The Jay lab seeks to discover pathways that could be targeted to prevent congenital heart disease. To do so, we have taken an “experimental epidemiologic” approach to delineate the genetic and environmental factors that affect the risk of heart defects caused by a mutation of the cardiac transcription factor NKX2-5 in the mouse. NKX2-5 was one of the first genes associated with human congenital heart disease. Mutations cause the same defects in man and mouse.
We have mapped multiple genetic loci that affect the risk of very specific anatomic defects. They depict a genetic architecture that helps to explain commonly observed clinical patterns related to incomplete penetrance and phenotypic variability.
In addition, the risk of congenital heart disease in the mouse offspring is associated with maternal age. Epidemiologic studies consistently report the same association in humans. Conventional wisdom would suggest that the basis of the age-associated risk resides in the egg, but our results suggest that it is actually the mother. Genetic polymorphisms in the mother affect the severity of the maternal-age associated risk. Most strikingly, voluntary exercise by the mothers can mitigate the age-associated risk. This proves in principle that it is possible to prevent congenital heart disease without directly targeting the cause in the embryo.
Patrick Y. Jay, M.D., Ph.D.
Washington University School of Medicine
McDonnell Pediatrics Research Building
660 S. Euclid Avenue Box 8208
St. Louis, MO 63110
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