Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn.
Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn.
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DOI：
10.1038/pr.2017.143
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发表时间：
2018-01
影响因子：
3.6
通讯作者：
Ryckman KK
中科院分区：
文献类型：
--
作者：
Kaluarachchi DC;Smith CJ;Klein JM;Murray JC;Dagle JM;Ryckman KK
新生儿持续性肺动脉高压（PPHN）的特征是肺血管阻力（PVR）升高。内源性一氧化氮在PVR的调节中起关键作用。一氧化氮是由尿素循环（UC）提供的L -精氨酸产生的.我们假设UC酶基因多态性和低浓度UC中间体与PPHN相关。以家系为基础的候选基因分析，研究6种UC酶基因的48个单核苷酸多态性。对94例PPHN患儿及其父母进行基因分型。我们还对32例PPHN和64例对照进行了病例对照分析，以确定初始新生儿筛查时氨基酸水平与PPHN之间的关联。氨甲酰磷酸合成酶1（CPS 1）基因的3个SNP与PPHN有显著相关性（p=0.02）。PPHN患者的酪氨酸水平显著降低（p=0.003），苯丙氨酸水平显著升高（p=0.01）。两组间精氨酸或瓜氨酸水平无差异。这项研究表明CPS 1和PPHN中的SNP之间存在潜在关联。PPHN患者血清酪氨酸水平显著降低，苯丙氨酸水平显著升高。这些发现值得在更大的患者队列中进一步复制。
Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR). Endogenous nitric oxide is critical for regulation of PVR . Nitric oxide is generated from L –arginine, supplied by the urea cycle (UC). We hypothesized that polymorphisms in UC enzyme genes and low concentrations of UC intermediates are associated with PPHN. Family based candidate gene analysis to study 48 single nucleotide polymorphisms in 6 UC enzyme genes. Genotyping was done on 94 infants with PPHN and their parents. We also performed a case-control analysis of 32 cases with PPHN and 64 controls to identify the association between amino acid levels on initial newborn screening and PPHN. Three SNPs in carbamoyl phosphate synthetase 1 gene (CPS1) showed significant association with PPHN (p=0.02). Tyrosine levels were significantly lower (p=0.003) and phenylalanine levels were significantly higher (p=0.01) in cases with PPHN. There was no difference in the arginine or citrulline levels between the two groups. This study suggests a potential association between SNPs in the CPS1 and PPHN. Tyrosine level was significantly lower and phenylalanine level was significantly higher in cases with PPHN. These findings warrant further replication in larger cohorts of patients.
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