The role of menopause and genes in cardiometabolic health.

Roa Díaz, Zayne Milena (2022). The role of menopause and genes in cardiometabolic health. (Unpublished). (Dissertation, University of Bern, the Faculty of Medicine and the Faculty of Human Sciences)

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Background:
Cardiovascular disease (CVD) remains the leading cause of death worldwide. Although CVD has been considered a male disease primarily, it is now more common in women. However, women develop heart disease about 7-10 years later than men. Menopause marks the age at which women's risk of heart disease increases significantly. The prevalence of cardiovascular risk factors, such as hypertension, dyslipidemia, and obesity, increases sharply around menopause and continues to rise throughout the postmenopausal period. Additionally, earlier onset of menopause has been associated with an increased risk of type 2 diabetes (T2D), CVD, all-cause mortality, and reduced life expectancy. To date, most studies have failed to assess the directionality of the association between early onset of menopause and cardiometabolic risk. Genetic studies on premature ovarian failure suggest different pathways beyond hormones to explain the increased CVD risk associated with menopause. Therefore, the possibility of shared risk factors, including genetic, lifestyle, and environmental factors, for both early menopause and elevated CVD risk warrants consideration of genelifestyle interactions that may explain variability in cardiometabolic disease incidence.

Aims:
The overall aim of this thesis was to develop knowledge about the role of menopause, and the genetic basis of cardiovascular diseases and ovarian aging on cardiometabolic diseases. The aims of the five articles that are part of this thesis were to 1) discuss current knowledge of the impact of menopause, hormone therapy, genes, lifestyle, and environment on CMD risk in aging women; 2) determine whether early menopause is associated with changes in cardiovascular risk factors (CVRF); 3) estimate the observational association between age at natural menopause and blood pressure traits; 4) systematically summarize the evidence on gene-diet interactions and cardiovascular disease risk, and 5) identify the application, clinical scope, and limitations of artificial intelligence in the care of menopausal women.

Methods:
The methods applied in the five articles part of this thesis are presented below. 1) I conducted a search and review of the literature on menopause and cardiometabolic diseases (CMD) and, together with experts in the field, I summarized the evidence into two categories: menopausal characteristics and CMD risk and mechanisms underlying CMD risk at menopause; 2) I analyzed data from 981 menopausal women (baseline and first follow-up) from the CoLaus study. To assess the association between early menopause and cardiometabolic risk factors, I used linear regression and linear mixed models; in addition, nonlinear associations were explored; 3) In the cross-sectional and one-sample Mendelian randomization analysis, I analyzed data from 4451 menopausal women from the CoLaus and Rotterdam studies (RS-I-3, RS-II-1, and RS-III-1). For the two-sample Mendelian randomization analysis, I used the association estimates of ANM-SNPs and menopausal age reported in the largest GWAS and the association estimates of those ANM-SNPs with blood pressure traits in 168,575 women from the UK Biobank; 4) I conducted a systematic review in which I ultimately synthesized 59 articles; 5) I conducted an unstructured review of the literature on artificial intelligence and health in menopausal women.

Results:
The findings of the five articles included in this thesis were: 1) the physiological mechanism underlying the association between menopause and CMD remains unclear. Evidence of causal association is lacking; longitudinal studies evaluating ANM-SNPs, hormones, environmental exposures, and including women before menopause are needed in menopausal women's health; 2) Early menopause is not associated with changes in cardiovascular risk factors, except insulin; 3) Age at natural menopause is not causally associated with hypertension, systolic or diastolic blood pressure in postmenopausal women. DNA damage repair pathways
require further investigation as possible pathways underpinning
cardiovascular risk in postmenopausal stages; 4) evidence on gene-diet interactions and cardiovascular risk is inconclusive, studies are underpowered, corrections for multiple testing and replication are lacking; 5) artificial intelligence is poorly implemented in menopause and cardiovascular disease research. Diagnosis of menopausal symptoms and osteoporosis are the first areas to apply AI.

Conclusions:
In this doctoral thesis, I contributed knowledge on the role of genetic factors, menopause and CMD. I provided an overview of current knowledge on menopause and CMD, highlighting advances in the identification of new genetic bases of menopause, the role of endogenous and exogenous hormones in CVD during the menopausal transition, and the identification of the limitations of knowledge in this field. I identified that early menopause is not associated with cardiovascular risk factors, except with insulin. In addition, for the first time in the literature, I discovered that the timing of menopause is not associated with blood pressure traits and that DNA damage response pathways may be mechanisms behind the increases risk of CMD during postmenopause. I also found that the current status of gene-diet interactions with cardiovascular disease is inconclusive and has limited clinical utility. Finally, I described how the application of machine learning and artificial intelligence in menopause is in its early stages, and fields such as cardiometabolic health are far behind in their adoption.

Item Type:	Thesis (Dissertation)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine (ISPM)
Graduate School:	Graduate School for Health Sciences (GHS)
UniBE Contributor:	Roa Diaz, Zayne Milena, Franco Duran, Oscar Horacio, Muka, Taulant
Subjects:	600 Technology > 610 Medicine & health 300 Social sciences, sociology & anthropology > 360 Social problems & social services
Language:	English
Submitter:	Doris Kopp Heim
Date Deposited:	23 Mar 2023 15:37
Last Modified:	23 Mar 2023 23:27
Additional Information:	PhD in Health Sciences (Epidemiology)
URI:	https://boris.unibe.ch/id/eprint/180566