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Published on: September 19, 2016
HMGCR as a promising molecular target for therapeutic intervention in aortic aneurisms: a mendelian randomization
Peng-Fei Zheng1,2,3, Zhao-Fen Zheng1,2,3, Zheng-Yu Liu1,2,3
1Cardiology Department, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, Hunan, 410000, China.
Insights
This study found that targeting HMGCR, a gene involved in cholesterol production, causally increases the risk of aortic aneurysms. These findings support using HMGCR inhibitors to treat thoracic and abdominal aortic aneurysms.
Area of Science:
- Cardiovascular Genetics
- Pharmacogenomics
- Aneurysm Research
Background:
- Epidemiological studies suggest a link between low-density lipoprotein cholesterol (LDL-C) and aneurysms, but causality is not established.
- Investigating the causal role of LDL-C-lowering targets is crucial for understanding aneurysm development.
Purpose of the Study:
- To assess the causal impact of targeting specific LDL-C-lowering genes (HMGCR, PCSK9, NPC1L1, CETP, APOB, LDLR) on various aneurysm types.
- To utilize Mendelian Randomization (MR) analysis to establish causal relationships.
Main Methods:
- Employed Summary-data-based MR (SMR), inverse-variance-weighted MR (IVW-MR), and multivariable MR (MVMR) analyses.
- Utilized expression quantitative trait loci (eQTLs) and genetic variants near drug target genes as genetic instruments for LDL-C-lowering drug targets.
Main Results:
- Increased HMGCR expression showed significant associations with higher risks of aortic, thoracic aortic, and abdominal aortic aneurysms.
- HMGCR-mediated LDL-C levels were positively correlated with aortic, thoracic aortic, abdominal aortic, and cerebral aneurysms.
- PCSK9 and CETP genes also demonstrated positive associations with aortic and abdominal aortic aneurysms, with effects persisting after adjusting for covariates.
Conclusions:
- Mendelian Randomization analysis provides strong evidence for a causal link between HMGCR and an increased risk of thoracic and abdominal aortic aneurysms.
- Findings support the use of HMGCR inhibitors for treating thoracic and abdominal aortic aneurysms.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
