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Editor's Note
October 2016

Reproductive Aging and Cardiovascular Disease Risk

JAMA Cardiol. 2016;1(7):778. doi:10.1001/jamacardio.2016.2638

Men and women have key biological differences that alter cardiovascular disease risk and status. Premature menopause has been linked to earlier cardiovascular events, including coronary artery disease and stroke. In this issue of JAMA Cardiology, Muka et al1 provide a meta-analysis that emphasizes the connection between reproductive aging and cardiovascular aging. This is a timely report, as the National Institutes of Health has recently enacted directives on the importance of considering sex as a variable in preclinical and clinical studies. Premature menopause is linked to reproductive factors, such as age at menarche and parity, as well as body mass index and environmental risks, including cigarette smoking. It is often assumed that the association between earlier menopause and the increase in cardiovascular events relates primarily to the reduction in protective hormones, but genetic studies of premature ovarian failure suggest distinct pathways beyond hormones.

Age at onset of menopause is heritable and under genetic influence. Genome-wide association studies have identified genetic polymorphisms linked to early menopause, and strikingly, these loci encode genes in DNA repair and immune mediator pathways. The association of genetic regions with premature menopause has been replicated in additional cohorts and additional investigations, suggesting that DNA repair, in particular, is critically important for reproductive lifespan in women. The mismatch repair genes MSH6 and MCM8, genes implicated in the repair of double-stranded breaks, have both been associated with premature ovarian failure.2,3 The broad expression pattern of these genes suggests that more direct molecular mechanisms may be responsible for the tie to cardiovascular disease, as defective DNA repair can alter immune and vascular health.

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Article Information

Conflict of Interest Disclosures: The author completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

References
1.
Muka  T, Oliver-Williams  C, Kunutsor  S,  et al.  Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis  [published online September 14, 2016].  JAMA Cardiol. doi:10.1001/jamacardio.2016.2415.
2.
Stolk  L, Perry  JR, Chasman  DI,  et al; LifeLines Cohort Study.  Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.  Nat Genet. 2012;44(3):260-268.PubMedArticle
3.
Perry  JR, Hsu  YH, Chasman  DI,  et al; kConFab investigators; ReproGen Consortium.  DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.  Hum Mol Genet. 2014;23(9):2490-2497.PubMedArticle
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