Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn (original) (raw)
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Pediatrics, 2016
Background-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. Methods-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. Results-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. Conclusions-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.
European Journal of Pediatrics, 2021
Persistent pulmonary hypertension of the new-borns (PPHN) is one of the main etiologies of morbidity as well as mortality in neonates. Previous studies found that genetic polymorphisms in urea cycle enzymes are associated with PPHN. Few of the genetic polymorphisms in neonates have been recognized with PPHN. We aimed to find out the prevalence of the CPS-I gene polymorphism and to correlate the genotype with the serum nitric oxide (NO) levels in Egyptian neonates with idiopathic PPHN. We included neonates diagnosed with PPH (n = 150) while the control group included healthy neonates with matched age and sex (n = 100). The CPS-I gene polymorphism: A/C, trans-version substitution, rs4399666 genotype was identified using TaqMan-based quantitative PCR. The results revealed that the CPS-I A/C rs4399666 gene polymorphism and lower serum NO levels were significantly associated with idiopathic PPHN in neonates. In addition, serum NO level was significantly associated with an rs4366999 A/C v...
The Turkish journal of pediatrics
Genetic polymorphisms in the gene that codes for endothelial nitric oxide synthase (eNOS) have been associated with less nitric oxide availability and with various cardiovascular diseases in humans. The objective of this study was to analyze the genotype distributions and allele frequencies for the Glu298Asp (G894T) and T(-786)C polymorphisms of the eNOS gene among neonates with respiratory distress in comparison to healthy control subjects. Fifty premature neonates with respiratory distress and 55 neonates without any respiratory problem were included in the study. Genomic DNA from all the neonates was analyzed by polymerase chain reaction. A polymerase chain reaction-restriction fragment length polymorphism analysis of eNOS gene polymorphisms was performed, and the results were compared. There were no significant differences between the groups regarding either genotype distributions or the allele frequencies for the Glu298Asp and T(-786)C polymorphisms. These results suggest that ...
Respiratory Research, 2019
Background: Persistent 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. Methods: This 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. Results: Among 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 in TBX4 and BMPR2 and six with variants of unknown significance in BMPR2, SMAD9, TGFB1, KCNA5 and TRPC6. Three SNPs (rs192759073, rs1047883 and rs2229589) in CPS1 and one SNP (rs1044008) in NOTCH3 were significantly associated with PPHN (p < 0.05). CPS1 and SMAD9 were identified as risk genes for PPHN (p < 0.05). Conclusions: In this study, we identified genetic variants in PPHN patients, and we reported CPS1, NOTCH3 and SMAD9 as 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.
Circulation, 2002
Background-A defect of nitric oxide (NO) synthesis in the lung of high-altitude pulmonary edema (HAPE) has been suggested to contribute to its exaggerated pulmonary hypertension. Several polymorphisms have been identified in the gene encoding endothelial nitric oxide synthase (eNOS), which is a key enzyme responsible for NO synthesis, some of which were reported to be associated with vascular disorders. Methods and Results-We studied 41 HAPE-susceptible subjects (HAPE-s) and 51 healthy climbers (control group) in a Japanese population. We examined 2 polymorphisms of the eNOS gene, including the Glu298Asp variant and 27-base pair (bp) variable numbers of tandem repeats using polymerase chain reaction followed by restriction fragment length polymorphism. The Asp allelic frequency of the Glu298Asp variant was 25.6% in the HAPE-s and 9.8% in the controls, which was significantly different between the two groups (Pϭ0.0044). The eNOS4a allelic frequency of 27-bp variable numbers of tandem repeats was 23.2% in the HAPE-s, significantly higher than that of 6.9% in the controls (Pϭ0.0016).
Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn
Respiratory Research, 2020
Aims Persistent 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 results In 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 ...
