Environmental and Genetic Interactions in Congenital Heart Disease

Doctor's Name: 
Degenhardt, Karl, MD
Children’s Hospital of Philadelphia, Philadelphia, PA

Despite significant advances in the epidemiology of congenital heart disease and the genetics of congenital heart disease, it is still difficult to pinpoint a specific cause in a given child born with a heart defect. Ever increasing evidence points to complex interactions between groups of genes, or between genes and environmental exposures. Our understanding of such interactions is limited in part due to how rarely animal models reproduce the type of susceptibility to congenital heart disease seen in people. We have identified a mouse mutant that develops a specific congenital heart disease, total anomalous pulmonary venous return (TAPVR). Like human families with disease genes, the mice only get TAPVR some of the time when they have the mutation. These mice represent a unique opportunity to test genetic influences and environmental exposures that make a congenital heart defect more or less likely. The gene that makes these mice susceptible is called Sema3d, and this same gene has been implicated in human congenital heart disease. Sema3d is in a class of cell-to-cell signaling molecules called “semaphorins.” One effect of semaphorin signaling is to inhibit blood vessel growth. Another class of signaling molecules, VEGF’s have the opposite effect: they stimulate blood vessel growth. Therefore, VEGF genes, and related genes may interact with Sema3d to effect whether congenital heart disease occurs (ie. they may interact genetically). Blood vessel growth is stimulated by low oxygen conditions (which often activates VEGF genes).  So, low oxygen represents a type of environmental exposure that could influence whether TAPVR occurs in our animal model. This is relevant people when oxygen delivery to a developing fetus in the womb may be compromised, such as in anemia, high altitude environments, or when an expecting mother smokes.

     There are two aims to the proposed research. The first aim is to test the effect of low oxygen on the frequency of congenital heart disease. We will do this by placing pregnant mice in a low oxygen environment. We predict this will lead to more frequent heart defects in the mouse pups. The second aim is to test potential genetic interactions. We will do this by disrupting genes in the VEGF pathway using gene targeting. We predict that by targeting antagonistic signals, we will restore the balance of blood vessel growth signals in Sema3d mutant mice. This, in turn, will reduce the frequency of congenital heart disease in these mice.

     These experiments are important first steps in unraveling the complex interactions that result in congenital heart disease. We hope to better understand how one might be more or less sensitive to specific maternal conditions based on individual genetics. In addition, we hope to understand how in normal conditions, different genes may act together to make heart defects occur.

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