Genetically determined reproductive aging and coronary heart disease: a bidirectional two-sample Mendelian Randomization.
The Journal of clinical endocrinology and metabolism 2021
Dam V, Onland-Moret NC, Burgess S, Chirlaque MD, Peters SAE, Schuit E, Tikk K, Weiderpass E, Oliver-Williams C, Wood AM, Tjønneland A, Dahm CC, Overvad K, Boutron-Ruault MC, Schulze MB, Trichopoulou A, Ferrari P, Masala G, Krogh V, Tumino R, Matullo G, Panico S, Boer JMA, Verschuren WMM, Waaseth M, Sánchez Pérez MJ, Amiano P, Imaz L, Moreno-Iribas C, Melander O, Harlid S, Nordendahl M, Wennberg P, Key TJ, Riboli E, Santiuste C, Kaaks R, Katzke V, Langenberg C, Wareham NJ, Schunkert H, Erdmann J, Willenborg C, Hengstenberg C, Kleber ME, Delgado G, März W, Kanoni S, Dedoussis G, Deloukas P, Nikpay M, McPherson R, Scholz M, Teren A, Butterworth AS, and van der Schouw YT
DOI : 10.1210/clinem/dgac171
PubMed ID : 35306566
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.
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.
Two-sample MR, using both cohort data as well as summary statistics, with four methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression.
Data from EPIC-CVD and summary statistics from UK Biobank and publicly available GWAS were pooled for the different analyses.
CHD, CHD risk factors and ANM.
Across different methods of MR no association was found between genetically determined reproductive aging and CHD risk in women (Relative Risk Estimate (RRE)IVW=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.
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.