Archivos de Bronconeumología (English Edition), 2014
Introduction: One of the pathways involved in pulmonary arterial hypertension (PAH) is the nitric oxide (NO) pathway. A polymorphism in the inducible NO synthase (NOS2) gene has been described, consisting of the CCTTT pentanucleotide repeat, which causes a reduction in NO production. The aim of this study was to determine if this polymorphism increases susceptibility to developing PAH. Methods: Sixty-four patients with a diagnosis of PAH groups i and iv and 50 healthy controls were compared. DNA genotyping of the samples for this polymorphism was performed using PCR. The distribution between both groups was compared and correlated with clinical and hemodynamic parameters and therapeutic response. Results: A significantly different distribution was observed in the number of repeats between patients and controls (P<.0001). When the samples were categorized by short forms (both alleles with less than 12 repeats) and long forms (≥12 repeats), it was observed that the former had an almost 4-fold risk of developing PAH (odds ratio: 3.83; 95% CI: 1.19-12.32, P=.024). There were no differences between the most common types of PAH, either in therapeutic response or survival. There was no correlation between hemodynamic parameters and the number of repeats in the patients, and only a weak correlation with systolic PAH. Conclusions: There are significant differences in the distribution of the NOS2 promotor CCTTT polymorphism between patients with PAH and the healthy population. A minor CCTTT pentanucleotide repeat in the NOS2 gene may increase the risk of developing PAH. A. Baloira Villar et al. / Arch Bronconeumol. 2014;50(4):141-145 superior de desarrollar HAP (odds ratio: 3,83; IC 95%: 1,32; p = 0,024). No hubo diferencias entre los tipos más frecuentes de HAP ni en la respuesta terapéutica o supervivencia. No existió correlación entre parámetros hemodinámicos y el número de repeticiones en los pacientes, solo débil correlación con la presión arterial pulmonar sistólica. Conclusiones: Existen diferencias significativas en la distribución del polimorfismo CCTTT del gen NOS2 entre pacientes con HAP y población sana. Una menor repetición del pentanucleótido CCTTT en el gen de la NOS2 podría incrementar el riesgo de desarrollar HAP.
Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn
Pediatric Research, 2012
Articles Translational Investigation nature publishing group INTRODUCTION: Persistent pulmonary hypertension of the newborn (PPhN) is associated with substantial infant morbidity and mortality. Recently, genetic associations have been found in idiopathic pulmonary arterial hypertension. RESULTS: PPhN was significantly (P < 0.05) associated with genetic variants in corticotropin-releasing hormone (cRh) receptor 1, CRHR1 and cRh-binding protein, CRHBP. association with CRHR1 rs4458044 passed the Bonferroni threshold for significance. No mutations were found in the bone morphogenetic protein receptor type II (BMPR2) gene. DISCUSSION: We describe previously unreported genetic associations between PPhN and CRHR1 and CRHBP. These findings may have implications for further understanding the pathophysiology of PPhN and treatment.
Genetic basis of pulmonary arterial hypertension
Journal of the American College of Cardiology, 2004
Mutations in two receptors of the transforming growth factor-beta family have recently been shown to be present in the majority of cases of inherited (familial) pulmonary arterial hypertension (PAH). Study of the biology of these receptors, bone morphogenetic protein receptor type-2 (BMPR2), and activin-like kinase type-1 (ALK-1) will certainly reveal pathogenic mechanisms of disease. Exonic mutations in BMPR2 are found in about 50% of patients with familial PAH, and ALK1 mutations are found in a minority of patients with hereditary hemorrhagic telangiectasia and co-existent PAH. Because familial PAH is highly linked to chromosome 2q33, it is likely that the remaining 50% of family cases without exonic mutations have either intronic BMPR2 abnormalities or alterations in the promoter or regulatory genes. Also, only about 10% of patients with "sporadic" idiopathic PAH have identifiable BMPR2 mutations. Mutations in BMPR2 confer a 15% to 20% chance of developing PAH in a carrier's lifetime. Thus, there must be gene-gene or gene-environment interactions that either enhance or prevent the development of the vascular disease in persons carrying a mutation, and there must be other patterns of susceptibility based on genetic makeup. To elucidate the genetic basis of PAH further, investigations are needed, including genome scanning for major and minor genes, analysis of genetic profiles of patients for candidate genes likely to modify risk for disease (e.g., serotonin transporter alleles, nitric oxide-synthases), proteomics, transgenic mice, and altered signal transduction. Advances in genetic testing, presymptomatic screening, and biomarkers should permit early detection of disease in those at risk of PAH and allow trials of preventive therapy in carriers. (J Am Coll