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Rare gene variants help explain preemies’ lung disease, Stanford study shows

Because they're born before their lungs are fully mature, premature babies are at risk for a serious lung disease. Over the last several decades, this disease, bronchopulmonary dysplasia, has evolved into both a great medical success story and a persistent mystery. But a new Stanford study, published this week, is helping clarify the mysterious part.

First, the success story: Today, doctors can prevent BPD in many babies who would have died of it in the past. Artificial surfactant, which helps keep the air sacs of the lungs open, and extensive research on when it's appropriate and safe to put preemies on a respirator have both greatly reduced the risk of lung injuries after birth, which can contribute to BPD. The improvement has been especially remarkable for babies born on the later end of the premature spectrum.

However, BPD is still a big problem for infants who arrive more than 12 weeks early. Doctors still have trouble figuring out which of these early preemies are at risk, and why. An editorial accompanying the new Stanford study, which appears in the American Journal of Respiratory and Critical Care Medicine, explains how scientists' understanding of BPD has evolved:

It is now widely appreciated that the persistence of BPD is strongly linked with factors far beyond postnatal lung injury alone. Importantly, the BPD and related respiratory outcomes clearly have antenatal origins... Growing data support the concept that BPD is at least partly a "fetal disease."

The editorial names several factors in the prenatal environment that weigh into BPD risk, including certain pregnancy complications and also maternal smoking or drug use. It's not just the environment that plays into risk, though; twin studies also hint that genes also factor in, and knowing which genes are involved would provide enormous clues to how the disease occurs.

A prior Stanford study that attempted to connect common human gene variants to BPD risk didn't turn up any good candidates. So, in the new study, the Stanford team focused instead on rare genetic variants. Using data from California's extensive repository of newborn blood spots (small blood samples collected as part of the state's program to screen newborns for genetic diseases), they turned up 258 rare gene variants for further investigation, all of which are linked to cell processes that could plausibly be involved in BPD.

"We hope these results will guide future research that can determine the most important pathophysiologic pathways leading to BPD," said Hugh O'Brodovich, MD, the study's senior author. The idea isn't to target the genes themselves for treatment, but rather to help researchers figure out what goes wrong at a molecular level in the lungs of babies who get BPD.

"We also hope this work will be used to discover how clinicians can minimize the chance that an extremely premature baby will develop the disease," he added.

Previously: Study of outcomes for early preemies highlights complex choices for families and doctors, Stanford-led study suggests changes to brain scanning guidelines for preemies and Counseling parents of the earliest-born preemies: A mom and two physicians talk about the challenges
Photo by James Gaither

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