Published online March 30, 2009
PEDIATRICS Vol. 123 No. 4 April 2009, pp. 1116-1123 (doi:10.1542/peds.2008-0313)
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ARTICLE

Determination of Genetic Predisposition to Patent Ductus Arteriosus in Preterm Infants

John M. Dagle, MD, PhDa, Nathan T. Lepp, MDa, Margaret E. Cooper, MS, MSISb, Kendra L. Schaa, BSa, Keegan J.P. Kelsey, BSa, Kristin L. Orr, BSc, Diana Caprau, MDa, Cara R. Zimmerman, BSc, Katherine M. Steffen, BAc, Karen J. Johnson, RNa, Mary L. Marazita, PhDb,d and Jeffrey C. Murray, MDa

a Department of Pediatrics
c Carver College of Medicine, University of Iowa, Iowa City, Iowa
b Center for Craniofacial and Dental Genetics
d Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania

OBJECTIVE. Patent ductus arteriosus is a common morbidity associated with preterm birth. The incidence of patent ductus arteriosus increases with decreasing gestational age to ~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 β 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 β, tumor necrosis factor receptor–associated factor 1, and prostacyclin synthase in the persistent patency of the ductus arteriosus seen in preterm infants.

Key Words: patent ductus arteriosus • genetic predisposition • premature infants

Abbreviations: DA—ductus arteriosus • PDA—patent ductus arteriosus • IVH—intraventricular hemorrhage • SNP—single-nucleotide polymorphism • AGTR1—angiotensin II type I receptor • TFAP2B—transcription factor AP-2 β • TRAF1—tumor necrosis factor receptor–associated factor 1 • PTGIS—prostacyclin synthase • FBAT—Family-Based Association Test • CETP—cholesteryl ester transfer protein, plasma • CYP2D6—cytochrome P450, family 2, subfamily D, polypeptide 6 • CRHR1—corticotrophin-releasing hormone receptor 1 • LIPC—hepatic lipase

Accepted Jul 30, 2008.


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