title: 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. 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.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Schulkey
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Suk D
authors.initials: SD
authors.lastname: Regmi
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Magnan
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Danzo
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Herman
authors.initials: H
authors.lastname: Luther
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Alayna K
authors.initials: AK
authors.lastname: Hutchinson
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Panzer
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Grady
authors.affiliation: 1] Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA. [2] Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
authors.affiliation: 1] Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA. [2] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110 USA.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
mesh_terms: D017668:Age of Onset; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D059305:Diet, High-Fat; D005260:Female; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006331:Heart Diseases / Q000151:congenital* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006943:Hyperglycemia; D008423:Maternal Age; D051379:Mice; D009765:Obesity; D010053:Ovary / Q000637:transplantation; D010641:Phenotype; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000235:genetics / Q000502:physiology*; D040641:Quantitative Trait Loci / Q000235:genetics; D012306:Risk; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors
references.citation: J Clin Invest. 1999 Dec;104(11):1567-73
references.pmid: 10587520
references.citation: Obstet Gynecol. 2000 Nov;96(5 Pt 1):701-6
references.pmid: 11042304
references.citation: Nat Rev Genet. 2001 Mar;2(3):165-74
references.pmid: 11256068
references.citation: J Appl Physiol (1985). 2001 May;90(5):1900-8
references.pmid: 11299284
references.citation: Pediatr Cardiol. 2003 May-Jun;24(3):195-221
references.pmid: 12632215
references.citation: Science. 2004 Apr 16;304(5669):445-8
references.pmid: 15031436
references.citation: Birth Defects Res A Clin Mol Teratol. 2004 Sep;70(9):572-9
references.pmid: 15368555
references.citation: Lancet. 1991 Mar 2;337(8740):527-30
references.pmid: 1671898
references.citation: Lancet. 1991 Jul 20;338(8760):131-7
references.pmid: 1677062
references.citation: J Paediatr Child Health. 1993 Oct;29(5):344-9
references.pmid: 8240861
references.citation: Science. 1998 Jul 3;281(5373):108-11
references.pmid: 9651244
references.citation: Development. 1999 Mar;126(6):1269-80
references.pmid: 10021345
references.citation: Paediatr Perinat Epidemiol. 2004 Nov;18(6):415-24
references.pmid: 15535817
references.citation: Circulation. 2007 Jun 12;115(23):2995-3014
references.pmid: 17519397
references.citation: Paediatr Perinat Epidemiol. 2009 Jan;23(1):29-40
references.pmid: 19228312
references.citation: BJOG. 2009 Jul;116(8):1111-9
references.pmid: 19485989
references.citation: Circulation. 2010 Mar 23;121(11):1313-21
references.pmid: 20212279
references.citation: Mamm Genome. 2010 Apr;21(3-4):115-29
references.pmid: 20127486
references.citation: Sci Transl Med. 2010 May 26;2(33):33ra37
references.pmid: 20505214
references.citation: Am J Med Genet A. 2011 Sep;155A(9):2137-45
references.pmid: 21815253
references.citation: Mol Biosyst. 2012 Apr;8(4):1187-96
references.pmid: 22282227
references.citation: FASEB J. 2012 Jun;26(6):2607-19
references.pmid: 22426117
references.citation: Circ Cardiovasc Genet. 2012 Jun;5(3):293-300
references.pmid: 22534315
references.citation: PLoS One. 2012;7(7):e42330
references.pmid: 22860113
references.citation: Eur J Appl Physiol. 2013 May;113(5):1311-20
references.pmid: 23184236
references.citation: Genet Epidemiol. 2014 Apr;38(3):198-208
references.pmid: 24585533
references.citation: PLoS One. 2014;9(3):e92031
references.pmid: 24643011