目的:高低密度脂蛋白(LDL)胆固醇与包括急性心肌梗死(AMI)在内的冠状动脉疾病(CAD)的风险增加有关。然而,降脂药物治疗是否与AMI风险降低有因果关系,目前尚不清楚.我们使用孟德尔随机化(MR)来评估影响降脂药靶点功能的遗传变异对AMI的影响。
方法:与作为工具的脂质相关的单核苷酸多态性(SNP)从全球脂质遗传学联盟(GLGC)中提取。AMI的全基因组关联研究(GWAS)数据来自英国生物银行。使用两个样本MR分析来研究高密度脂蛋白(HDL)胆固醇,低密度脂蛋白(LDL)胆固醇,和甘油三酯(TG)与AMI(n=3,927)。使用与药物靶基因处或附近的LDL胆固醇相关的遗传变异体来模拟药物靶MR中对AMI事件的药物作用。
结果:遗传预测LDL-C升高(LDL-C每增加38.67mg/dL,OR1.006,95%CI1.004-1.007)和TG(TG每增加90.72mg/dL,1.004,1.002-1.006)与AMI风险增加有关,但HDL-C升高的风险降低(HDL-C每增加15.51mg/dL,0.997,0.995-0.999)在单变量MR中。LDL-C的关联仍然很重要,但在多变量MR中,HDL-C和TG向零衰减。在PCSK9区域(evolocumab的药物靶标)和NPC1L1(依泽替米贝的药物靶标)附近或附近具有遗传变异的遗传代理较低的LDL-C与AMI的风险降低相关(分别为0.997、0.994-0.999和0.986、0.975-0.998),而HMGCR区域的遗传变异(他汀类药物的药物靶标)显示与AMI的边缘关联(0.995,0.990-1.000).排除药物靶标相关SNP后,药物靶区域外的LDL-C相关SNPs对AMI仍然有因果效应(0.994,0.993-0.996)。
结论:研究结果表明,遗传预测的LDL-C可能在AMI的发展中起主要作用。药物MR结果表明,依泽替米贝和evolocumab可能会降低AMI的风险,因为它们具有降低LDL-C的作用,还有其他非药物相关的降脂途径可能与AMI有因果关系。
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.