A previously unknown gene-environment interaction between maternal diabetes and transcriptional regulator Notch1 raises the risk of congenital heart disease (CHD) in children, a paper published in the Journal of Clinical Investigation: Insight states.

Babies born to mothers with diabetes have a three- to five-fold increased risk of developing congenital heart defects, Vidu Garg, MD, and co-authors noted in the study. That’s been common knowledge for a long time, but the molecular workings behind the fact are still largely unexplored and unknown. Garg and colleagues said the link between gestational diabetes and CHD in infants is likely a result of genetic and environmental reactions working together.

CHD is the most common type of birth defect in infants worldwide, the authors wrote, affecting around eight million children each year. It’s a leading cause of noninfectious infant morbidity and mortality, but scientists don’t know much about its etiology. Established theories led Garg and colleagues’ research.

“The importance of gene dosage for the occurrence of cardiac malformations has been shown, along with the concept of an oligogenic etiology for CHD, supporting the concept that mild alterations in gene expression levels may lead disease phenotypes,” Garg and co-authors wrote. “Similarly, numerous environmental risk factors for CHD have been reported, each of which increases the risk of having a child with CHD.”

Garg and his team said in the paper they previously discovered that an interaction between the genes Endothelial Nitric Oxide Synthase and Notch1 resulted in severe CHD in animal models. Since diabetes has previously been associated with low nitric oxide levels in blood, the researchers hypothesized that, in mouse and fly models, a Notch1 mutation in combination with maternal diabetes would result in risky heart defects.

Blood vessels see low nitric oxide levels in pregnant women with hyperglycemia because diabetes decreases chromatic accessibility of Endothelial Nitric Oxide Synthase, the authors wrote. This results in an overexpression of Jarid2, which is a repressor of Notch1. By mimicking these human interactions in animal models, Garg and colleagues found that an increased expression of Jarid2 resulted in lower Notch1 expression—too low for normal heart development.

Through these pathways, the researchers were able to identify the epigenetics and inner workings of gene-environment interactions that result in congenital heart defects in babies born to mother with gestational diabetes.

More research may be needed in the area, Garg and co-authors said in the study, but their recent findings support an important gene-environment interaction between diabetes and CHD that hadn’t been previously described.

“Only a subset of infants that are exposed to hyperglycemia develop a congenital heart defect, which supports the idea that there are genetically susceptible individuals,” Garg said in a release from Nationwide Children’s Hospital. “That raises the question: Can we identify those genetically susceptible infants and their mothers?”