PTGS1 Genetic Variation and Increased Risk for Persistent Pulmonary Hypertension of the Newborn
| Status: | Recruiting |
|---|---|
| Conditions: | High Blood Pressure (Hypertension) |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 4/17/2018 |
| Start Date: | January 2006 |
| End Date: | December 2020 |
| Contact: | G. Ganesh Konduri, MD |
| Email: | gkonduri@mcw.edu |
| Phone: | 414-266-6820 |
Prostaglandin G/H Synthase-1 (PTGS1) Genetic Variation and Increased Risk for Persistent Pulmonary Hypertension of the Newborn (PPHN)
The purpose of this study is to determine if normally occurring variations in a specific gene
called PTGS-1 are associated with an increased risk of narrowing of the ductus arteriosus
from exposure to over-the-counter pain medicines (NSAIDs).
called PTGS-1 are associated with an increased risk of narrowing of the ductus arteriosus
from exposure to over-the-counter pain medicines (NSAIDs).
Persistent pulmonary hypertension of the newborn (PPHN) occurs when the pulmonary vascular
resistance fails to decrease at birth during the transition to postnatal life. The affected
infants have severe hypoxemia, a 10% risk of mortality, and among survivors, a 30% incidence
of long term neurodevelopmental and hearing deficits. The etiology of PPHN in the majority of
affected infants remains unknown. Although constriction of fetal ductus arteriosus in
response to maternal intake of non-steroidal anti-inflammatory drugs (NSAID) has been
implicated in PPHN case reports, our laboratory was the first to provide objective evidence
for such an association. Nearly 87% of infants with PPHN were exposed to NSAID in utero. Yet
25% of control infants also were exposed without developing PPHN. The basis for the
biological susceptibility of some neonates to in utero NSAID exposure remains poorly
understood. The hypothesis of this proposal is that PTGS1 genetic variation is associated
with increased susceptibility to ductal constriction from in utero NSAID exposure and an
increased risk of PPHN. This hypothesis will be tested through the following specific aims:
Determine the incidence of PTGS1 sequence variants in PPHN patients versus matched controls.
PTGS1 sequence will include all 11 exons, a minimum of 100 bp of exon flanking sequences, and
1 kbp of upstream regulatory information. Cycle sequencing will be performed followed by
analysis using capillary electrophoresis. Differences in the frequency of sequence variants
will be determined using Fisher's exact test. The study will also quantify NSAID exposure in
meconium samples using a previously established GC/MS assay and correlate exposure levels to
both the incidence of PPHN and the presence or absence of PTGS1 sequence variants using
regression analysis. Benefits include the ability to predict risk for PPHN based on PTGS1
sequence and avoidance of such risk in the future, thereby reducing patient morbidity and
mortality.
resistance fails to decrease at birth during the transition to postnatal life. The affected
infants have severe hypoxemia, a 10% risk of mortality, and among survivors, a 30% incidence
of long term neurodevelopmental and hearing deficits. The etiology of PPHN in the majority of
affected infants remains unknown. Although constriction of fetal ductus arteriosus in
response to maternal intake of non-steroidal anti-inflammatory drugs (NSAID) has been
implicated in PPHN case reports, our laboratory was the first to provide objective evidence
for such an association. Nearly 87% of infants with PPHN were exposed to NSAID in utero. Yet
25% of control infants also were exposed without developing PPHN. The basis for the
biological susceptibility of some neonates to in utero NSAID exposure remains poorly
understood. The hypothesis of this proposal is that PTGS1 genetic variation is associated
with increased susceptibility to ductal constriction from in utero NSAID exposure and an
increased risk of PPHN. This hypothesis will be tested through the following specific aims:
Determine the incidence of PTGS1 sequence variants in PPHN patients versus matched controls.
PTGS1 sequence will include all 11 exons, a minimum of 100 bp of exon flanking sequences, and
1 kbp of upstream regulatory information. Cycle sequencing will be performed followed by
analysis using capillary electrophoresis. Differences in the frequency of sequence variants
will be determined using Fisher's exact test. The study will also quantify NSAID exposure in
meconium samples using a previously established GC/MS assay and correlate exposure levels to
both the incidence of PPHN and the presence or absence of PTGS1 sequence variants using
regression analysis. Benefits include the ability to predict risk for PPHN based on PTGS1
sequence and avoidance of such risk in the future, thereby reducing patient morbidity and
mortality.
Inclusion Criteria:
- Infants born greater than or equal to 34 weeks gestational age diagnosed with PPHN and
normal, healthy infants born greater than or equal to 34 weeks gestational age.
Exclusion Criteria:
- Patients will be excluded if they are diagnosed with lethal congenital anomalies
- structural congenital heart disease except presence of patent ductus arteriosus (PDA)
or patent foramen ovale
- structural gastrointestinal tract abnormality that could interfere with meconium
passage
- congenital anomalies such as diaphragmatic hernia, Potter's syndrome, or pulmonary
hypoplasia
We found this trial at
1
site
9000 W Wisconsin Ave #270
Milwaukee, Wisconsin 53226
Milwaukee, Wisconsin 53226
(414) 266-2000
Principal Investigator: Ganesh Konduri, MD
Children's Hospital of Wisconsin Nothing matters more than our children. At Children's Hospital of Wisconsin,...
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