Da Zhou, Jiahao Song, Guangyu Han, Xiaoming Zhang, Xunming Ji, Ran Meng
{"title":"降脂策略与颅内动脉瘤风险之间的因果关系：药物靶点孟德尔随机化研究。","authors":"Da Zhou, Jiahao Song, Guangyu Han, Xiaoming Zhang, Xunming Ji, Ran Meng","doi":"10.1016/j.jacl.2025.01.003","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Observational studies have suggested potential correlations between unfavorable lipid profiles and the occurrence of intracranial aneurysms (IAs), proposing that lipid-lowering therapies might curb IA progression and prevent rupture. This study aimed to explore the causal impacts of lipid-reducing strategies on the risk of IAs.</p><p><strong>Methods: </strong>We employed 3 genetic tools as proxies for our exposures and assessed causal effects using outcome genome-wide association study data from the FinnGen Biobank. Single nucleotide polymorphisms strongly associated with low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, and triglycerides, located within ±100 kb of the region of target genes, were selected as instrumental variables for drug-target Mendelian randomization (MR). Additionally, gene expression and protein MR analyses were conducted to elucidate the causal effects of lipid levels from transcriptional and translational perspectives, using two-sample MR (TSMR) and summary-data-based MR (SMR).</p><p><strong>Results: </strong>Drug-target MR analysis revealed that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition-mediated LDL-C reduction was associated with an increased risk of IA development (OR = 1.406, P = 3.28E-09). In contrast, protein MR demonstrated that higher PCSK9 expression had protective effects against IA incidence (OR<sub>TSMR</sub> = 0.896, P = 1.79E-03; OR<sub>SMR</sub> = 0.881, P = 1.78E-02). Subgroup analyses further suggested that PCSK9 might reduce the risk of IA rupture (OR<sub>TSMR</sub> = 0.893, P = 1.08E-02; OR<sub>SMR</sub> = 0.866, P = 3.39E-02).</p><p><strong>Conclusion: </strong>Our MR analyses indicated a potential causal relationship between higher PCSK9 expression and a reduced risk of both IA formation and rupture, highlighting the dual role of PCSK9 inhibitors in cerebrovascular disease. Hence, careful consideration is warranted when prescribing PCSK9 inhibitors, particularly in patients at risk for developing IAs.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The causal association between lipid-lowering strategies and risk of intracranial aneurysms: A drug-target Mendelian randomization study.\",\"authors\":\"Da Zhou, Jiahao Song, Guangyu Han, Xiaoming Zhang, Xunming Ji, Ran Meng\",\"doi\":\"10.1016/j.jacl.2025.01.003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Observational studies have suggested potential correlations between unfavorable lipid profiles and the occurrence of intracranial aneurysms (IAs), proposing that lipid-lowering therapies might curb IA progression and prevent rupture. This study aimed to explore the causal impacts of lipid-reducing strategies on the risk of IAs.</p><p><strong>Methods: </strong>We employed 3 genetic tools as proxies for our exposures and assessed causal effects using outcome genome-wide association study data from the FinnGen Biobank. Single nucleotide polymorphisms strongly associated with low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, and triglycerides, located within ±100 kb of the region of target genes, were selected as instrumental variables for drug-target Mendelian randomization (MR). Additionally, gene expression and protein MR analyses were conducted to elucidate the causal effects of lipid levels from transcriptional and translational perspectives, using two-sample MR (TSMR) and summary-data-based MR (SMR).</p><p><strong>Results: </strong>Drug-target MR analysis revealed that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition-mediated LDL-C reduction was associated with an increased risk of IA development (OR = 1.406, P = 3.28E-09). In contrast, protein MR demonstrated that higher PCSK9 expression had protective effects against IA incidence (OR<sub>TSMR</sub> = 0.896, P = 1.79E-03; OR<sub>SMR</sub> = 0.881, P = 1.78E-02). Subgroup analyses further suggested that PCSK9 might reduce the risk of IA rupture (OR<sub>TSMR</sub> = 0.893, P = 1.08E-02; OR<sub>SMR</sub> = 0.866, P = 3.39E-02).</p><p><strong>Conclusion: </strong>Our MR analyses indicated a potential causal relationship between higher PCSK9 expression and a reduced risk of both IA formation and rupture, highlighting the dual role of PCSK9 inhibitors in cerebrovascular disease. Hence, careful consideration is warranted when prescribing PCSK9 inhibitors, particularly in patients at risk for developing IAs.</p>\",\"PeriodicalId\":15392,\"journal\":{\"name\":\"Journal of clinical lipidology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-01-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of clinical lipidology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jacl.2025.01.003\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of clinical lipidology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jacl.2025.01.003","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
The causal association between lipid-lowering strategies and risk of intracranial aneurysms: A drug-target Mendelian randomization study.
Background: Observational studies have suggested potential correlations between unfavorable lipid profiles and the occurrence of intracranial aneurysms (IAs), proposing that lipid-lowering therapies might curb IA progression and prevent rupture. This study aimed to explore the causal impacts of lipid-reducing strategies on the risk of IAs.
Methods: We employed 3 genetic tools as proxies for our exposures and assessed causal effects using outcome genome-wide association study data from the FinnGen Biobank. Single nucleotide polymorphisms strongly associated with low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, and triglycerides, located within ±100 kb of the region of target genes, were selected as instrumental variables for drug-target Mendelian randomization (MR). Additionally, gene expression and protein MR analyses were conducted to elucidate the causal effects of lipid levels from transcriptional and translational perspectives, using two-sample MR (TSMR) and summary-data-based MR (SMR).
Results: Drug-target MR analysis revealed that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition-mediated LDL-C reduction was associated with an increased risk of IA development (OR = 1.406, P = 3.28E-09). In contrast, protein MR demonstrated that higher PCSK9 expression had protective effects against IA incidence (ORTSMR = 0.896, P = 1.79E-03; ORSMR = 0.881, P = 1.78E-02). Subgroup analyses further suggested that PCSK9 might reduce the risk of IA rupture (ORTSMR = 0.893, P = 1.08E-02; ORSMR = 0.866, P = 3.39E-02).
Conclusion: Our MR analyses indicated a potential causal relationship between higher PCSK9 expression and a reduced risk of both IA formation and rupture, highlighting the dual role of PCSK9 inhibitors in cerebrovascular disease. Hence, careful consideration is warranted when prescribing PCSK9 inhibitors, particularly in patients at risk for developing IAs.
期刊介绍：
Because the scope of clinical lipidology is broad, the topics addressed by the Journal are equally diverse. Typical articles explore lipidology as it is practiced in the treatment setting, recent developments in pharmacological research, reports of treatment and trials, case studies, the impact of lifestyle modification, and similar academic material of interest to the practitioner.
Sections of Journal of clinical lipidology will address pioneering studies and the clinicians who conduct them, case studies, ethical standards and conduct, professional guidance such as ATP and NCEP, editorial commentary, letters from readers, National Lipid Association (NLA) news and upcoming event information, as well as abstracts from the NLA annual scientific sessions and the scientific forums held by its chapters, when appropriate.
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