Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19.
Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19.
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DOI：
10.1371/journal.pgen.1010042
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发表时间：
2022-03
期刊：
影响因子：
4.5
通讯作者：
Breen G
中科院分区：
文献类型：
--
作者：
Palmos AB;Millischer V;Menon DK;Nicholson TR;Taams LS;Michael B;Sunderland G;Griffiths MJ;COVID Clinical Neuroscience Study Consortium;Hübel C;Breen G
于二零二一年十一月，COVID-19疫情死亡人数超过五百万人。我们应用孟德尔随机化，包括> 3，000种血液蛋白作为暴露，以确定可能分别指示住院风险或需要呼吸支持或因COVID-19死亡的潜在生物标志物。在使用遗传仪器并在孟德尔随机化假设下进行多次检测校正后，我们的结果与血液中GCNT 4、CD 207、RAB 14、C1 GALT 1C 1和ABO五种蛋白质水平升高与COVID-19导致的住院或呼吸支持/死亡风险增加有因果关系（OR = 1.12-1.35）。较高水平的FAAH 2仅与住院风险增加相关（OR = 1.19）。相反，较高水平的SELL、SELE和PECAM-1降低住院或需要呼吸支持/死亡的风险（OR = 0.80-0.91）。较高水平的LCTL、SFTPD、KEL和ATP 2A 3仅与住院风险降低相关（OR = 0.86-0.93），而较高水平的ICAM-1仅与呼吸支持/COVID-19死亡风险降低相关（OR = 0.84）。我们的研究结果表明，血型标志物和结合蛋白在住院治疗和呼吸支持/死亡的需要。此外，他们还表明，内源性大麻素酶水平较高可能会增加住院治疗的风险。我们的研究重复了先前与COVID-19相关的血液标志物的发现，并优先考虑其他血液标志物用于严重COVID-19的风险预测。此外，我们确定了可能与疾病病理学有关的药物靶点。截至2021年11月，已有超过500万人死于COVID-19。虽然疫苗接种提供了良好的保护，但重要的是要充分了解严重形式的COVID-19背后的生物学。孟德尔随机化有助于鉴定可能参与严重形式的病理生理学的血液蛋白质。在这里，我们调查了> 3，000种血蛋白是否可能在因COVID-19住院或因COVID-19需要呼吸支持或死亡中发挥作用。使用遗传工具并在孟德尔随机化的假设下，我们的结果与五种蛋白质的较高水平与COVID-19结局的风险增加和一种蛋白质的较高水平与住院相关的因果关系一致。我们的研究结果也与较高水平的四种蛋白质（主要在细胞粘附中发挥作用）与住院和呼吸支持/死亡风险降低有因果关系，以及较高水平的四种蛋白质与住院风险降低有因果关系一致。这些蛋白质可能代表了新的生物标志物，可用于严重程度的风险预测，并可能通过优先考虑可药物化的靶点来产生新的治疗方法。
In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12–1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80–0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86–0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology. As of November 2021, more than five million people have died due to COVID-19. Although vaccinations provide good protection, it is important to fully understand the biology behind the severe forms of COVID-19. Mendelian randomization facilitates the identification of blood proteins that may be involved in the pathophysiology of severe forms. Here, we investigated whether >3,000 blood proteins might play a role in hospitalization due to COVID-19 or the requirement of respiratory support or death due to COVID-19. Using genetic instruments and under the assumption of Mendelian randomization, our results are consistent with higher levels of five proteins being causally associated with an increased risk of both COVID-19 outcomes and higher levels of one protein associated with hospitalization. Our results are also consistent with higher levels of four proteins–mainly playing a role in cell adhesion–being causally associated with a decreased risk of hospitalization and respiratory support/death, and higher levels of four proteins being causally associated with a decreased risk of hospitalization. These proteins may represent new biomarkers useful in risk prediction of severity and may lead to new therapeutics by prioritizing druggable targets.
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影响因子：
2
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan N;Thompson J
通讯作者：
Thompson J
影响因子：
7.7
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan NA;Thompson JR
通讯作者：
Thompson JR
DOI：
10.1038/s41431-021-00831-y
发表时间：
2021-06
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
Cotroneo CE;Mangano N;Dragani TA;Colombo F
通讯作者：
Colombo F
影响因子：
4.6
作者：
Sasaki, M;Namioka, Y;Ito, T;Izumiyama, N;Fukui, S;Watanabe, A;Kashima, M;Sano, M;Shioya, T;Miura, M
通讯作者：
Miura, M
影响因子：
4.6
作者：
Enroth, Stefan;Maturi, Varun;Gyllensten, Ulf
通讯作者：
Gyllensten, Ulf