PDF(Pubmed)
Abstract：
Immune checkpoint inhibitors (ICIs) and Janus kinase inhibitors (JAKis) have raised concerns over serious unexpected cardiovascular adverse events. The widespread pleiotropy in genome-wide association studies offers an opportunity to identify cardiovascular risks from in-development drugs to help inform appropriate trial design and pharmacovigilance strategies. This study uses the Mendelian randomization (MR) approach to study the causal effects of 9 cardiovascular risk factors on ischemic stroke risk both independently and by mediation, followed by an interrogation of the implicated expression quantitative trait loci (eQTLs) to determine if the enriched pathways can explain the adverse stroke events observed with ICI or JAKi treatment. Genetic predisposition to higher systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), waist-to-hip ratio (WHR), low-density lipoprotein cholesterol (LDL), triglycerides (TG), type 2 diabetes (T2DM), and smoking index were associated with higher ischemic stroke risk. The associations of genetically predicted BMI, WHR, and TG on the outcome were attenuated after adjusting for genetically predicted T2DM [BMI: 53.15% mediated, 95% CI 17.21%-89.10%; WHR: 42.92% (4.17%-81.67%); TG: 72.05% (10.63%-133.46%)]. JAKis, programmed cell death protein 1 and programmed death ligand 1 inhibitors were implicated in the pathways enriched by the genes related to the instruments for each of SBP, DBP, WHR, T2DM, and LDL. Overall, MR mediation analyses support the role of T2DM in mediating the effects of BMI, WHR, and TG on ischemic stroke risk and follow-up pathway enrichment analysis highlights the utility of this approach in the early identification of potential harm from drugs.
摘要：
免疫检查点抑制剂（ICIs）和Janus激酶抑制剂（JAKis）引起了人们对严重的意外心血管不良事件的担忧。全基因组关联研究中广泛的多效性为识别开发中药物的心血管风险提供了机会，以帮助告知适当的试验设计和药物警戒策略。本研究使用孟德尔随机化（MR）方法来研究9个心血管危险因素对缺血性卒中风险的独立和调解的因果影响。随后询问相关表达数量性状基因座(eQTL),以确定富集途径是否可以解释ICI或JAKi治疗观察到的不良卒中事件.高收缩压（SBP）的遗传易感性，舒张压（DBP），体重指数（BMI），腰臀比（WHR），低密度脂蛋白胆固醇（LDL），甘油三酯（TG），2型糖尿病（T2DM），吸烟指数与更高的缺血性卒中风险相关。遗传预测的BMI的关联，WHR,在调整遗传预测的T2DM[BMI：53.15%介导，95%CI17.21%-89.10%;WHR:42.92%(4.17%-81.67%);TG:72.05%(10.63%-133.46%)]。JAKIS,程序性细胞死亡蛋白1和程序性死亡配体1抑制剂涉及与每种SBP仪器相关的基因富集的途径，DBP,WHR,T2DM,LDL。总的来说,MR中介分析支持T2DM在介导BMI效应中的作用，WHR,和TG对缺血性卒中风险和随访通路富集分析突出了该方法在早期识别药物潜在危害中的实用性。
