Department of Cardiovascular Medicine Tohoku University Graduate School of Medicine Sendai Japan.
Department of Integrative Genomics Tohoku Medical Megabank Organization Tohoku University Sendai Japan.
J Am Heart Assoc. 2020 Nov 3;9(21):e015902. doi: 10.1161/JAHA.120.015902. Epub 2020 Oct 24.
Background Although chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (APE) share some clinical manifestations, a limited proportion of patients with CTEPH have a history of APE. Moreover, in histopathologic studies, it has been revealed that pulmonary vasculature lesions similar to pulmonary arterial hypertension existed in patients with CTEPH. Thus, it remains unknown whether these 3 disorders also share genetic backgrounds. Methods and Results Whole exome screening was performed with DNA isolated from 51 unrelated patients with CTEPH of Japanese ancestry. The frequency of genetic variants associated with pulmonary arterial hypertension or APE in patients with CTEPH was compared with those in the integrative Japanese Genome Variation Database 3.5KJPN. Whole exome screening analysis showed 17 049 nonsynonymous variants in patients with CTEPH. Although we found 6 nonsynonymous variants that are associated with APE in patients with CTEPH, there was no nonsynonymous variant associated with pulmonary arterial hypertension. Patients with CTEPH with a history of APE had nonsynonymous variants of , which encodes factor V. In contrast, patients with CTEPH without a history of APE had a nonsynonymous variant of , which encodes thrombomodulin. Moreover, thrombin-activatable fibrinolysis inhibitor, which is one of the pathogenic proteins in CTEPH, was significantly more activated in those who had the variants of compared with those without it. Conclusions These results provide the first evidence that patients with CTEPH have some variants associated with APE, regardless of the presence or absence of a history of APE. Furthermore, the variants might be different between patients with CTEPH with and without a history of APE.
背景 虽然慢性血栓栓塞性肺动脉高压（CTEPH）和急性肺栓塞（APE）具有一些共同的临床表现，但有一小部分 CTEPH 患者有 APE 病史。此外，在组织病理学研究中，已经发现 CTEPH 患者的肺血管病变类似于肺动脉高压。因此，目前尚不清楚这 3 种疾病是否也具有遗传背景。 方法和结果 对 51 例日本血统的 CTEPH 患者的 DNA 进行全外显子组筛选。比较 CTEPH 患者中与肺动脉高压或 APE 相关的遗传变异频率与综合日本基因组变异数据库 3.5KJPN 中的频率。全外显子组筛选分析显示 CTEPH 患者有 17049 个非同义变异。虽然我们在 CTEPH 患者中发现了 6 个与 APE 相关的非同义变异，但没有与肺动脉高压相关的非同义变异。有 APE 病史的 CTEPH 患者存在编码因子 V 的 的非同义变异。相比之下，没有 APE 病史的 CTEPH 患者存在编码血栓调节蛋白的 的非同义变异。此外，在有 变异的患者中，纤溶酶原激活物抑制物（CTEPH 中的一种致病蛋白）的活性明显更高。 结论 这些结果首次提供了证据，表明 CTEPH 患者存在与 APE 相关的一些变异，无论是否有 APE 病史。此外，有和无 APE 病史的 CTEPH 患者的变异可能不同。
