遗传邻近降脂药物对急性心肌梗死的影响：药物靶点孟德尔随机研究。

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

机构信息

Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 38 Xueyuan Road, Beijing, 100191, China.

Department of Biostatistics, School of Public Health, Peking University, Beijing, China.

出版信息

Lipids Health Dis. 2024 Jun 3;23(1):163. doi: 10.1186/s12944-024-02133-w.

DOI:10.1186/s12944-024-02133-w

PMID:38831433

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11145822/

Abstract

OBJECTIVE

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.

METHODS

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.

RESULTS

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).

CONCLUSIONS

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.

摘要

目的

高低密度脂蛋白（LDL）胆固醇与冠心病（CAD）包括急性心肌梗死（AMI）的风险增加有关。然而，降脂药物治疗是否与AMI风险降低有关仍知之甚少。我们使用孟德尔随机化（MR）来评估影响降脂药物靶点功能的遗传变异与 AMI 之间的关系。

方法

从全球脂质遗传学联盟（GLGC）中提取与脂质相关的单核苷酸多态性（SNP）作为工具。AMI 的全基因组关联研究（GWAS）数据来自英国生物银行。使用两样本 MR 分析研究高密度脂蛋白（HDL）胆固醇、低密度脂蛋白（LDL）胆固醇和甘油三酯（TG）与 AMI 之间的关联（n=3927）。使用与药物靶点基因内或附近的 LDL 胆固醇相关的遗传变异来模拟药物对药物靶点 MR 中 AMI 事件的影响。

结果

遗传预测 LDL-C（LDL-C 每增加一个标准差为 38.67mg/dL，OR 1.006，95%CI 1.004-1.007）和 TG（TG 每增加一个标准差为 90.72mg/dL，1.004，1.002-1.006）与 AMI 风险增加相关，但与 HDL-C 风险降低相关（HDL-C 每增加一个标准差为 15.51mg/dL，0.997，0.995-0.999）。在单变量 MR 中，LDL-C 的关联仍然显著，但在多变量 MR 中，HDL-C 和 TG 的关联减弱。遗传上接近 PCSK9 区域（依洛尤单抗的药物靶点）和 NPC1L1（依折麦布的药物靶点）的 LDL-C 降低与 AMI 风险降低相关（0.997，0.994-0.999 和 0.986，0.975-0.998），而 HMGCR 区域（他汀类药物的药物靶点）的遗传变异与 AMI 呈边缘关联（0.995，0.990-1.000）。在排除药物靶点相关 SNP 后，药物靶点区域外与 LDL-C 相关的 SNP 仍然与 AMI 有因果关系（0.994，0.993-0.996）。