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Determination of genetic predisposition to patent ductus arteriosus in preterm infants
John M Dagle1, Nathan T Lepp, Margaret E Cooper
1Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA. john-dagle@uiowa.edu
Insights
Genetic factors contribute to persistent patent ductus arteriosus in preterm infants. Variations in specific genes, including transcription factor AP-2 beta and prostacyclin synthase, are linked to this common condition.
Area of Science:
- Neonatal Medicine
- Genetics
- Pediatric Cardiology
Background:
- Patent ductus arteriosus (PDA) is a frequent complication in preterm infants, with incidence rising as gestational age decreases.
- Approximately 70% of infants born at 25 weeks' gestation develop PDA.
- Understanding the underlying causes of PDA is crucial for improving infant outcomes.
Purpose of the Study:
- To investigate the potential role of genetic risk factors in the development of PDA among preterm infants.
- To identify specific gene polymorphisms associated with persistent PDA.
Main Methods:
- Single-nucleotide polymorphisms (SNPs) in 130 candidate genes were analyzed in DNA from 204 preterm infants (<32 weeks gestation).
- Family-based association tests were used to assess allele overtransmission.
- Follow-up analysis included an additional 162 infants and focused on promising genetic markers.
Main Results:
- Initial screening identified 7 genes with significant genetic variations (P < .01).
- SNPs in transcription factor AP-2 beta and tumor necrosis factor receptor-associated factor 1 remained significant after further analysis.
- Haplotype analysis revealed an association between genetic variations in prostacyclin synthase and PDA.
Conclusions:
- Genetic variations in transcription factor AP-2 beta, tumor necrosis factor receptor-associated factor 1, and prostacyclin synthase are associated with persistent PDA in preterm infants.
- These findings suggest a genetic predisposition contributing to PDA in this vulnerable population.
- Further research into these genetic pathways may lead to novel therapeutic targets.
Objective:
Patent ductus arteriosus is a common morbidity associated with preterm birth. The incidence of patent ductus arteriosus increases with decreasing gestational age to approximately 70% in infants born at 25 weeks' gestation. Our major goal was to determine if genetic risk factors play a role in patent ductus arteriosus seen in preterm infants.
Methodology:
We investigated whether single-nucleotide polymorphisms in genes that regulate smooth muscle contraction, xenobiotic detoxification, inflammation, and other processes are markers for persistent patency of ductus arteriosus. Initially, 377 single-nucleotide polymorphisms from 130 genes of interest were evaluated in DNA samples collected from 204 infants with a gestational age of <32 weeks. A family-based association test was performed on genotyping data to evaluate overtransmission of alleles.
Results:
P values of <.01 were detected for genetic variations found in 7 genes. This prompted additional analysis with an additional set of 162 infants, focusing on the 7 markers with initial P values of <.01, and 1 genetic variant in the angiotensin II type I receptor previously shown to be related to patent ductus arteriosus. Of the initial positive signals, single-nucleotide polymorphisms in the transcription factor AP-2 beta and tumor necrosis factor receptor-associated factor 1 genes remained significant. Additional haplotype analysis revealed genetic variations in prostacyclin synthase to be associated with patent ductus arteriosus. An angiotensin II type I receptor polymorphism previously reported to be associated with patent ductus arteriosus after prophylactic indomethacin administration was not associated with the presence of a patent ductus arteriosus in our population.
Conclusions:
Overall, our data support a role for genetic variations in transcription factor AP-2 beta, tumor necrosis factor receptor-associated factor 1, and prostacyclin synthase in the persistent patency of the ductus arteriosus seen in preterm infants.
