Objective: To better understand the relationship between cardiovascular disease risk and age-at-natural menopause using genetic data. Methods: Early menopause is associated with cardiovascular disease risk. We constructed a genetic risk score comprising 56 age-at-natural menopause decreasing alleles in men and women from the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and the Rotterdam Study. If the genetic predisposition to earlier age-at-natural menopause is associated with increased cardiovascular disease risk, it is reasonable to ask whether the risk is shared by men carrying the alleles, despite not experiencing menopause. We estimated the hazard ratio for the score for time to first cardiovascular event. To investigate the possible genetic pleiotropy between age-at-natural menopause and cardiovascular disease, we performed cross-trait linkage disequilibrium score regressions between age-at-natural menopause and cardiovascular disease and risk factors using genome-wide association studies. Results: Twenty-two thousand five hundred and sixty-eight cardiovascular disease-free participants at baseline were analyzed (9,808 men, 12,760 women). Each additional unit of the genetic propensity to earlier age-at-natural menopause increased the hazard of both cardiovascular disease and cardiac death in women (cardiovascular disease: hazard ratio 1.10 [1.04-1.16], P = 9.7 × 10 -4 ; cardiac death: 1.12 [1.02-1.24], P = 0.03), whereas no effect was observed for either outcome in men (hazard ratio 0.99 [0.95-1.04], P = 0.71; 1.05 [0.94-1.16], P = 0.34). We found significant negative genetic correlations in women, but not men, between age-at-natural menopause and cardiovascular disease and risk factors. Conclusion: Genetic variants associated with earlier age-at-natural menopause are associated with increased cardiovascular disease risk in women, but not men, suggesting sex-specific genetic effects on cardiovascular disease risk.
Bibliographical noteFunding Information:
Funding/support: Rotterdam Study Funding—The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Maryam Kavousi is supported by the ZonMw Veni grant (Veni, 91616079). O.H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.); Metagenics Inc.; and the AXA Research Fund. None of the funders had any role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of this article. The generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. Atherosclerosis Risk in Communities Study Funding—The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Framingham Heart Study (FHS) Funding—The FHS phenotype-genotype analyses were supported by the National Institute of Aging (R56AG29451). This research was conducted in
part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (National Institutes of Health Contract No. N01-HC-25195, HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). Genotyping, quality control and calling of the Illumina HumanExome BeadChip in the Framingham Heart Study was supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O’Donnell, Principal Investigators).
Financial disclosure/conflicts of interest: MK is supported by the ZonMw Veni grant (Veni,91616079). OHF works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.); Metagenics Inc.; and the AXA Research Fund. †Deceased July 2017. Supplemental digital content is available for this article. DirectURL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website (www.menopause.org). Address correspondence to: Chloé Sarnowski, PhD, Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, 3rd floor (CT346), Boston, MA 02118. E-mail: firstname.lastname@example.org
- Age-at-natural menopause
- Cardiovascular disease
- DNA damage response pathway
- Genetic correlation
- Genetic risk score