الفهرس 
Neonatal Persistent Pulmonary HypertensionOnly 14 pages are availabe for public view
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Abstract
Failure of the transition to a cardiorespiratory circulation at birth
results in persistent pulmonary hypertension of the newborn which
is characterized by elevated pulmonary vascular resistance with
extrapulmonary right-to-left shunting of blood across the patent ductus
arteriosus or the foramen ovale .
Persistent pulmonary hypertension can cause life-threatening
hypoxemia in newborn infants .
Transitional pulmonary hypertension occurs in 1.9 of every 1000
newborn infants and is associated with a mortality rate of 11 percent.
PPHN can be easily triggered in newborns by hypoxic lung diseases such
as meconium aspiration syndrome, respiratory distress syndrome and
pneumonia.
Administration of inhaled nitric oxide can be an effective
treatment for persistent pulmonary hypertension in newborn
infants. Endogenous nitric oxide is critical in the transition to a
pulmonary circulation at birth and in the regulation of pulmonary
vascular resistance.
Cells generate nitric oxide from the precursor l-arginine , an amino
acid supplied by the urea cycle. Theoretically, therefore, a link exists
between nitric oxide production and the urea cycle.
We hypothesized that low concentrations of arginine would
correlate with the presence of persistent pulmonary hypertension in
newborns and that the supply of this precursor would be affected by a
functional polymorphism (the substitution of asparagine for threonine at position 1405 [T1405N]) in carbamoyl-phosphate synthetase, which
controls the rate-limiting step of the urea cycle.
At 36 weeks’ gestation, the enzymes in the urea cycle function at
only 40 to 90 percent of the levels found in adults. Carbamoyl-phosphate
synthetase catalyzes the first, rate-determining step of the urea cycle.
Genetic variations in the activity of this enzyme affect the downstream
availability of the urea-cycle intermediates.
We recently described a C-to-A nucleotide transversion in exon 36
of the gene that encodes carbamoyl-phosphate synthetase, resulting in the
substitution of asparagine (Asn) for threonine (Thr) at position 1405
(T1405N), which is in the critical N-acetylglutamate–binding domain.
The study is aimed to find out the association between Carbamoyl
Phosphate Synthetase 1 (CPS1) gene polymorphism “A/C, Trans version
Substitution, rs4399666” and prevalence of PPHN.
This is a case-control study , was conducted in the Pediatric
department , Faculty of Medicine , Ain ShamsUniversity. One hundred
neonates presented with PPHN were recruited in this study and
compared to age and sex matched control group (n=100) .
The main results of the study revealed that:
The CPS1 A/C rs4399666 gene polymorphism were detected in
DNA of studied groups (PPHN and healthy controls) , The wild
genotype was detected only in 15 participants (ten in the PPHN
group and five cases in the control group) , however , the mutant
CPS1 A/C rs4399666 genotype was frequently distributed among
both groups . The results revealed that single nucleotide
polymorphism of CPS1 A/C rs4399666 was detected in
approximately 90% of the participants , however, no significant
difference was reached between both groups (2
: 1.8, p=0.18) For CPS-1 rs4399666 A/C gene polymorphism, a significant
association was observed between the frequencies of different
genotype with PPHN in neonates (2
: 7.4, p=0.02). The results
revealed that the Heterozygous AC genotype was frequently
distributed (58%) among the healthy control group, as well as in
PPHN neonates in which it constitutes 40% of cases . However, the
homozygous AA genotype was less frequent distributed in both
groups, followed by the homozygous CC genotype which was
detected only in 22% of neonates with PPHN and 10% of healthy
controls.
To find out the association between the specific allele expression in
CPS-1 rs4399666 A/C gene polymorphism and PPHN in neonates,
a comparative Chi-square test was conducted. The mutant CPS-1
rs4399666 A/C genotypes are divided according to allele
expression into two groups including the AA genotype which was
compared to non-AA genotype (AC&CC) , and the CC genotype
which was compared to non-CC genotypes (AA &AC) . Results
revealed non-significant association between the CC genotype
when compared to non-CC (2
:1.8, p=0.16). Similar finding was
detected between AA and non-AA genotype (2
: 1.8, p=0.18).
With respection to the genotype frequency, it was found that the
CC and AA genotypes are more distributed in PPHN group
compared to control group, but no-significant difference was
achieved.
The serum Nitric oxide level was analyzed in the studied
participants and the level in PPHN was compared with the healthy
control group. The Kolmogorov-Smirnov normality test examines
if variables are normally distributed, the test showed that the data
are normally distributed among the two groups, therefor comparative parametric test “Kruskal-Wallis” test was conducted.
The results revealed a high significant association for the serum
nitric oxide level between PPHN neonates and controls ( 2: 88.2,
p=0.0001), the serum nitric oxide level is increased by 2.6 folds in
healthy neonates compared to PPHN cases. the median expression
level in PPHN neonates was 6.4 , range: 2.6 – 11.6. In contrast to
16.8 , range: 2.8-38.0 in the healthy control group.
The association between serum nitric oxide level and CPS1
rs4399666 genotypes were analyzed using Analysis of variances
test (ANOVA). The results revealed a high significant association
between the serum of nitric oxide and the presence of CPS1
rs4399666 gene mutation (F: 17.2, p=0.007), lower nitric oxide
level was associated with mutant gene form compared to wild type.
On contrary, no significant association was detected between the
different genotypes in neonates with mutant CPS1 gene and the
serum nitric oxide level.
In order to access the risk probability of CSP1 A/C rs4399666 gene
polymorphism with development of PPHN in neonates, the
unconditional logistic regression analysis was conducted.
Regarding the investigated SNPs, after correction for multiple
comparisons, the CPS1 gene mutation was not an independent risk
factor for PPHN in neonates (0
=-0.24, OR=0.44, p>0.05).
Furthermore, the dominant and recessive models were analyzed,
and the genotypic models for CPS1 gene polymorphism was tested
as follows (AA vs CC and AC), and (CC versus AA and AC), the
results revealed that neither the dominant or recessive CPS1
genotypes are significantly raise the risk for PPHN in neonates
(p>0.05)
Summary
٨٢
Based on our results we recommend for further studies n lar Based on our results we recommend for further studies n larger patients
and longer period of follow up to emphasize our conclusion.