Reassessing the association between age at menarche and cardiovascular disease: observational and Mendelian randomization analyses
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Aims
Observational studies have shown a U-shaped association between age at menarche (AAM) and cardiovascular disease (CVD). We assessed non-linearity of the observational association and the potential causal relationship between AAM and CVD using data from the European Prospective Investigation into Cancer and Nutrition—Cardiovascular Disease (EPIC-CVD) study and the UK Biobank.
Methods and results
We included women without pre-existing myocardial infarction (MI) or stroke at baseline. We estimated hazard ratios for incident MI, ischaemic and haemorrhagic stroke later in life using Cox regression in observational analyses and conducted non-linear Mendelian randomization (MR) based on fractional polynomials and linear MR based on inverse-variance weighted regression. We analysed 283 210 women with a median AAM of 13 (IQR 12–14) years in both EPIC-CVD and the UK Biobank, of which 8468 experienced a MI, 5501 an ischaemic and 1887 a haemorrhagic stroke. The association between AAM and MI and ischaemic stroke was U-shaped with higher risks in women aged ≤12 and ≥16 compared with those aged 13 years at menarche. Our MR analyses found no evidence for non-linearity between genetically proxied AAM and any CVD endpoint later in life, but each year higher genetically proxied AAM was related to a lower risk of MI (hazard ratio 0.92 [95% CI 0.86–0.99]), but not to ischaemic and haemorrhagic stroke.
Conclusion
This study supported non-linear observational associations between AAM and MI and ischaemic stroke. MR analyses suggested a causal relationship between higher AAM and risk of MI without an indication for non-linearity. There was no support for a potential causal link with ischaemic and haemorrhagic stroke.
Observational studies have shown a U-shaped association between age at menarche (AAM) and cardiovascular disease (CVD). We assessed non-linearity of the observational association and the potential causal relationship between AAM and CVD using data from the European Prospective Investigation into Cancer and Nutrition—Cardiovascular Disease (EPIC-CVD) study and the UK Biobank.
Methods and results
We included women without pre-existing myocardial infarction (MI) or stroke at baseline. We estimated hazard ratios for incident MI, ischaemic and haemorrhagic stroke later in life using Cox regression in observational analyses and conducted non-linear Mendelian randomization (MR) based on fractional polynomials and linear MR based on inverse-variance weighted regression. We analysed 283 210 women with a median AAM of 13 (IQR 12–14) years in both EPIC-CVD and the UK Biobank, of which 8468 experienced a MI, 5501 an ischaemic and 1887 a haemorrhagic stroke. The association between AAM and MI and ischaemic stroke was U-shaped with higher risks in women aged ≤12 and ≥16 compared with those aged 13 years at menarche. Our MR analyses found no evidence for non-linearity between genetically proxied AAM and any CVD endpoint later in life, but each year higher genetically proxied AAM was related to a lower risk of MI (hazard ratio 0.92 [95% CI 0.86–0.99]), but not to ischaemic and haemorrhagic stroke.
Conclusion
This study supported non-linear observational associations between AAM and MI and ischaemic stroke. MR analyses suggested a causal relationship between higher AAM and risk of MI without an indication for non-linearity. There was no support for a potential causal link with ischaemic and haemorrhagic stroke.
Date Issued
2025-08-01
Date Acceptance
2025-01-30
Citation
European Journal of Preventive Cardiology, 2025, 32 (10), pp.857-866
ISSN
2047-4873
Publisher
Oxford University Press (OUP)
Start Page
857
End Page
866
Journal / Book Title
European Journal of Preventive Cardiology
Volume
32
Issue
10
Copyright Statement
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40099743
PII: 8084708
Subjects
Age at menarche
Cardiovascular risk
Individual participant data meta-analysis
Mendelian randomization
Non-linearity
Publication Status
Published
Coverage Spatial
England
Article Number
zwaf051
Date Publish Online
2025-03-18