Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates
Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates
复制标题
中国新生儿队列中新生儿持续性肺动脉高压的遗传因素鉴定
DOI：
10.1186/s12931-019-1148-1
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发表时间：
2019-08-05
影响因子：
5.8
通讯作者：
Zhou, Wenhao
中科院分区：
文献类型：
--
作者：
Liu, Xu;Mei, Mei;Zhou, Wenhao
新生儿持续性肺动脉高压（PPHN）是新生儿重症监护病房（NICU）患者面临的严重临床问题。PPHN的遗传发病机制尚不清楚。只有少数的遗传多态性已被确定在婴儿PPHN。我们的研究旨在探讨PPHN的潜在遗传病因。方法本研究招募了2016年1月至2017年12月在复旦大学儿童医院NICU住院的PPHN患者。对所有患者进行外显子组测序。对已报道的PPHN/肺动脉高压（PAH）相关基因的变异进行了评估。单核苷酸多态性（SNP）的关联和基因水平进行了分析，在74例PPHN和115非PPHN对照匹配的基线characteristics.ResultsAmong患者队列，74（64.3%）患者为晚期早产儿和足月儿（≥ 34周妊娠）和41（35.7%）早产儿（<34周妊娠）。早产儿PPHN表现出低出生体重和高频率的支气管肺发育不良，呼吸窘迫综合征（RDS）和死亡率。9名患者（仅1名早产儿）被鉴定为携带遗传变异，包括TBX4和BMPR2中致病/可能致病的变异3名，BMPR2、SMAD9、TGFB1、KCNA5和TRPC6中意义不明的变异6名。三种snp CP S1中的rs192759073、rs1047883和rs2229589，以及一个SNP NOTCH 3中rs1044008与PPHN显著相关CPS1和SMAD9是PPHN的危险基因（P <0.05（p <0.05）。结论在这项研究中，我们鉴定了PPHN患者的遗传变异，并证实了CPS 1，NOTCH 3和SMAD 9是中国单中心队列中晚期早产和足月PPHN的风险基因我们的发现为PPHN的发病机制提供了额外的遗传学证据，并为疾病治疗的潜在策略提供了新的见解。
BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a severe clinical problem among neonatal intensive care unit (NICU) patients. The genetic pathogenesis of PPHN is unclear. Only a few genetic polymorphisms have been identified in infants with PPHN. Our study aimed to investigate the potential genetic etiology of PPHN.MethodsThis study recruited PPHN patients admitted to the NICU of the Children’s Hospital of Fudan University from Jan 2016 to Dec 2017. Exome sequencing was performed for all patients. Variants in reported PPHN/pulmonary arterial hypertension (PAH)-related genes were assessed. Single nucleotide polymorphism (SNP) association and gene-level analyses were carried out in 74 PPHN cases and 115 non-PPHN controls with matched baseline characteristics.ResultsAmong the patient cohort, 74 (64.3%) patients were late preterm and term infants (≥ 34 weeks gestation) and 41 (35.7%) were preterm infants (< 34 weeks gestation). Preterm infants with PPHN exhibited low birth weight and a high frequency of bronchopulmonary dysplasia, respiratory distress syndrome (RDS) and mortality. Nine patients (only one preterm infant) were identified as harboring genetic variants, including three with pathogenic/likely pathogenic variants inTBX4andBMPR2and six with variants of unknown significance inBMPR2,SMAD9,TGFB1,KCNA5andTRPC6. Three SNPs (rs192759073, rs1047883 and rs2229589) inCPS1and one SNP (rs1044008) inNOTCH3were significantly associated with PPHN (p< 0.05).CPS1andSMAD9were identified as risk genes for PPHN (p< 0.05).ConclusionsIn this study, we identified genetic variants in PPHN patients, and we reportedCPS1,NOTCH3andSMAD9as risk genes for late preterm and term PPHN in a single-center Chinese cohort. Our findings provide additional genetic evidence of the pathogenesis of PPHN and new insight into potential strategies for disease treatment.