{"title":"基因修饰的降脂药物靶点、脂质特征与肌萎缩侧索硬化症之间的关系：一项孟德尔随机化研究。","authors":"Zhaoqi Yan, Yifeng Xu, Keke Li, Liangji Liu","doi":"10.1007/s13760-023-02393-w","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>The use of circulating lipid traits as biomarkers to predict the risk of amyotrophic lateral sclerosis (ALS) is currently controversial, and the evidence-based medical evidence for the use of lipid-lowering agents, especially statins, on ALS risk remains insufficient. Our aim was to apply a Mendelian randomization (MR) approach to assess the causal impact of lipid-lowering agents and circulating lipid traits on ALS risk.</p><h3>Materials and methods</h3><p>Our study included primary and secondary analyses, in which the risk associations of lipid-lowering gene inhibitors, lipid traits, and ALS were assessed by the inverse variance weighting method as the primary approach. The robustness of the results was assessed using LDSC assessment, conventional MR sensitivity analysis, and used Mediating MR to explore potential mechanisms of occurrence. In the secondary analysis, the association of lipid-lowering genes with ALS was validated using the Summary data-based Mendelian Randomization (SMR) method.</p><h3>Results</h3><p>Our results showed strong evidence between genetic proxies for Apolipoprotein B (ApoB) inhibitor (<i>OR</i> = 0.76, 95% <i>CI</i> = 0.68 − 0.86; <i>P</i> = 5.58 × 10<sup>−6</sup>) and reduced risk of ALS. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (<i>OR</i> = 1.06, 95% CI = 0. 85–1.33) was not found to increase ALS risk. SMR results suggested that ApoB expression was associated with increased ALS risk, and colocalization analysis did not support a significant common genetic variation between ApoB and ALS. Mediator MR analysis suggested a possible mediating role for interleukin-6 and low-density lipoprotein cholesterol (LDL-C). While elevated LDL-C was significantly associated with increased risk of ALS among lipid traits, total cholesterol (TC) and ApoB were weakly associated with ALS. LDSC results suggested a potential genetic correlation between these lipid traits and ALS.</p><h3>Conclusions</h3><p>Using ApoB inhibitor can lower the risk of ALS, statins do not trigger ALS, and LDL-C, TC, and ApoB levels can predict the risk of ALS.</p></div>","PeriodicalId":7042,"journal":{"name":"Acta neurologica Belgica","volume":"124 2","pages":"485 - 494"},"PeriodicalIF":2.0000,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Association between genetically proxied lipid-lowering drug targets, lipid traits, and amyotrophic lateral sclerosis: a mendelian randomization study\",\"authors\":\"Zhaoqi Yan, Yifeng Xu, Keke Li, Liangji Liu\",\"doi\":\"10.1007/s13760-023-02393-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>The use of circulating lipid traits as biomarkers to predict the risk of amyotrophic lateral sclerosis (ALS) is currently controversial, and the evidence-based medical evidence for the use of lipid-lowering agents, especially statins, on ALS risk remains insufficient. Our aim was to apply a Mendelian randomization (MR) approach to assess the causal impact of lipid-lowering agents and circulating lipid traits on ALS risk.</p><h3>Materials and methods</h3><p>Our study included primary and secondary analyses, in which the risk associations of lipid-lowering gene inhibitors, lipid traits, and ALS were assessed by the inverse variance weighting method as the primary approach. The robustness of the results was assessed using LDSC assessment, conventional MR sensitivity analysis, and used Mediating MR to explore potential mechanisms of occurrence. In the secondary analysis, the association of lipid-lowering genes with ALS was validated using the Summary data-based Mendelian Randomization (SMR) method.</p><h3>Results</h3><p>Our results showed strong evidence between genetic proxies for Apolipoprotein B (ApoB) inhibitor (<i>OR</i> = 0.76, 95% <i>CI</i> = 0.68 − 0.86; <i>P</i> = 5.58 × 10<sup>−6</sup>) and reduced risk of ALS. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (<i>OR</i> = 1.06, 95% CI = 0. 