Determination of Genetic Predisposition to Patent Ductus Arteriosus in Preterm Infants

Abstract

Patent ductus arteriosus (PDA) is a common morbidity associated with preterm birth. The incidence of PDA increases with decreasing gestational age to about 70% in infants born at 25 weeks gestation. Although medical treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is used to close the ductus arteriosus, approximately 30% of infants with a PDA do not respond to pharmacologic attempts at closure. We investigated whether single nucleotide polymorphisms (SNPs) in genes that regulate smooth muscle contraction, xenobiotic detoxification, inflammation and other processes are markers for persistent patency of the DA. Initially, 377 SNPs from 130 genes of interest were evaluated in DNA samples collected from 204 infants with a gestational age of less than 32 weeks. A family-based association test (FBAT) was performed on genotyping data to evaluate overtransmission of alleles. P-values of less than 0.01 were detected for genetic variations found in seven genes. The analysis was then replicated with an independent set of 162 infants, focusing on the seven markers with initial p-values less than 0.01, and one genetic variant in the angiotensin II type I receptor (AGTR1) previously shown to be related to PDA. Of the initial positive signals, SNPs in the transcription factor AP-2 beta (TFAP2B) and TNF receptor-associated factor 1 (TRAF1) genes remained significant, both with p-values of 0.005. An AGTR1 polymorphism previously reported to be associated with PDA following prophylactic indomethacin administration was not associated with the presence of a PDA in our population (p = 0.48). Overall, our data support a role for a genetic contribution to the risk of PDAs in preterm infants.

Very Low Birth Weight Monochorionic Diamniotic Twins as a Risk Factor for Symptomatic Patent Ductus Arteriosus

“…Recently, identification of specific genes for PDA has been reported [9,10,11,12,13,21]. Genes that interfere with remodeling of vascular smooth muscle cells of the ductal media are thought to lead to PDA.…”

“…Treszl et al [21] reported polymorphism in the AGTR1 gene (rs5186), which is related to angiotensin II-related vasoconstriction that influences PDA closure with indomethacin. Dagle et al [13] reported a significant association of alleles in the TFAP2B and EPAS1 genes (both found to be expressed in the smooth muscle cells of mouse ductus arteriosus, playing key roles in ductal closure), with subsequent need for surgical ligation in preterm infants. Because PDA usually occurs sporadically, it has not been regarded as a typical genetic disorder.…”

“…In addition, some prior studies have shown that sPDA is highly familial. Although it is estimated that both genetic and environmental factors may contribute to sPDA, evidence is still lacking in VLBW infants [9,10,11,12,13]. …”

Controversies in Management of Patent Ductus Arterious in the Preterm Infant

“…Delayed ductal closure is related to prematurity and exaggerated by comorbidities such as respiratory distress syndrome and sepsis. A genetic basis for ductal patency has also been suggested by mutations and polymorphisms within genes interfering with remodeling of vascular smooth muscle cells of ductal media [15].…”

Identification of differentially regulated genes in human patent ductus arteriosus

“…2 This may be due to many factors including decreased tone due to presence of immature smooth muscle myosin isoforms and impairment of calcium entry through L-type calcium channels, increased sensitivity to prostaglandin E2 (PGE 2 ) and nitric oxide, or increased levels of PGE 2 . [3][4][5] The clinical consequences of a patent ductus arteriosus (PDA) are related to the degree of left-to-right shunt through the PDA with its associated change in blood flow to the lungs, kidneys, and intestines. 2 Preterm infants of <30 weeks gestation with severe respiratory distress have a 65% incidence of persistent ductus patency beyond the fourth day of life.…”