Genetic Contribution to Patent Ductus Arteriosus in the Premature Newborn

Abstract

BACKGROUND. The most common congenital heart disease in the newborn population, patent ductus arteriosus, accounts for significant morbidity in preterm newborns. In addition to prematurity and environmental factors, we hypothesized that genetic factors play a significant role in this condition. OBJECTIVE. The objective of this study was to quantify the contribution of genetic factors to the variance in liability for patent ductus arteriosus in premature newborns. PATIENTS AND METHODS. A retrospective study (1991–2006) from 2 centers was performed by using zygosity data from premature twins born at ≤36 weeks' gestational age and surviving beyond 36 weeks' postmenstrual age. Patent ductus arteriosus was diagnosed by echocardiography at each center. Mixed-effects logistic regression was used to assess the effect of specific covariates. Latent variable probit modeling was then performed to estimate the heritability of patent ductus arteriosus, and mixed-effects probit modeling was used to quantify the genetic component. RESULTS. We obtained data from 333 dizygotic twin pairs and 99 monozygotic twin pairs from 2 centers (Yale University and University of Connecticut). Data on chorioamnionitis, antenatal steroids, gestational age, body weight, gender, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, oxygen supplementation, and bronchopulmonary dysplasia were comparable between monozygotic and dizygotic twins. We found that gestational age, respiratory distress syndrome, and institution were significant covariates for patent ductus arteriosus. After controlling for specific covariates, genetic factors or the shared environment accounted for 76.1% of the variance in liability for patent ductus arteriosus. CONCLUSIONS. Preterm patent ductus arteriosus is highly familial (contributed to by genetic and environmental factors), with the effect being mainly environmental, after controlling for known confounders.