论文标题：Identification of COL3A1 variants associated with sporadic thoracic aortic dissection: a case-control study (鉴定COL3A1变异与散发性胸主动脉夹层发病的相关性研究)

期刊： Frontiers of Medicine

作者：Yanghui Chen, Yang Sun, Zongzhe Li, Chenze Li, Lei Xiao, Jiaqi Dai, Shiyang Li, Hao Liu, Dong Hu, Dongyang Wu, Senlin Hu, Bo Yu, Peng Chen, Ping Xu, Wei Kong, Dao Wen Wang

发表时间：28 May 2021

DOI：10.1007/s11684-020-0826-1

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导读

华中科技大学同济医学院附属同济医院心血管内科汪道文、陈杨辉和孙阳等在Frontiers of Medicine发表研究论文《鉴定COL3A1变异与散发性胸主动脉夹层发病的相关性研究》（Identification of COL3A1 variants associated with sporadic thoracic aortic dissection: a case-control study）。

胸主动脉夹层（TAD）是一种起病急骤、病死率高的心脏大血管疾病。既往研究表明，TAD复杂的遗传背景多与结缔组织疾病有关，如FBN1基因所致的马凡综合征、COL3A1基因所致的埃勒斯-当洛综合征等。这类综合征型TAD在临床中仅占不到20%，而对于临床上最常见、好发于中老年人的散发性TAD，其遗传致病基因尚不清晰。

本研究通过两阶段的病例对照研究，利用全外显子组测序技术，全面评估现已报道的29个与TAD发病相关基因上的突变位点。该研究描绘了中国人散发性TAD的遗传图谱，揭示了基因检测对于诊断TAD的重要性；并进一步鉴定出致散发性TAD的新基因——COL3A1。

摘 要

散发性胸主动脉夹层（STAD）是指没有明确家族聚集性且不伴结缔组织疾病的一类胸主动脉夹层，目前其遗传因素尚未可知。本研究通过纳入223例STAD患者和414例健康对照进行全外显子组测序，数据经过严格的质量控制（人群结构分层、亲缘关系和组源关系分析）后，全面评估现已报道的29个与TAD发病相关基因上的突变位点。经过SKAT-O检验和10000次置换检验后，我们发现COL3A1基因突变与STAD密切相关（P=7.35×10^-6）；该结果在第二人群（423例STAD和734例对照）中进一步得到了验证（P=0.021）。此外，通过生物信息学分析，我们发现COL3A1可通过细胞外基质信号通路影响夹层的发病。本研究描绘了中国汉族人群STAD的遗传图谱，并发现COL3A1基因突变可增加主动脉夹层的发病。我们希望通过此项研究扩展STAD相关的遗传学病因和病理生理学机制，从而进一步为患者提供可靠的基因诊断和治疗手段。

点 评

本文通过全外显子组测序，仅针对现有报道的29个基因进行分析。然而，仍有很多新的、未被认知的致病基因需要进一步挖掘。我们也将致力于研究TAD的遗传学，去探索和寻找新的致病基因和诊疗手段。

摘要

Thoracic aortic dissection (TAD) without familial clustering or syndromic features is known as sporadic TAD (STAD). So far, the genetic basis of STAD remains unknown. Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population (N = 637). After population structure and genetic relationship and ancestry analyses, we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD. We found that COL3A1 was significantly relevant to STAD (P = 7.35 × 10⁻⁶) after 10 000 times permutation test (P = 2.49 × 10⁻³). Moreover, another independent cohort, including 423 cases and 734 non-STAD subjects (N = 1157), replicated our results (P = 0.021). Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues, and its expression was related to the extracellular matrix (ECM) pathway. Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway. We wanted to expand the knowledge of the genetic basis and pathology of STAD, which may further help in providing better genetic counseling to the patients.

原文信息

标题

Identification of COL3A1 variants associated with sporadic thoracic aortic dissection: a case-control study

作者

Yanghui Chen, Yang Sun, Zongzhe Li, Chenze Li, Lei Xiao, Jiaqi Dai, Shiyang Li, Hao Liu, Dong Hu, Dongyang Wu, Senlin Hu, Bo Yu, Peng Chen, Ping Xu, Wei Kong, Dao Wen Wang

机构

1. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

2. Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430030, China

3. The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi 832008, China

4. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China

5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Corresponding Author Dao Wen Wang

Cite this article

Yanghui Chen, Yang Sun, Zongzhe Li, Chenze Li, Lei Xiao, Jiaqi Dai, Shiyang Li, Hao Liu, Dong Hu, Dongyang Wu, Senlin Hu, Bo Yu, Peng Chen, Ping Xu, Wei Kong, Dao Wen Wang. Identification of COL3A1 variants associated with sporadic thoracic aortic dissection: a case--control study. Front. Med., 2021, 15(3): 438–447 https://doi.org/10.1007/s11684-020-0826-1

https://journal.hep.com.cn/fmd/EN/10.1007/s11684-020-0826-1

https://link.springer.com/article/10.1007/s11684-020-0826-1

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