Equipped with data from umbilical cord gene chips, researchers may be able to predict which preterm infants are at greater risk for developing bronchopulmonary dysplasia (BPD), a disease that scars and inflames underdeveloped lungs in premature infants.
The study, which appeared online Oct. 4 in Genome Biology, found that infants whose chromatin-remodeling pathway is aberrantly expressed have a greater tendency to develop the disease. BPD occurs in 20 to 40 percent of infants born below 1,000 grams and before the 28th week of gestation. The study defined cases as infants who needed supplemental oxygen at 36 weeks from the mother’s last menstrual period.
Infants who developed BPD were born earlier, weighed less, required more days of supplemental oxygen and ventilation, and had higher rates of sepsis and retinopathy of prematurity. There was no difference in the sex ratio of infants affected. Other factors associated with the disease—the second leading cause of death at this gestational age—include surfactant deficiency and maternal infections like chorioamnionitis.
Although researchers have identified factors that accompany BPD, they are unsure why only some infants develop the disease, said the study’s senior author, Isaac Kohane, the Lawrence J. Henderson associate professor of pediatrics and health sciences and technology at HMS and Children’s Hospital Boston. He is also a faculty member in the Harvard–MIT Division of Health Sciences and Technology.
Kohane, lead author Jennifer Cohen, a neonatology fellow at Children’s, and their colleagues collected the umbilical cords of 54 premature infants—20 of whom developed BPD. After analyzing RNA expression profiles for each of the umbilical cords, the researchers found that the genes themselves showed little difference between the BPD and control infants, but that three specific pathways, including those for oxidative phosphorylation, mitochondrial energy metabolism, and DNA repair, were differentially expressed. In particular, infants with a predisposition for BPD showed a lower level of expression in genes of the chromatin-remodeling pathway, which may leave portions of the genome exposed for continual or increased transcription.
A similar dysregulation of the chromatin-remodeling pathway exists in adults with chronic obstructive lung disease. Histone deacetylase–inhibiting (HDI) drugs, Kohane said, are currently in test trials for patients with this disorder. It is thought that the aberrant chromatin-remodeling pathway in these adults enables increased expression of inflammatory genes. HDI drugs prevent the transcription of these genes by causing DNA to wrap more tightly around histones.
“If these results are reproduced in subsequent studies, it would allow us to predict at birth who is at a greater risk,” said Kohane. “Maybe we could prevent BPD before it develops.”
Larger sample sizes are necessary to produce prognostic markers from umbilical cord profiles, Kohane cautioned. Still, he speculated that infants with BPD may have the same genetic vulnerability as adults who face oxidative stressors like pollution and smoking before developing lung disease. “The same disease may be manifested at different times in life because of different oxidative exposures,” he said.