Zheng Peng-Fei, Zheng Zhao-Fen, Liu Zheng-Yu, He Jin, Rong Jing-Jing, Pan Hong-Wei
Cardiology Department, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, Hunan, 410000, China.
Clinical Research Center for Heart Failure in Hunan Province, No.61 West Jiefang Road, Furong District, Changsha, Hunan, 410000, China.
Nutr Metab (Lond). 2024 Oct 14;21(1):81. doi: 10.1186/s12986-024-00849-1.
Despite the exploration of the connections between serum low-density lipoprotein cholesterol (LDL-C) levels and aneurisms in epidemiological studies, causality remains unclear. Therefore, this study aimed to assess the causal impact of LDL-C-lowering targets (HMGCR, PCSK9, NPC1L1, CETP, APOB, and LDLR) on various forms of aneurisms using Mendelian Randomization (MR) analysis.
Two genetic instruments acted as proxies for exposure to LDL-C-lowering drugs: expression quantitative trait loci of drug target genes and genetic variants linked to LDL-C near drug target genes. Summary-data-based MR (SMR), inverse-variance-weighted MR (IVW-MR), and multivariable MR (MVMR) methods were employed to compute the effect estimates.
The SMR analysis revealed substantial associations between increased HMGCR expression and a heightened risk of aortic aneurism (odds ratio [OR] = 1.603, 95% confidence interval [CI] = 1.209-2.124), thoracic aortic aneurism (OR = 1.666, 95% CI = 1.122-2.475), and abdominal aortic aneurism (OR = 1.910, 95% CI = 1.278-2.856). Likewise, IVW-MR analysis demonstrated positive correlations between HMGCR-mediated LDL-C and aortic aneurism (OR = 2.228, 95% CI = 1.702-2.918), thoracic aortic aneurism (OR = 1.751, 95% CI = 1.191-2.575), abdominal aortic aneurism (OR = 4.784, 95% CI = 3.257-7.028), and cerebral aneurism (OR = 1.993, 95% CI = 1.277-3.110). Furthermore, in the MVMR analysis, accounting for body mass index, smoking, and hypertension, a significant positive relationship was established between HMGCR-mediated LDL-C levels and the development of aortic aneurisms, encompassing both thoracic and abdominal subtypes. Similarly, consistent positive associations were observed for PCSK9 and CETP genes, as well as PCSK9-mediated and CETP-mediated LDL-C levels, with the occurrence of aortic aneurism and abdominal aortic aneurism. Nonetheless, the evidence for potential associations between APOB, NPC1L1 and LDLR with specific subtypes of aortic aneurisms lacked consistent support from both SMR and IVW-MR analyses.
Our MR analysis offered compelling evidence of a plausible causal link between HMGCR and an increased risk of aortic aneurism, encompassing both thoracic and abdominal types. These groundbreaking findings further bolster the case for the deployment of HMGCR inhibitors in the treatment of aortic aneurisms, including both thoracic and abdominal variants.
尽管在流行病学研究中探索了血清低密度脂蛋白胆固醇（LDL-C）水平与动脉瘤之间的联系，但其因果关系仍不明确。因此，本研究旨在使用孟德尔随机化（MR）分析评估降低LDL-C靶点（HMGCR、PCSK9、NPC1L1、CETP、APOB和LDLR）对各种形式动脉瘤的因果影响。
两种基因工具作为接触降低LDL-C药物的代理：药物靶基因的表达定量性状位点和与药物靶基因附近LDL-C相关的基因变异。采用基于汇总数据的MR（SMR）、逆方差加权MR（IVW-MR）和多变量MR（MVMR）方法计算效应估计值。
SMR分析显示，HMGCR表达增加与主动脉瘤风险升高（优势比[OR]=1.603，95%置信区间[CI]=1.209-2.124）、胸主动脉瘤（OR=1.666，95%CI=1.122-2.475）和腹主动脉瘤（OR=1.910，95%CI=1.278-2.856）之间存在显著关联。同样，IVW-MR分析表明，HMGCR介导的LDL-C与主动脉瘤（OR=2.228，95%CI=1.702-2.918）、胸主动脉瘤（OR=1.751，95%CI=1.191-2.575）、腹主动脉瘤（OR=4.784，95%CI=3.257-7.028）和脑动脉瘤（OR=1.993，95%CI=1.277-3.110）之间呈正相关。此外，在MVMR分析中，考虑体重指数、吸烟和高血压因素后，HMGCR介导的LDL-C水平与包括胸主动脉瘤和腹主动脉瘤亚型在内的主动脉瘤发生之间建立了显著的正相关关系。同样，观察到PCSK9和CETP基因以及PCSK9介导和CETP介导的LDL-C水平与主动脉瘤和腹主动脉瘤的发生之间存在一致的正相关。然而，APOB、NPC1L1和LDLR与主动脉瘤特定亚型之间潜在关联的证据在SMR和IVW-MR分析中均缺乏一致支持。
我们的MR分析提供了令人信服的证据，表明HMGCR与包括胸主动脉瘤和腹主动脉瘤在内的主动脉瘤风险增加之间存在合理的因果联系。这些开创性的发现进一步支持了在治疗包括胸主动脉瘤和腹主动脉瘤变体在内的主动脉瘤时使用HMGCR抑制剂的理由。
