Scientists Discover New Genes and Signaling Pathways Involved in Severe Lung Disease in Premature Infants

A set of new genes and signaling pathways linked to the development of severe lung disease in premature infants was found by researchers from Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago and collaborators.

Their study, “Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth,” published in the journal BMC Genetics, is the largest whole exome sequencing (WES) study to date focused on the relationship between genetic alterations, lung function, and prematurity.

WES is a method of examining the DNA sequence of all genes encoding for proteins (exome) on a given sample.

WES was performed on a subset of 146 premature infants born at less than 29 weeks with severe bronchopulmonary dysplasia (BPD) — a lung condition that usually affects premature infants, requires oxygen therapy after birth, and increases the infants’ chances of developing pulmonary hypertension (PH). All premature infants analyzed in the study were participants in the Prematurity and Respiratory Outcomes Program (PROP; NCT01435187).

Infants were divided into two groups, depending on disease severity: the affected group (85 infants), who required respiratory support up to 36 weeks post-menstrual age (gestational age plus time elapsed from birth); and the unaffected group (61 infants) who did not require respiratory support at 36 weeks post-menstrual age.

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Researchers looked for direct associations between disease status and genetic variants (both common and rare) linked to BPD, as well as specific signaling pathways potentially involved in disease development.

Results showed a total of 345 unique genetic variants associated with BPD among infants in the affected group, whereas 292 unique genetic variants linked to BPD were identified among infants in the unaffected group. Out of all these unique genetic variants, 28 (19 in the affected group and nine in the unaffected group) were also found in a previous WES study investigating BPD-associated variants.

“Our results lend further support to the theory that some chronic respiratory problems in premature babies have a genetic basis,” Aaron Hamvas, MD, division head of neonatology at Lurie Children’s and Professor of Pediatrics at Northwestern University Feinberg School of Medicine, said in a press release.

Interestingly, investigators found that the signaling cascade responsible for the production of the gonadotropin-releasing hormone, which is involved in sex differences and reproductive functions, was overrepresented in infants with higher disease severity.

“Our observation that a hormonal pathway is related to more severe lung disease is intriguing because we know that there are sex differences in the risk for chronic lung disease in premature infants, with boys more susceptible to worse outcomes,” Hamvas said.

In addition, researchers found that a signaling pathway involved in heart development was also overrepresented among premature infants with severe lung disease.

“Our discovery that genetic changes in a cardiac pathway are associated with chronic lung disease might explain why so many of these babies go on to develop pulmonary hypertension,” Hamvas said. “One of our research projects is actively pursuing this connection, trying to understand the direct mechanisms involved.”

“Some of the genetic pathways we found make sense biologically and warrant further research. Ultimately, we hope that early genetic testing could help us identify infants at high risk for severe lung disease, and reveal the precise genetic cause of their disease, so that we can treat it most effectively. Better understanding of genetic causes of lung disease in these babies will bring us closer to developing more precise treatments,” he concluded.