EFCAB4B (CRACR2A) genetic variants associated with COVID-19 fatality
EFCAB4B (CRACR2A) genetic variants associated with COVID-19 fatality
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与 COVID-19 死亡相关的 EFCAB4B (CRACR2A) 基因变异
DOI：
10.1101/2022.01.17.22269412
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Wang D
由严重急性呼吸系统综合征冠状病毒2 （SARS-CoV-2）引起的2019年冠状病毒病（COVID-19）大流行已在全球造成超过2.35亿例病例，480万人死亡（2021年10月）。严重的COVID-19的部分特征是血管血栓形成和细胞因子风暴，这是由于内皮细胞和t细胞分泌的因子在血浆中浓度升高所致。在这里，使用英国生物银行记录的患者数据，我们证明了Rab46 （CRACR2A）变异对临床结果的重要性。通过logistic回归分析，我们确定EFCAB4B基因的三个单核苷酸多态性（snp）导致Rab46错义突变，这些突变与COVID-19的死亡无关，独立于危险因素。这三种snp引起氨基酸残基的变化，这些氨基酸残基在物种间高度保守，表明它们在蛋白质结构和功能中的重要性。两个snp rs17836273 （A98T）和rs36030417 （H212Q）分别在EF-hand和coil -coil结构域的重要功能域中引起氨基酸取代。通过分子模拟，我们认为苏氨酸在98位的取代导致EF-hand钙结合域的结构变化。由于Rab46是一种调节内皮细胞分泌和t细胞信号传导的Rab GTPase，因此这些错义变异可能在严重COVID-19患者中观察到的血栓和炎症特征的分子机制中发挥作用。
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 235 million cases worldwide and 4.8 million deaths (October 2021). Severe COVID-19 is characterised in part by vascular thrombosis and a cytokine storm due to increased plasma concentrations of factors secreted from endothelial and T-cells. Here, using patient data recorded in the UK Biobank, we demonstrate the importance of variations in Rab46 (CRACR2A) with clinical outcomes. Using logistic regression analysis, we determined that three single nucleotide polymorphisms (SNPs) in the gene EFCAB4B cause missense mutations in Rab46, which are associated with COVID-19 fatality independently of risk factors. All three SNPs cause changes in amino acid residues that are highly conserved across species, indicating their importance in protein structure and function. Two SNPs, rs17836273 (A98T) and rs36030417 (H212Q), cause amino acid substitutions in important functional domains: the EF-hand and coiled-coil domain respectively. By using molecular modelling, we suggest that the substitution of threonine at position 98 causes structural changes in the EF-hand calcium binding domain. Since Rab46 is a Rab GTPase that regulates both endothelial cell secretion and T-cell signalling, these missense variations may play a role in the molecular mechanisms underlying the thrombotic and inflammatory characteristics observed in patients with severe COVID-19 outcomes.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1016/j.bbrc.2014.11.095
发表时间：
2015-01-02
影响因子：
3.1
作者：
Wilson, Lesley A.;McKeown, Lynn;Tumova, Sarka;Li, Jing;Beech, David J.
通讯作者：
Beech, David J.
影响因子：
3.9
作者：
Misceo, Doriana;Holmgren, Asbjorn;Frengen, Eirik
通讯作者：
Frengen, Eirik
影响因子：
5.4
作者：
Atzrodt, Cassandra L.;Maknojia, Insha;Clements, Thomas P.
通讯作者：
Clements, Thomas P.
影响因子：
8.4
作者：
Boyle, Aimee L.;Rabe, Martin;Kros, Alexander
通讯作者：
Kros, Alexander