Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences, Ontario, Canada (M.C., J.S., M.P., P.M.-S., R.L., A.S., H.C.G., G.P.).
Departments of Biochemistry (M.C., G.P.).
Circulation. 2019 Sep 9;140(10):819-830. doi: 10.1161/CIRCULATIONAHA.119.040180. Epub 2019 Jun 18.
Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets, but no systematic screen of the proteome has been performed.
First, using Mendelian randomization (MR) analyses, we assessed 653 circulating proteins as possible causal mediators for 3 different subtypes of ischemic stroke: large artery atherosclerosis, cardioembolic stroke, and small artery occlusion. Second, we used MR to assess whether identified biomarkers also affect risk for intracranial bleeding, specifically intracerebral and subarachnoid hemorrhages. Third, we expanded this analysis to 679 diseases to test a broad spectrum of side effects associated with hypothetical therapeutic agents for ischemic stroke that target the identified biomarkers. For all MR analyses, summary-level data from genome-wide association studies (GWAS) were used to ascertain genetic effects on circulating biomarker levels versus disease risk. Biomarker effects were derived by meta-analysis of 5 GWAS (N≤20 509). Disease effects were derived from large GWAS analyses, including MEGASTROKE (N≤322 150) and UK Biobank (N≤408 961) studies.
Several biomarkers emerged as causal mediators for ischemic stroke. Causal mediators for cardioembolic stroke included histo-blood group ABO system transferase, coagulation factor XI, scavenger receptor class A5 (SCARA5), and tumor necrosis factor-like weak inducer of apoptosis (TNFSF12). Causal mediators for large artery atherosclerosis included ABO, cluster of differentiation 40, apolipoprotein(a), and matrix metalloproteinase-12. SCARA5 (odds ratio [OR]=0.78; 95% CI, 0.70-0.88; P=1.46×10) and TNFSF12 (OR=0.86; 95% CI, 0.81-0.91; P=7.69×10) represent novel protective mediators of cardioembolic stroke. TNFSF12 also increased the risk of subarachnoid (OR=1.53; 95% CI, 1.31-1.78; P=3.32×10) and intracerebral (OR=1.34; 95% CI, 1.14-1.58; P=4.05×10) hemorrhages, whereas SCARA5 decreased the risk of subarachnoid hemorrhage (OR=0.61; 95% CI, 0.47-0.81; P=5.20×10). Multiple side effects beyond stroke were identified for 6 of 7 biomarkers, most (75%) of which were beneficial. No adverse side effects were found for coagulation factor XI, apolipoprotein(a), and SCARA5.
Through a systematic MR screen of the circulating proteome, causal roles for 5 established and 2 novel biomarkers for ischemic stroke were identified. Side-effect profiles were characterized to help inform drug target prioritization. In particular, SCARA5 represents a promising target for treatment of cardioembolic stroke, with no predicted adverse side effects.
需要新型、有效且安全的药物来治疗缺血性中风。具有因果遗传证据的循环蛋白生物标志物是有前途的药物靶点，但尚未对蛋白质组进行系统筛查。
首先，我们使用孟德尔随机化（MR）分析，评估了 653 种循环蛋白作为 3 种不同类型缺血性中风（大动脉粥样硬化、心源性栓塞性中风和小动脉闭塞）的可能因果中介物。其次，我们使用 MR 来评估鉴定的生物标志物是否也会影响颅内出血的风险，特别是脑内和蛛网膜下腔出血。第三，我们将该分析扩展到 679 种疾病，以测试针对鉴定的生物标志物的缺血性中风治疗的假想治疗药物的广泛的副作用。对于所有的 MR 分析，全基因组关联研究（GWAS）的汇总数据用于确定循环生物标志物水平与疾病风险的遗传影响。生物标志物效应通过 5 项 GWAS 的荟萃分析得出（N≤20509）。疾病效应源自大型 GWAS 分析，包括 MEGASTROKE（N≤322150）和 UK Biobank（N≤408961）研究。
有几个生物标志物被鉴定为缺血性中风的因果中介物。心源性栓塞性中风的因果中介物包括组织血型 ABO 系统转移酶、凝血因子 XI、清道夫受体 A 类 5（SCARA5）和肿瘤坏死因子样弱凋亡诱导因子（TNFSF12）。大动脉粥样硬化的因果中介物包括 ABO、分化群 40、载脂蛋白（a）和基质金属蛋白酶-12。SCARA5（比值比[OR]=0.78；95%置信区间，0.70-0.88；P=1.46×10）和 TNFSF12（OR=0.86；95%置信区间，0.81-0.91；P=7.69×10）代表心源性栓塞性中风的新型保护型中介物。TNFSF12 还增加了蛛网膜下腔出血（OR=1.53；95%置信区间，1.31-1.78；P=3.32×10）和脑内出血（OR=1.34；95%置信区间，1.14-1.58；P=4.05×10）的风险，而 SCARA5 降低了蛛网膜下腔出血的风险（OR=0.61；95%置信区间，0.47-0.81；P=5.20×10）。在 7 个生物标志物中，有 6 个鉴定出了 7 个以上的中风以外的副作用，其中大多数（75%）是有益的。凝血因子 XI、载脂蛋白（a）和 SCARA5 没有发现不良反应。
通过对循环蛋白质组进行系统的 MR 筛查，鉴定了 5 个已建立的和 2 个新型缺血性中风的因果生物标志物。对副作用进行了特征描述，以帮助确定药物靶点的优先级。特别是，SCARA5 是治疗心源性栓塞性中风的一个很有前途的靶点，没有预测到不良的副作用。
