Genetically Determined Lifestyle and Cardiometabolic Risk Factors Mediate the Association of Genetically Predicted Age at Menarche With Genetic Predisposition to Myocardial Infarction: A Two-Step, Two-Sample Mendelian Randomization Study

Frontiers in Cardiovascular Medicine

article

Jilin Zheng¹  Ken Chen¹  Tao Huang³  Chunli Shao⁴  Ping Li¹  Jingjia Wang⁴  Wenyao Wang⁴  Kuo Zhang¹  Xiangbin Meng⁴  Jun Gao⁴  Xuliang Wang¹  Yupeng Liu¹  Jingjing Song¹  Eran Dong⁵  Yi-Da Tang¹ 

[1] State Key Laboratory of Cardiovascular Disease, Department of Cardiology, National Center for Cardiovascular Diseases, Fuwai Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences;Graduate School of Peking Union Medical College, Peking Union Medical College, Chinese Academy of Medical Sciences;Key Laboratory of Molecular Cardiovascular Sciences, Department of Epidemiology and Biostatistics, Center for Intelligent Public Health, Academy for Artificial Intelligence, School of Public Health, Ministry of Education, Peking University;Key Laboratory of Molecular Cardiovascular Sciences, Department of Cardiology, Institute of Vascular Medicine, Ministry of Education, Peking University Third Hospital;NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital;Key Laboratory of Molecular Cardiovascular Sciences, Institute of Cardiovascular Sciences, Ministry of Education, Peking University

关键词: age at menarche;    cardiometabolic risk factors;    myocardial infarction;    Mendelian randomization;    lifestyle;    mediation analysis;   

DOI  :  10.3389/fcvm.2022.821068

学科分类：地球科学(综合)

来源: Frontiers

【 摘 要 】

Background Observational studies have shown an association between early age at menarche (AAM) and myocardial infarction (MI) with recorded cases. In this Mendelian randomization (MR) study, we used large amounts of summary data from genome-wide association studies (GWASs) to further estimate the association of genetically predicted AAM with genetically predicated risk of MI and investigate to what extent this association is mediated by genetically determined lifestyles, cardiometabolic factors, and estrogen exposure. Methods A two-step, two-sample MR study was performed by mediation analysis. Genetic variants identified by GWAS meta-analysis of reproductive genetics consortium ( n = 182,416) were selected for genetically predicted AAM. Genetic variants identified by the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus The Coronary Artery Disease Genetics Consortium ( n = 184,305) were selected for genetically predicted risk of MI. Genetic variants from other international GWAS summary data were selected for genetically determined mediators. Results This MR study showed that increase in genetically predicted AAM was associated with lower risk of genetically predicted MI (odds ratio 0.91, 95% confidence interval 0.84–0.98). Inverse variance weighted (IVW) MR analysis also showed that decrease in genetically predicted AAM was associated with higher genetically predicted alcohol intake frequency, current smoking behavior, higher waist-to-hip ratio, and higher levels of systolic blood pressure (SBP), fasting blood glucose, hemoglobin A1c (HbA1c), and triglycerides (TGs). Furthermore, increase in genetically predicted AAM was associated with genetically predicted longer sleep duration, higher levels of high-density lipoproteins, and older age at which hormone replacement therapy was started. The most essential mediators identified were genetically predicted current smoking behavior and levels of HbA1c, SBP, and TGs, which were estimated to genetically mediate 13.9, 12.2, 10.5, and 9.2%, respectively, with a combined mediation proportion of 37.5% in the association of genetically predicted AAM with genetically predicted increased risk of MI in an MR framework. Conclusion Our MR analysis showed that increase in genetically predicted AAM was associated with lower genetically predicted risk of MI, which was substantially mediated by genetically determined current smoking behavior and levels of HbA1c, SBP, and TGs. Intervening on the above mediators may reduce the risk of MI.

【 授权许可】

CC BY