Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn
Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn
复制标题
新生儿持续性肺动脉高压缺氧相关基因频繁突变
DOI：
10.1186/s12931-020-1314-5
复制
发表时间：
2020-02-13
影响因子：
5.8
通讯作者：
Zhou, Wenhao
中科院分区：
文献类型：
--
作者：
Wang, Mingbang;Zhuang, Deyi;Zhou, Wenhao
目的新生儿持续性肺动脉高压(PPHN)的特征是出生后持续高水平的肺血管阻力，病因不明；高纬度藏族新生儿的动脉血氧饱和度高于低纬度汉族新生儿，提示遗传适应可能允许足够的氧气使藏族人群具有对肺动脉高压的抗性；我们已通过候选基因测序确定了与PPHN相关的遗传因素；方法与结果首先对20例藏族PPHN患者的外显子全序列进行测序，并与已发表的50个健康高原藏族高原缺氧相关基因的基因组序列进行比较，共发现166个PPHN相关变异，其中49%来自43个缺氧相关基因；考虑到许多研究表明西藏和汉族的遗传背景差异是以低氧相关的遗传多态性为特征的，因此有必要进一步验证低氧相关变异与PPHN的关联是否独立于高原生活。在验证阶段，对80例低海拔地区汉族PPHN患者的237个低氧相关基因进行了测序，包括处于发现阶段的基因和已知的低氧耐受性基因，其中127个基因的413个变异与PPHN相关。结论低氧相关基因与PPHN的关联不依赖于高原生活，同时还发现了21个与PPHN相关的罕见突变，其中包括3个罕见的微管蛋白酪氨酸连接酶家族成员3基因(TTLL3：p.E317K，TTLL3：p.P777S)和整合素亚单位αM基因(ITGAM：p.E1071D)。这些新发现为PPHN的遗传学基础提供了重要信息。
AimsPersistent pulmonary hypertension of the newborn (PPHN) is characterized by sustained high levels of pulmonary vascular resistance after birth with etiology unclear; Arterial blood oxygen saturation of Tibetan newborns at high latitudes is higher than that of Han newborns at low latitudes, suggesting that genetic adaptation may allow sufficient oxygen to confer Tibetan populations with resistance to pulmonary hypertension; We have previously identified genetic factors related to PPHN through candidate gene sequencing; In this study, we first performed whole exome sequencing in PPHN patients to screen for genetic-related factors.Methods and resultsIn this two-phase genetic study, we first sequenced the whole exome of 20 Tibetan PPHN patients and compared it with the published genome sequences of 50 healthy high-altitude Tibetanshypoxia-related genes, a total of 166 PPHN-related variants were found, of which 49% were from 43 hypoxia-related genes; considering many studies have shown that the differences in the genetic background between Tibet and Han are characterized by hypoxia-related genetic polymorphisms, so it is necessary to further verify whether the association between hypoxia-related variants and PPHN is independent of high-altitude life. During the validation phase, 237 hypoxia-related genes were sequenced in another 80 Han PPHN patients living in low altitude areas, including genes at the discovery stage and known hypoxia tolerance, of which 413 variants from 127 of these genes were shown to be significantly associated with PPHN.hypoxia-related genes.ConclusionsOur results indicates that the association of hypoxia-related genes with PPHN does not depend on high-altitude life, at the same time, 21 rare mutations associated with PPHN were also found, including three rare variants of the tubulin tyrosine ligase-like family member 3 gene (TTLL3:p.E317K,TTLL3:p.P777S) and the integrin subunit alpha M gene (ITGAM:p.E1071D). These novel findings provide important information on the genetic basis of PPHN.