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. 2022 Jun 16;107(7):e2952-e2961.
doi: 10.1210/clinem/dgac171.

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

Veerle Dam  1   2 , N Charlotte Onland-Moret  1 , Stephen Burgess  3   4   5 , Maria-Dolores Chirlaque  6   7 , Sanne A E Peters  1   8 , Ewoud Schuit  1 , Kaja Tikk  9   10 , Elisabete Weiderpass  11 , Clare Oliver-Williams  4   5 , Angela M Wood  4 , Anne Tjønneland  12   13 , Christina C Dahm  14 , Kim Overvad  14   15 , Marie-Christine Boutron-Ruault  16 , Matthias B Schulze  17 , Antonia Trichopoulou  18   19 , Pietro Ferrari  11 , Giovanna Masala  20 , Vittorio Krogh  21 , Rosario Tumino  22 , Giuseppe Matullo  23   24 , Salvatore Panico  25 , Jolanda M A Boer  26 , W M Monique Verschuren  1   26 , Marit Waaseth  27 , Maria José Sánchez Pérez  28   29 , Pilar Amiano  29   30 , Liher Imaz  29   30 , Conchi Moreno-Iribas  31 , Olle Melander  32 , Sophia Harlid  33 , Maria Nordendahl  7 , Patrik Wennberg  7 , Timothy J Key  34 , Elio Riboli  35 , Carmen Santiuste  29   36 , Rudolf Kaaks  37 , Verena Katzke  37 , Claudia Langenberg  38 , Nicholas J Wareham  38 , Heribert Schunkert  39   40 , Jeanette Erdmann  41 , Christina Willenborg  41 , Christian Hengstenberg  42 , Marcus E Kleber  43 , Graciela Delgado  43 , Winfried März  43   44   45 , Stavroula Kanoni  46 , George Dedoussis  47 , Panos Deloukas  46   48   49 , Majid Nikpay  50 , Ruth McPherson  50 , Markus Scholz  51   52 , Andrej Teren  52   53 , Adam S Butterworth  4 , Yvonne T van der Schouw  1
Affiliations

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

Veerle Dam et al. J Clin Endocrinol Metab. .

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.

Keywords: Mendelian Randomization; coronary heart disease; reproductive aging; risk factors.

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Figures

Figure 1.
Figure 1.
Visual of the data sources used for each Mendelian randomization.
Figure 2.
Figure 2.
Results for the MR of ANM variants and coronary heart disease in women of the 4 different Mendelian randomization methods used.
Figure 3.
Figure 3.
Results for the MR of ANM variants and coronary heart disease in men of the 4 different Mendelian randomization methods used.
Figure 4.
Figure 4.
Results for the MR of ANM variants and coronary heart disease risk factors in women for the inversed variance-weighted (IVW) method.
Figure 5.
Figure 5.
Results for the MR of ANM variants and coronary heart disease risk factors in men for the inversed variance-weighted (IVW) method.
Figure 6.
Figure 6.
Results for the MR of CHD and CHD risk factors and ANM for the inversed variance-weighted (IVW) method. We used the sex-combined GWAS summary statistics for the exposure because sex-specific summary statistics were not available. The outcome ANM is only available in women, so the outcome variants are in women only.
See this image and copyright information in PMC

References

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