Affiliation:
1. National Heart and Lung Institute Imperial College London London United Kingdom
2. Nuffield Department of Population Health University of Oxford Oxford United Kingdom
3. Medical Research Council Biostatistics Unit University of Cambridge Cambridge United Kingdom
4. Department of Applied Economics, Erasmus School of Economics Erasmus University Rotterdam Rotterdam The Netherlands
5. Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus University Rotterdam Rotterdam The Netherlands
6. Department of Medicine University of Cambridge Cambridge United Kingdom
7. Department of Chronic Disease Epidemiology Yale School of Public Health New Haven CT
8. Department of Circulation and Medical Imaging Norwegian University of Science and Technology Trondheim Norway
9. Centre for Fertility and Health Norwegian Institute of Public Health Oslo Norway
10. Department of Obstetrics and Gynaecology Chelsea and Westminster Hospital NHS Foundation Trust London United Kingdom
11. Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom
Abstract
Background
Observational studies suggest that reproductive factors are associated with cardiovascular disease, but these are liable to influence by residual confounding. This study explores the causal relevance of reproductive factors on cardiovascular disease in women using Mendelian randomization.
Methods and Results
Uncorrelated (
r
2
<0.001), genome‐wide significant (
P
<5×10
−8
) single‐nucleotide polymorphisms were extracted from sex‐specific genome‐wide association studies of age at first birth, number of live births, age at menarche, and age at menopause. Inverse‐variance weighted Mendelian randomization was used for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischemic stroke, and stroke. Earlier genetically predicted age at first birth increased risk of coronary artery disease (odds ratio [OR] per year, 1.49 [95% CI, 1.28–1.74],
P
=3.72×10
−7
) heart failure (OR, 1.27 [95% CI, 1.06–1.53],
P
=0.009), and stroke (OR, 1.25 [95% CI, 1.00–1.56],
P
=0.048), with partial mediation through body mass index, type 2 diabetes, blood pressure, and cholesterol traits. Higher genetically predicted number of live births increased risk of atrial fibrillation (OR for <2, versus 2, versus >2 live births, 2.91 [95% CI, 1.16–7.29],
P
=0.023), heart failure (OR, 1.90 [95% CI, 1.28–2.82],
P
=0.001), ischemic stroke (OR, 1.86 [95% CI, 1.03–3.37],
P
=0.039), and stroke (OR, 2.07 [95% CI, 1.22–3.52],
P
=0.007). Earlier genetically predicted age at menarche increased risk of coronary artery disease (OR per year, 1.10 [95% CI, 1.06–1.14],
P
=1.68×10
−6
) and heart failure (OR, 1.12 [95% CI, 1.07–1.17],
P
=5.06×10
−7
); both associations were at least partly mediated by body mass index.
Conclusions
These results support a causal role of a number of reproductive factors on cardiovascular disease in women and identify multiple modifiable mediators amenable to clinical intervention.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine