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Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Onland-Moret, N Charlotte  ORCID logo  https://orcid.org/0000-0002-2360-913X
Chirlaque, Maria-Dolores  ORCID logo  https://orcid.org/0000-0001-9242-3040
Peters, Sanne AE 

Abstract

BACKGROUND: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. OBJECTIVES: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. DESIGN: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. PARTICIPANTS: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. MAIN OUTCOME MEASURES: CHD, CHD risk factors, and ANM. RESULTS: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. CONCLUSION: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.

Description

Keywords

Mendelian Randomization, coronary heart disease, reproductive aging, risk factors, Aging, Coronary Disease, Female, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide

Journal Title

J Clin Endocrinol Metab

Conference Name

Journal ISSN

0021-972X
1945-7197

Volume Title

Publisher

The Endocrine Society
Sponsorship
MRC (MC_UU_00006/1)
Medical Research Council (G0800270)
European Research Council (268834)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MC_UU_12015/5)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)