Effects of genetically proxied lipid-lowering drugs on acute myocardial infarction: a drug-target mendelian randomization study

• Published in: Lipids in health and disease Vol. 23; no. 1; p. 163
• Main Authors: Xiao, Wendi, Li, Yueying, Zhuang, Zhenhuang, Song, Zimin, Wang, Wenxiu, Huang, Ninghao, Dong, Xue, Jia, Jinzhu, Liu, Zhonghua, Zhao, Yimin, Qi, Lu, Huang, Tao
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.06.2024; BioMed Central; BMC
• Subjects: Aged; Analysis; Antilipemic agents; Cardiovascular agents; Care and treatment; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Complications and side effects; Coronary artery disease; Dosage and administration; Female; Genome-Wide Association Study; Heart attack; Humans; Hydroxymethylglutaryl CoA Reductases - genetics; Hypolipidemic Agents - therapeutic use; Lipid-lowering agents; Male; Membrane Proteins - genetics; Membrane Transport Proteins - genetics; Mendelian randomization; Mendelian Randomization Analysis; Middle Aged; Myocardial Infarction - drug therapy; Myocardial Infarction - genetics; Polymorphism, Single Nucleotide; Proprotein Convertase 9 - genetics; Risk factors; Single nucleotide polymorphisms; Triglycerides - blood; China; Lipid-lowering agents; Coronary artery disease; Mendelian randomization
• ISSN: 1476-511X; 1476-511X
• DOI: 10.1186/s12944-024-02133-w

High low-density-lipoprotein (LDL) cholesterol has been associated with an increased risk of coronary artery diseases (CAD) including acute myocardial infarction (AMI). However, whether lipids lowering drug treatment is causally associated with decreased risk of AMI remains largely unknown. We used Mendelian randomization (MR) to evaluate the influence of genetic variation affecting the function of lipid-lowering drug targets on AMI. Single-nucleotide polymorphisms (SNPs) associated with lipids as instruments were extracted from the Global Lipids Genetics Consortium (GLGC). The genome-wide association study (GWAS) data for AMI were obtained from UK Biobank. Two sample MR analysis was used to study the associations between high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) with AMI (n = 3,927). Genetic variants associated with LDL cholesterol at or near drug target gene were used to mimic drug effects on the AMI events in drug target MR. Genetically predicted higher LDL-C (per one SD increase in LDL-C of 38.67 mg/dL, OR 1.006, 95% CI 1.004-1.007) and TG (per one SD increase in TG of 90.72 mg/dL, 1.004, 1.002-1.006) was associated with increased risk of AMI, but decreased risk for higher HDL-C (per one SD increase in HDL-C of 15.51 mg/dL, 0.997, 0.995-0.999) in univariable MR. Association remained significant for LDL-C, but attenuated toward the null for HDL-C and TG in multivariable MR. Genetically proxied lower LDL-C with genetic variants at or near the PCSK9 region (drug target of evolocumab) and NPC1L1 (drug target of ezetimibe) were associated with decreased risk of AMI (0.997, 0.994-0.999 and 0.986, 0.975-0.998, respectively), whereas genetic variants at HMGCR region (drug target of statin) showed marginal association with AMI (0.995, 0.990-1.000). After excluding drug target-related SNPs, LDL-C related SNPs outside the drug target region remained a causal effect on AMI (0.994, 0.993-0.996). The findings suggest that genetically predicted LDL-C may play a predominant role in the development of AMI. The drug MR results imply that ezetimibe and evolocumab may decrease the risk of AMI due to their LDL-C lowering effect, and there are other non-drug related lipid lowering pathways that may be causally linked to AMI.