TY - JOUR

T1 - Genetically determined reproductive aging and coronary heart disease

T2 - a bidirectional two-sample Mendelian Randomization

AU - Dam, Veerle

AU - Onland-Moret, N Charlotte

AU - Burgess, Stephen

AU - Chirlaque, Maria-Dolores

AU - Peters, Sanne A E

AU - Schuit, Ewoud

AU - Tikk, Kaja

AU - Weiderpass, Elisabete

AU - Oliver-Williams, Clare

AU - Wood, Angela M

AU - Tjønneland, Anne

AU - Dahm, Christina C

AU - Overvad, Kim

AU - Boutron-Ruault, Marie-Christine

AU - Schulze, Matthias B

AU - Trichopoulou, Antonia

AU - Ferrari, Pietro

AU - Masala, Giovanna

AU - Krogh, Vittorio

AU - Tumino, Rosario

AU - Matullo, Giuseppe

AU - Panico, Salvatore

AU - Boer, Jolanda M A

AU - Verschuren, W M Monique

AU - Waaseth, Marit

AU - Sánchez Pérez, Maria José

AU - Amiano, Pilar

AU - Imaz, Liher

AU - Moreno-Iribas, Conchi

AU - Melander, Olle

AU - Harlid, Sophia

AU - Nordendahl, Maria

AU - Wennberg, Patrik

AU - Key, Timothy J

AU - Riboli, Elio

AU - Santiuste, Carmen

AU - Kaaks, Rudolf

AU - Katzke, Verena

AU - Langenberg, Claudia

AU - Wareham, Nicholas J

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - Willenborg, Christina

AU - Hengstenberg, Christian

AU - Kleber, Marcus E

AU - Delgado, Graciela

AU - März, Winfried

AU - Kanoni, Stavroula

AU - Dedoussis, George

AU - Deloukas, Panos

AU - Nikpay, Majid

AU - McPherson, Ruth

AU - Scholz, Markus

AU - Teren, Andrej

AU - Butterworth, Adam S

AU - van der Schouw, Yvonne T

N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

PY - 2022

Y1 - 2022

N2 - 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 four 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 GWAS 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 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.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.

AB - 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 four 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 GWAS 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 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.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.

U2 - 10.1210/clinem/dgac171

DO - 10.1210/clinem/dgac171

M3 - Journal article

C2 - 35306566

VL - 107

SP - e2952–e2961

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 7

ER -