study is used to determine the causal association between lipid-lowering drugs and different types of AA. The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, P = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, P = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, P = 1.78 × 10-04). PCSK9 (proprotein convertase subtilisin/kexin type 9) and CETP (cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, P = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, P = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA.
CONCLUSIONS: This
study provides causal evidence for the genetic association between lipid-lowering drugs and AA. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size.
This Mendelian randomization
study used publicly available data involving over 1 million individuals to demonstrate the causal relationship between five target genes of LDL-C-lowering medicines and the risk of aortic aneurysms, and implied one lipid-lowering drug may link with the lumen size of aortic aneurysms.
RESULTS: High expression of HMGCR, PCSK9, and CETP was positively correlated with the risk of aortic aneurysms, highlighting that the corresponding lipid-lowering drugs may be preferred for preventing arterial aneurysms in high-risk individuals with dyslipidemia. We found that genetically predicted HMGCR inhibitors were positively associated with smaller aortic lumen size, which is the first time to support the causal association of gene HMGCR on the lumen size of aortic aneurysms.