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

Abstract

Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn 1, 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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Figure 1: Reciprocal ovarian transplants between young and old mothers localize the basis of the maternal-age-associated risk to the mother.
Figure 2: A high-fat diet does not accelerate the onset of the maternal age effect.
Figure 3: The maternal-age-associated risk of VSD is a quantitative genetic trait.
Figure 4: Exercise can mitigate the risk associated with maternal ageing.

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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.

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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.

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Correspondence to Patrick Y. Jay.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Breeding scheme and experimental conditions.

Nkx2-5+/− offspring from several maternal genetic backgrounds and experimental conditions were phenotyped. Nkx2-5+/− C57BL/6N males were crossed to FVB/N or A/J females to produce F1 hybrids. The cross to a C57BL/6N female maintains the inbred strain. Nkx2-5+/− F1 hybrids were intercrossed to produce the F2 progeny. The hearts of newborn Nkx2-5+/− F2 pups were phenotyped to calculate the incidence of a defect and the effect of maternal age. C57BL/6N × FVB/N F1 hybrid mothers were bred in either sedentary/chow, high-fat diet, early or late onset exercise conditions. C57BL/6N × A/J F1 hybrid and C57BL/6N inbred mothers were studied only in the sedentary/chow condition. The number of mothers in each cross and experimental condition that were used to produce pups in this study are shown.

Extended Data Figure 2 Incidences of ASD in the reciprocal ovarian transplant experiment.

The relative incidences of ASD in the reciprocal ovarian transplant experiment are consistent with a maternal basis of the age-associated effect. The differences that were significant in the VSD data, however, are not significant here because of the lower incidence of ASD, as depicted by the y-axis drawn on a scale comparable to that for VSD. The total number of pups in each group is shown.

Extended Data Figure 3 Growth charts for C57BL/6N × FVB/N F1 mothers under sedentary, early onset exercise and high-fat diet conditions.

C57BL/6N × FVB/N F1 mothers on a high-fat diet develop marked obesity as they age. They weigh substantially more than mothers in the sedentary or early onset exercise groups. Mothers in the latter two groups weigh the same.

Extended Data Figure 4 Incidences of ASD in the offspring of C57BL/6N × FVB/N mothers.

Maternal age may affect the risk of ASD, but the lower incidence of ASD and other defects that are less common than VSD preclude firm statistical conclusions. For example, the incidences of ASD are shown for the Nkx2-5+/− offspring of young and old C57BL/6N × FVB/N mothers in the sedentary, early onset exercise, and high-fat diet conditions. The y-axis is drawn on a scale comparable to that for VSD incidence. ASD incidences are higher, but not significantly, among the offspring of old mothers compared to young mothers. The incidences are not significantly different between experimental conditions. The total number of pups in each group is shown.

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Schulkey, C., Regmi, S., Magnan, R. et al. The maternal-age-associated risk of congenital heart disease is modifiable. Nature 520, 230–233 (2015). https://doi.org/10.1038/nature14361

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