Datasheet1_Establishing plausibility of cardiovascular adverse effects of immunotherapies using Mendelian randomisation.docx

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.

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）与贾纳斯激酶抑制剂（Janus kinase inhibitors, JAKis）曾引发学界对其引发严重未预料心血管不良事件的担忧。全基因组关联研究中广泛存在的多效性特征，为从在研药物中筛查心血管风险提供了契机，有助于指导合理的临床试验设计与药物警戒策略制定。本研究采用孟德尔随机化（Mendelian randomization, MR）方法，分别探究9种心血管危险因素对缺血性脑卒中风险的独立因果效应及中介因果效应；随后对所涉及的表达数量性状位点（expression quantitative trait loci, eQTLs）进行分析，以明确富集通路能否解释免疫检查点抑制剂（ICIs）或贾纳斯激酶抑制剂（JAKis）治疗中观察到的不良脑卒中事件。
遗传易感的高收缩压（systolic blood pressure, SBP）、高舒张压（diastolic blood pressure, DBP）、高体质量指数（body mass index, BMI）、高腰臀比（waist-to-hip ratio, WHR）、高低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL）、高甘油三酯（triglycerides, TG）、2型糖尿病（type 2 diabetes, T2DM）及高吸烟指数，均与缺血性脑卒中风险升高存在关联。
在对遗传预测的2型糖尿病进行校正后，遗传预测的体质量指数、腰臀比及甘油三酯与结局的关联均有所减弱[体质量指数：中介占比53.15%，95%置信区间（confidence interval, CI）17.21%~89.10%；腰臀比：42.92%（4.17%~81.67%）；甘油三酯：72.05%（10.63%~133.46%）]。
贾纳斯激酶抑制剂、程序性死亡蛋白1（programmed death protein 1, PD-1）与程序性死亡配体1（programmed death ligand 1, PD-L1）抑制剂，均与收缩压、舒张压、腰臀比、2型糖尿病及低密度脂蛋白胆固醇的工具基因所富集的通路存在关联。
总体而言，孟德尔随机化中介分析证实了2型糖尿病在体质量指数、腰臀比及甘油三酯对缺血性脑卒中风险的中介作用；后续的通路富集分析则凸显了该方法在早期识别药物潜在不良反应中的应用价值。