Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke.
Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke.
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DOI：
10.1038/s41467-022-33675-1
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发表时间：
2022-10-17
影响因子：
16.6
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中风是第二大死亡原因，且治疗需求大量未得到满足。为了确定潜在的中风治疗靶点，我们在两个样本孟德尔随机化框架中估计了 308 种血浆蛋白对中风结果的因果影响，并评估中风危险因素的中介作用。我们发现基因预测的六种蛋白质血浆水平与中风之间存在关联（P ≤ 1.62 × 10−4）。中风的遗传关联与四种蛋白质（TFPI、TMPRSS5、CD6、CD40）的遗传关联共定位（后验概率 >0.7）。孟德尔随机化支持心房颤动、体重指数、吸烟、血压、白质高信号和 2 型糖尿病作为卒中危险因素 (P≤≤0.0071)。体重指数、白质高信号和心房颤动似乎介导 TFPI、IL6RA、TMPRSS5 与中风的关联。此外，使用孟德尔随机化，三十六个蛋白质与这些危险因素中的一个或多个相关。我们的结果强调了中风的因果途径和潜在的治疗靶点。孟德尔随机化可用于模拟蛋白质靶向药物在个体群体中的作用。在这里，作者在两个样本孟德尔随机化框架中鉴定了中风的潜在因果蛋白，提供了潜在的中风治疗靶点。
Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10−4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke. Mendelian randomization can be used to mimic the effects of protein-targeting drugs in a population of individuals. Here, the authors have identified potential causal proteins for stroke in a two-sample Mendelian randomization framework, providing potential stroke therapeutic targets.