Determination of genetic predisposition to patent ductus arteriosus in preterm infants

• Published in: Pediatrics (Evanston) Vol. 123; no. 4; p. 1116
• Main Authors: Dagle, John M, Lepp, Nathan T, Cooper, Margaret E, Schaa, Kendra L, Kelsey, Keegan J P, Orr, Kristin L, Caprau, Diana, Zimmerman, Cara R, Steffen, Katherine M, Johnson, Karen J, Marazita, Mary L, Murray, Jeffrey C
• Format: Journal Article
• Language: English
• Published: United States 01.04.2009
• Subjects: Cholesterol Ester Transfer Proteins - genetics; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 Enzyme System - genetics; Ductus Arteriosus, Patent - genetics; Genetic Predisposition to Disease - epidemiology; Gestational Age; Haplotypes; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases - genetics; Intramolecular Oxidoreductases - genetics; Lipase - genetics; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1 - genetics; Receptors, Corticotropin-Releasing Hormone - genetics; TNF Receptor-Associated Factor 1 - genetics; Transcription Factor AP-2 - genetics
• ISSN: 1098-4275
• DOI: 10.1542/peds.2008-0313

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. 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. 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. 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.