Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic Diseases
Background The differential impact of serum lipids and their targets for lipid modification on cardiometabolic disease risk is debated. This study used Mendelian randomization to investigate the causal relationships and underlying mechanisms. Methods Genetic variants related to lipid profiles and ta...
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Wiley
2025-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.038857 |
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| author | Liwan Fu Qin Liu Hong Cheng Xiaoyuan Zhao Jingfan Xiong Jie Mi |
| author_facet | Liwan Fu Qin Liu Hong Cheng Xiaoyuan Zhao Jingfan Xiong Jie Mi |
| author_sort | Liwan Fu |
| collection | DOAJ |
| description | Background The differential impact of serum lipids and their targets for lipid modification on cardiometabolic disease risk is debated. This study used Mendelian randomization to investigate the causal relationships and underlying mechanisms. Methods Genetic variants related to lipid profiles and targets for lipid modification were sourced from the Global Lipids Genetics Consortium. Summary data for 10 cardiometabolic diseases were compiled from both discovery and replication data sets. Expression quantitative trait loci data from relevant tissues were employed to evaluate significant lipid‐modifying drug targets. Comprehensive analyses including colocalization, mediation, and bioinformatics were conducted to validate the results and investigate potential mediators and mechanisms. Results Significant causal associations were identified between lipids, lipid‐modifying drug targets, and various cardiometabolic diseases. Notably, genetic enhancement of LPL (lipoprotein lipase) was linked to reduced risks of myocardial infarction (odds ratio [OR]1, 0.65 [95% CI, 0.57–0.75], P1=2.60×10−9; OR2, 0.59 [95% CI, 0.49–0.72], P2=1.52×10−7), ischemic heart disease (OR1, 0.968 [95% CI, 0.962–0.975], P1=5.50×10−23; OR2, 0.64 [95% CI, 0.55–0.73], P2=1.72×10−10), and coronary heart disease (OR1, 0.980 [95% CI, 0.975–0.985], P1=3.63×10−14; OR2, 0.64 [95% CI, 0.54–0.75], P2=6.62×10−8) across 2 data sets. Moreover, significant Mendelian randomization and strong colocalization associations for the expression of LPL in blood and subcutaneous adipose tissue were linked with myocardial infarction (OR, 0.918 [95% CI, 0.872–0.967], P=1.24×10−3; PP.H4, 0.99) and coronary heart disease (OR, 0.991 [95% CI, 0.983–0.999], P=0.041; PP.H4=0.92). Glucose levels and blood pressure were identified as mediators in the total effect of LPL on cardiometabolic outcomes. Conclusions The study substantiates the causal role of lipids in specific cardiometabolic diseases, highlighting LPL as a potent drug target. The effects of LPL are suggested to be influenced by changes in glucose and blood pressure, providing insights into its mechanism of action. |
| format | Article |
| id | doaj-art-ec743bc1428d4a308370776de0f10816 |
| institution | Kabale University |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-ec743bc1428d4a308370776de0f108162025-02-04T11:00:01ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-02-0114310.1161/JAHA.124.038857Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic DiseasesLiwan Fu0Qin Liu1Hong Cheng2Xiaoyuan Zhao3Jingfan Xiong4Jie Mi5Center for Non‐Communicable Disease Management Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health Beijing ChinaDepartment of Ultrasound Children’s Hospital of the Capital Institute of Pediatrics Beijing ChinaDepartment of Epidemiology Capital Institute of Pediatrics Beijing ChinaDepartment of Epidemiology Capital Institute of Pediatrics Beijing ChinaChild and Adolescent Chronic Disease Prevention and Control Department Shenzhen Center for Chronic Disease Control Shenzhen ChinaCenter for Non‐Communicable Disease Management Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health Beijing ChinaBackground The differential impact of serum lipids and their targets for lipid modification on cardiometabolic disease risk is debated. This study used Mendelian randomization to investigate the causal relationships and underlying mechanisms. Methods Genetic variants related to lipid profiles and targets for lipid modification were sourced from the Global Lipids Genetics Consortium. Summary data for 10 cardiometabolic diseases were compiled from both discovery and replication data sets. Expression quantitative trait loci data from relevant tissues were employed to evaluate significant lipid‐modifying drug targets. Comprehensive analyses including colocalization, mediation, and bioinformatics were conducted to validate the results and investigate potential mediators and mechanisms. Results Significant causal associations were identified between lipids, lipid‐modifying drug targets, and various cardiometabolic diseases. Notably, genetic enhancement of LPL (lipoprotein lipase) was linked to reduced risks of myocardial infarction (odds ratio [OR]1, 0.65 [95% CI, 0.57–0.75], P1=2.60×10−9; OR2, 0.59 [95% CI, 0.49–0.72], P2=1.52×10−7), ischemic heart disease (OR1, 0.968 [95% CI, 0.962–0.975], P1=5.50×10−23; OR2, 0.64 [95% CI, 0.55–0.73], P2=1.72×10−10), and coronary heart disease (OR1, 0.980 [95% CI, 0.975–0.985], P1=3.63×10−14; OR2, 0.64 [95% CI, 0.54–0.75], P2=6.62×10−8) across 2 data sets. Moreover, significant Mendelian randomization and strong colocalization associations for the expression of LPL in blood and subcutaneous adipose tissue were linked with myocardial infarction (OR, 0.918 [95% CI, 0.872–0.967], P=1.24×10−3; PP.H4, 0.99) and coronary heart disease (OR, 0.991 [95% CI, 0.983–0.999], P=0.041; PP.H4=0.92). Glucose levels and blood pressure were identified as mediators in the total effect of LPL on cardiometabolic outcomes. Conclusions The study substantiates the causal role of lipids in specific cardiometabolic diseases, highlighting LPL as a potent drug target. The effects of LPL are suggested to be influenced by changes in glucose and blood pressure, providing insights into its mechanism of action.https://www.ahajournals.org/doi/10.1161/JAHA.124.038857cardiometabolic diseasescolocalizationdrug targetseQTLlipidsMendelian randomization |
| spellingShingle | Liwan Fu Qin Liu Hong Cheng Xiaoyuan Zhao Jingfan Xiong Jie Mi Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic Diseases Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cardiometabolic diseases colocalization drug targets eQTL lipids Mendelian randomization |
| title | Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic Diseases |
| title_full | Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic Diseases |
| title_fullStr | Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic Diseases |
| title_full_unstemmed | Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic Diseases |
| title_short | Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic Diseases |
| title_sort | insights into causal effects of genetically proxied lipids and lipid modifying drug targets on cardiometabolic diseases |
| topic | cardiometabolic diseases colocalization drug targets eQTL lipids Mendelian randomization |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.038857 |
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