Whole Exome Sequencing in Vaccine-Induced Thrombotic Thrombocytopenia (VITT).

IF 2.6 3区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
BioMed Research International Pub Date : 2024-07-14 eCollection Date: 2024-01-01 DOI:10.1155/2024/2860547
Betti Giusti, Elena Sticchi, Tommaso Capezzuoli, Rebecca Orsi, Lapo Squillantini, Marco Giannini, Samuele Suraci, Angela Antonietta Rogolino, Francesca Cesari, Martina Berteotti, Anna Maria Gori, Elena Lotti, Rossella Marcucci
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Abstract

Background: In February 2021, a few cases of unusual, severe thrombotic events associated with thrombocytopenia reported after vaccination with ChAdOx1 nCoV-19 (Vaxzevria) or with Johnson & Johnson's Janssen vaccine raise concern about safety. The vaccine-induced thrombotic thrombocytopenia (VITT) has been related to the presence of platelet-activating antibodies directed against platelet Factor 4. Objectives: We investigated VITT subject genetic background by a high-throughput whole exome sequencing (WES) approach in order to investigate VITT genetic predisposition. Methods: Six consecutive patients (females of Caucasian origin with a mean age of 64 years) were referred to the Atherothrombotic Diseases Center (Department of Experimental and Clinical Medicine, Azienda Ospedaliero-Universitaria Careggi, Florence) with a diagnosis of definite VITT underwent WES analysis. WES analysis was performed on the Illumina NextSeq500 platform. Results:WES analysis revealed a total of 140,563 genetic variants. Due to VITT's rare occurrence, we focused attention on rare variants. The global analysis of all high-quality rare variants did not reveal a significant enrichment of mutated genes in biological/functional pathways common to patients analyzed. Afterwards, we focused on rare variants in genes associated with blood coagulation and fibrinolysis, platelet activation and aggregation, integrin-mediated signaling pathway, and inflammation with particular attention to those involved in vascular damage, as well as autoimmune thrombocytopenia. According to ACMG criteria, 47/194 (24.2%) rare variants were classified as uncertain significance variants (VUS), whereas the remaining were likely benign/benign. Conclusion: WES analysis identifies rare variants possibly favoring the prothrombotic state triggered by the exposure to the vaccine. Functional studies and/or extensions to a larger number of patients might allow a more comprehensive definition of these molecular pathways.

疫苗诱发血小板减少症 (VITT) 的全外显子组测序。
背景:2021 年 2 月,接种 ChAdOx1 nCoV-19(Vaxzevria)疫苗或强生公司的杨森疫苗后出现的几例与血小板减少有关的异常严重血栓事件引起了人们对疫苗安全性的关注。疫苗诱发的血栓性血小板减少症(VITT)与针对血小板因子 4 的血小板激活抗体的存在有关。研究目的我们通过高通量全外显子组测序(WES)方法调查了 VITT 受试者的遗传背景,以研究 VITT 的遗传易感性。方法:连续六名确诊为 VITT 的患者(女性,高加索血统,平均年龄 64 岁)被转诊至动脉粥样硬化性血栓疾病中心(佛罗伦萨 Azienda Ospedaliero-Universitaria Careggi 实验与临床医学系),接受了 WES 分析。WES 分析在 Illumina NextSeq500 平台上进行。结果:WES 分析共发现 140,563 个基因变异。由于 VITT 的罕见性,我们重点关注了罕见变异。对所有高质量罕见变异的总体分析并未发现突变基因在所分析患者的常见生物/功能通路中明显富集。随后,我们重点研究了与血液凝固和纤维蛋白溶解、血小板活化和聚集、整合素介导的信号通路和炎症有关的基因中的罕见变异,尤其关注那些参与血管损伤的基因,以及自身免疫性血小板减少症。根据 ACMG 标准,47/194(24.2%)个罕见变异被归类为不确定意义变异(VUS),而其余变异则可能是良性/良性的。结论WES分析确定了可能有利于暴露于疫苗引发的血栓前状态的罕见变异。对更多患者进行功能研究和/或扩展研究可能会更全面地定义这些分子通路。
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来源期刊
BioMed Research International
BioMed Research International BIOTECHNOLOGY & APPLIED MICROBIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
6.70
自引率
0.00%
发文量
1942
审稿时长
19 weeks
期刊介绍: BioMed Research International is a peer-reviewed, Open Access journal that publishes original research articles, review articles, and clinical studies covering a wide range of subjects in life sciences and medicine. The journal is divided into 55 subject areas.
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