Letter | Published:

The maternal-age-associated risk of congenital heart disease is modifiable

Nature volume 520, pages 230233 (09 April 2015) | Download Citation

Abstract

Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn1,2,3,4,5,6,7. Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref. 8). Here, reciprocal ovarian transplants between young and old mothers establish a maternal basis for the age-associated risk in mice. A high-fat diet does not accelerate the effect of maternal ageing, so hyperglycaemia and obesity do not simply explain the mechanism. The age-associated risk varies with the mother's strain background, making it a quantitative genetic trait. Most remarkably, voluntary exercise, whether begun by mothers at a young age or later in life, can mitigate the risk when they are older. Thus, even when the offspring carry a causal mutation, an intervention aimed at the mother can meaningfully reduce their risk of congenital heart disease.

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Acknowledgements

C.E.S. was supported by a Ruth L. Kirschstein National Research Service Award from the Developmental Cardiology and Pulmonary Training Program (National Institutes of Health (NIH) T32 HL007873). P.Y.J. is an Established Investigator of the American Heart Association and the Lawrence J. & Florence A. DeGeorge Charitable Trust. This work was supported by the Children's Discovery Institute of Washington University and St Louis Children's Hospital, the Children's Heart Foundation, and the NIH (R01 HL105857). The Washington University Digestive Diseases Research Core Center provided histology services and is supported by the NIH (P30 DK52574). MRI studies were performed in the Washington University Diabetes Research Center, which is supported by the NIH (P30 DK020579). We thank J. Magee, J. Rubin, D. Rudnick and A. Schwartz for comments.

Author information

Affiliations

  1. Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.

    • Claire E. Schulkey
    • , Suk D. Regmi
    • , Rachel A. Magnan
    • , Megan T. Danzo
    • , Herman Luther
    • , Alayna K. Hutchinson
    • , Adam A. Panzer
    • , Mary M. Grady
    • , David B. Wilson
    •  & Patrick Y. Jay
  2. Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110 USA.

    • David B. Wilson
  3. Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110 USA.

    • Patrick Y. Jay

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Contributions

C.E.S., D.B.W. and P.Y.J. designed experiments. C.E.S., S.D.R., R.A.M., M.T.D., H.L., A.K.H., A.A.P., M.M.G. and P.Y.J. executed experiments. C.E.S. and P.Y.J. interpreted experiments. C.E.S. and P.Y.J. wrote the manuscript. D.B.W. critically reviewed the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Patrick Y. Jay.

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DOI

https://doi.org/10.1038/nature14361

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