85–1.33) was not found to increase ALS risk. SMR results suggested that ApoB expression was associated with increased ALS risk, and colocalization analysis did not support a significant common genetic variation between ApoB and ALS. Mediator MR analysis suggested a possible mediating role for interleukin-6 and low-density lipoprotein cholesterol (LDL-C). While elevated LDL-C was significantly associated with increased risk of ALS among lipid traits, total cholesterol (TC) and ApoB were weakly associated with ALS. LDSC results suggested a potential genetic correlation between these lipid traits and ALS.</p><h3>Conclusions</h3><p>Using ApoB inhibitor can lower the risk of ALS, statins do not trigger ALS, and LDL-C, TC, and ApoB levels can predict the risk of ALS.</p></div>\",\"PeriodicalId\":7042,\"journal\":{\"name\":\"Acta neurologica Belgica\",\"volume\":\"124 2\",\"pages\":\"485 - 494\"},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2023-10-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta neurologica Belgica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s13760-023-02393-w\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta neurologica Belgica","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s13760-023-02393-w","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Association between genetically proxied lipid-lowering drug targets, lipid traits, and amyotrophic lateral sclerosis: a mendelian randomization study
Background
The use of circulating lipid traits as biomarkers to predict the risk of amyotrophic lateral sclerosis (ALS) is currently controversial, and the evidence-based medical evidence for the use of lipid-lowering agents, especially statins, on ALS risk remains insufficient. Our aim was to apply a Mendelian randomization (MR) approach to assess the causal impact of lipid-lowering agents and circulating lipid traits on ALS risk.
Materials and methods
Our study included primary and secondary analyses, in which the risk associations of lipid-lowering gene inhibitors, lipid traits, and ALS were assessed by the inverse variance weighting method as the primary approach. The robustness of the results was assessed using LDSC assessment, conventional MR sensitivity analysis, and used Mediating MR to explore potential mechanisms of occurrence. In the secondary analysis, the association of lipid-lowering genes with ALS was validated using the Summary data-based Mendelian Randomization (SMR) method.
Results
Our results showed strong evidence between genetic proxies for Apolipoprotein B (ApoB) inhibitor (OR = 0.76, 95% CI = 0.68 − 0.86; P = 5.58 × 10−6) and reduced risk of ALS. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (OR = 1.06, 95% CI = 0. 85–1.33) was not found to increase ALS risk. SMR results suggested that ApoB expression was associated with increased ALS risk, and colocalization analysis did not support a significant common genetic variation between ApoB and ALS. Mediator MR analysis suggested a possible mediating role for interleukin-6 and low-density lipoprotein cholesterol (LDL-C). While elevated LDL-C was significantly associated with increased risk of ALS among lipid traits, total cholesterol (TC) and ApoB were weakly associated with ALS. LDSC results suggested a potential genetic correlation between these lipid traits and ALS.
Conclusions
Using ApoB inhibitor can lower the risk of ALS, statins do not trigger ALS, and LDL-C, TC, and ApoB levels can predict the risk of ALS.
期刊介绍：
Peer-reviewed and published quarterly, Acta Neurologica Belgicapresents original articles in the clinical and basic neurosciences, and also reports the proceedings and the abstracts of the scientific meetings of the different partner societies. The contents include commentaries, editorials, review articles, case reports, neuro-images of interest, book reviews and letters to the editor.
Acta Neurologica Belgica is the official journal of the following national societies:
Belgian Neurological Society
Belgian Society for Neuroscience
Belgian Society of Clinical Neurophysiology
Belgian Pediatric Neurology Society
Belgian Study Group of Multiple Sclerosis
Belgian Stroke Council
Belgian Headache Society
Belgian Study Group of Neuropathology
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