Bronchopulmonary Dysplasia: A Genetic Disease

Survival of low birth weight infants continues to improve because of marked advances in perinatal care,1 yet significant late pulmonary and neurocognitive impairments persist. Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, remains a major clinical problem, occurring in an estimated 10000 to 15000 infants each year in the United States alone. As initially described by Northway et al2 more than 40 years ago, BPD was originally characterized as resulting from severe acute lung injury in modestly premature newborns caused by the adverse effects of hyperoxia, inflammation, mechanical ventilation, and infection. These mechanisms are still recognized as major contributors to the pathogenesis of BPD, along with chorioamnionitis, maternal smoking and drug use, and delivery room management.3,4Over the past decades, however, changes in care, including antenatal steroid therapy, surfactant use, novel ventilator modalities and strategies, aggressive treatment of patent ductus arteriosus (PDA), and other factors, have altered the nature of BPD. Infants now surviving with BPD have been born at far earlier gestational ages than in the past. The “new BPD” is believed to represent less of the effects of severe lung injury and its repair and more of a disruption or arrest of lung development.5 This is illustrated most clearly by changes in lung structure found at autopsy of infants who died with BPD, featuring marked decreases in alveolarization and a dysmorphic vascular structure.6 Abnormalities of airways structure and function also persist during long-term follow-up, which lead to recurrent respiratory hospitalizations, reactive airways disease, exercise intolerance, and other problems.7 Despite therapeutic advances in the management of the sick newborn, strategies for identifying newborns at high risk for BPD and specific interventions that can be applied early to prevent BPD remain lacking and limit current approaches toward improving late outcomes.Susceptibility for the development of BPD is now recognized as being markedly influenced by complex interactions between genetic and environmental risk factors.8,9 Variability in the incidence and severity of BPD among premature infants with similar environmental risk factors suggests that genetic susceptibility plays a critical role in the pathogenesis of BPD. In an early study of preterm twins, Parker et al10 reported that genetic factors increase the risk for BPD and found striking associations in twin pairs independent of birth weight, gestational age, gender, severity of RDS, PDA, infection, antenatal steroids, and other factors. A subsequent study of 450 sets of preterm twins found that after controlling for the effects of covariates, most of the variances in liability for BPD could be accounted for by genetic and shared environmental factors.11 BPD occurred in one or both of the twins in 18 (29%) of 63 pairs of monozygotic twins and in 43 (23%) of 189 pairs of dizygotic twins. The ratio between the observed concordance12 and the expected concordance (3.69) was significantly higher in the monozygotic versus dizygotic group (P < .001). Without adjusting for covariates, BPD had a heritability of 63.6% in the subset of subjects with zygosity data. After controlling for covariates, genetic factors accounted for 53% (95% confidence interval: 16%–89%) (P = .004) of the variance in liability for BPD. The significant increase in concordance rates of BPD in monozygotic twins suggests a genetic susceptibility for the development of BPD. In fact, these findings suggest at least as strong a role for genetic factors in BPD as observed in such complex diseases in adults as systemic hypertension (30%), cancer (42%), and psychiatric disorders (>60%).12–14In another study, Lavoie et al15 compared the incidence of BPD in 318 twin pairs born at ≤30 weeks' gestation at a single center between 1993 and 2006. This study examined differences in correlations between monozygotic and dizygotic twin pairs and applied model-fitting approaches to quantify the relative contribution of genetic, shared environmental, and nonshared environmental effects. It is important to note that they compared the effects of different BPD definitions, including that which resulted from a National Institutes of Health workshop.5,16 Not only did they find that genetic effects accounted for ∼80% of the observed variance in BPD susceptibility, but also a striking link between genetic factors and persistence of the PDA was noted. Clinical traits were similar between monozygotic and dizygotic twins except for a higher incidence of respiratory distress syndrome and a lower incidence of bacteremia in dizygotic twins. Although previous studies have demonstrated a strong role for genetic effects in the pathogenesis of BPD, this study both confirmed and expanded our appreciation of how striking the effects of genetic susceptibility are in this process. This study was the first to apply a more precise, physiologic definition of BPD and, most importantly, a more rigorous analysis that distinguished common and nonshared environmental factors as well.Most importantly, this study speaks to the critical need for vigorous investigations to identify specific candidate genes that are known to be involved in the biological pathways governing the pathobiology of BPD.15 Numerous genes are required for normal lung growth and development, which are likely to contain sequence variations that modulate the risk for BPD. Published studies have identified several potential candidate genes, especially regarding surfactant proteins and cytokines,17–22 but many studies have reported small sample sizes, and the findings from most of them have not been replicated in subsequent cohorts. Regardless, this body of work represents an expansion of our thinking on the pathogenesis of BPD from a disease that is related exclusively to developmental and environmental factors to one that is also the consequence of interactions between genes and environment. The current challenge is to specifically identify candidate genes that contribute to the development of BPD and interactions between these genes and specific environmental stimuli that adversely affect lung injury, repair, and structure after preterm birth. Such investigations are likely to lead to novel strategies for the identification and treatment of infants at risk, thereby enhancing long-term respiratory outcomes in preterm infants.