Genetically predicted levels of the human plasma proteome and risk of stroke: a Mendelian Randomization study
Genetically predicted levels of the human plasma proteome and risk of stroke: a Mendelian Randomization study
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人类血浆蛋白质组的基因预测水平和中风风险：孟德尔随机研究
DOI：
10.1101/2021.10.22.21265375
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Chen L
蛋白质是生物学的效应分子，也是大多数药物的靶标。为了确定可能在中风发病机制中起因果作用的蛋白质和相关途径，我们使用了孟德尔随机化(MR)。我们在两个样本的MR框架中测试了308种血浆蛋白(从间隔研究中对4994名献血者进行测量)对中风预后的潜在因果效应，并评估了这些关联是否可能由心血管危险因素介导。通过英国生物库中的全基因组MR(Phe-MR)，我们扩展了分析以确定这些蛋白的药物靶向是否对其他情况有潜在的副作用或有益影响。MR显示中风与遗传预测的血浆TFP I、IL6RA、MMP12、CD40、TMPRSS5和CD6水平有关(P≤1.62×10−4)。我们用MR确定了与卒中相关的6个危险因素(房颤、体重指数、吸烟、血压、白质高信号和2型糖尿病)(P≤0.0071)。TFP I、IL6RA和TMPRSS5与卒中的关系可能通过这些危险因素如体重指数、白质高强度和心房颤动来调节。另外36种蛋白质可能是这些风险因素中的一个或多个的原因。PHE-MR表明，靶向TFPI可能对中风以外的其他动脉疾病和高脂血症有潜在的有益作用。我们的结果突出了中风的新的致病途径和潜在的治疗靶点。
Proteins are the effector molecules of biology and are the target of most drugs. To identify proteins and related pathways that may play a causal role in stroke pathogenesis, we used Mendelian randomisation (MR). We tested potential causal effects of 308 plasma proteins (measured in 4,994 blood donors from the INTERVAL study) on stroke outcomes (derived from the MEGASTROKE GWAS) in a two-sample MR framework and assessed whether these associations could be mediated by cardiovascular risk factors. We extended the analysis to identify whether pharmacological targeting of these proteins might have potential adverse side-effects or beneficial effects for other conditions through Phenome-wide MR (Phe-MR) in UK Biobank.MR showed an association between stroke and genetically predicted plasma levels of TFPI, IL6RA, MMP12, CD40, TMPRSS5 and CD6 (P≤1.62×10−4). We identified six risk factors (atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes) that were associated with stroke (P≤0.0071) using MR. The association of TFPI, IL6RA and TMPRSS5 with stroke could be mediated by these risk factors, such as body mass index, white matter hyperintensity and atrial fibrillation. Thirty-six additional proteins were potentially causal for one or more of these risk factors. The Phe-MR suggested that targeting TFPI could have potential beneficial effects on other disorders of arteries and hyperlipidaemia in addition to stroke. Our results highlight novel causal pathways and potential therapeutic targets for stroke.
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DOI：
10.1016/s0140-6736(18)30595-6
发表时间：
2018-08-18
期刊：
Lancet (London, England)
影响因子：
--
作者：
Mboi N;Murty Surbakti I;Trihandini I;Elyazar I;Houston Smith K;Bahjuri Ali P;Kosen S;Flemons K;Ray SE;Cao J;Glenn SD;Miller-Petrie MK;Mooney MD;Ried JL;Nur Anggraini Ningrum D;Idris F;Siregar KN;Harimurti P;Bernstein RS;Pangestu T;Sidharta Y;Naghavi M;Murray CJL;Hay SI
通讯作者：
Hay SI
影响因子：
6.7
作者：
Hoke, M;Kyrle, PA;Eichinger, S
通讯作者：
Eichinger, S
影响因子：
8.3
作者：
WOLF, PA;ABBOTT, RD;KANNEL, WB
通讯作者：
KANNEL, WB
影响因子：
30.8
作者：
Verbanck M;Chen CY;Neale B;Do R
通讯作者：
Do R
DOI：
10.1038/nrd.2016.230
发表时间：
2017-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Santos R;Ursu O;Gaulton A;Bento AP;Donadi RS;Bologa CG;Karlsson A;Al-Lazikani B;Hersey A;Oprea TI;Overington JP
通讯作者：
Overington JP