Gender and cardiovascular disease: are sex-biased microRNA networks a driving force behind heart failure with preserved ejection fraction in women?

Cardiovascular disease (CVD) is the primary cause of death among men and women worldwide. Nevertheless, our comprehension of how CVD progresses in women and elicits clinical outcomes is lacking, leading CVD to be under-diagnosed and under-treated in women. A clear example of this differential presentation of CVD pathophysiologies in females is the strikingly higher prevalence of heart failure with preserved ejection fraction (HFpEF). Women with a history of pre-eclampsia or those who present with co-morbidities such as obesity, hypertension, and diabetes mellitus are at increased risk of developing HFpEF. Long understood to be a critical CVD risk factor, our understanding of how gender differentially affects the development of CVD has been greatly expanded by extensive genomic and transcriptomic studies. These studies uncovered a pivotal role for differential microRNA (miRNA) expression in response to systemic inflammation, where their co-ordinated expression forms a post-transcriptional regulatory network that instigates microcirculation defects. Importantly, the potential sex-biased expression of the given miRNAs may explain sex-specific cardiovascular pathophysiologies in women, such as HFpEF. Sex-biased miRNAs are regulated by oestrogen (E2) in their transcription and processing or are expressed from loci on the X-chromosome due to incomplete X-chromosome inactivation. Interestingly, while E2-induced miRNAs predominantly appear to serve protective functions, it could be argued that many X-linked miRNAs have been found to challenge microvascular and myocardial integrity. Therefore, menopausal E2 deficiency, resulting in protective miRNA loss, and the augmentation of X-linked miRNA expression, may well contribute to the molecular mechanisms that underlie the female-specific cardiovascular aetiology in HFpEF.

The relationship between reproductive and biochemical ageing at the time of the menopausal transition.

The biochemical ageing status of women in the menopausal transition was studied using quantitative analysis of age- and autophagy-related gene activities (CDC42 and MAP1LC3 genes were selected as target genes). Free estradiol and progesterone levels in saliva were estimated. General linear models were used to determine the relationship between lifestyle, health status, socioeconomic factors and CDC42 and MAP1LC3 gene expression levels. Gene expression analysis revealed (1) an increasing expression of CDC42 gene after 45years in women, (2) expression level of CDC42 gene associated with menopausal status, (3) while endocrine status was found to associate with the expression of both of the studied age-related genes, (4) the "never used hormonal contraceptives" and "obese nutritional status" were the strongest factors for increased level of age-related gene expressions, and (5) changes in gene expression levels by ageing should be studied by considering not only chronological, but also biological ages. Gene expression profile of ageing has mostly been studied in model systems or human blood samples, but rarely in human saliva samples. The concordance of results between the present and former gene expression analyses, and the simplicity of saliva sample collection emphasizes the importance of saliva tissue samples in gene expression analyses especially in epidemiological surveys.

MAPK genes interact with diet and lifestyle factors to alter risk of breast cancer: the Breast Cancer Health Disparities Study.

Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from 3 population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 ancestry informative markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and estrogen receptor (ER)/progesterone receptor (PR) strata. MAP3K9 was associated with breast cancer overall (P(ARTP) = 0.02) with strongest association among women with the highest IA ancestry (P(ARTP) = 0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate, and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.

Do BRCA1 and BRCA2 mutation carriers have earlier natural menopause than their noncarrier relatives? Results from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer.

PURPOSE: Limited data suggest that germline BRCA1 mutations are associated with occult primary ovarian insufficiency and that BRCA1 and BRCA2 mutation carriers might have earlier natural menopause (NM) than their noncarrier relatives. PATIENTS AND METHODS: Eligible women were mutation carriers and noncarriers from families segregating a BRCA1 or BRCA2 mutation. Data were self-reported using uniform questionnaires at cohort entry and every 3 years thereafter. NM was defined as the cessation of menses for 12 months without another cause. Cox proportional hazards analysis modeled time from birth to NM, adjusting for multiple potential confounders. Analysis time was censored at the earliest of the following: last follow-up, bilateral oophorectomy, hysterectomy, commencement of hormone therapy, insertion of intrauterine device, or any cancer diagnosis. Hazard ratios (HRs) were estimated as a measure of how likely mutation carriers are, relative to noncarriers, to reach NM at a given age. RESULTS: A total of 1,840 women were eligible for analysis. Overall only 19% reached NM. A lower proportion of BRCA1 and BRCA2 mutation carriers reached NM compared with noncarriers. Conversely, a higher proportion of mutation carriers were censored at cancer diagnosis or oophorectomy than noncarriers. The adjusted HR estimates for NM were 1.03 (95% CI, 0.75 to 1.40; P = .9) for 445 BRCA1 mutation carriers and 559 noncarrier relatives and 1.01 (95% CI, 0.71 to 1.42; P = .9) for 374 BRCA2 mutation carriers and 462 noncarrier relatives. CONCLUSION: We found no evidence that BRCA1 and BRCA2 mutation carriers are at higher risk of NM at a given age than their noncarrier relatives.

The timing of the age at which natural menopause occurs.

The timing of natural menopause is a clinically important indicator of longevity and risk of morbidity and mortality. Demographic, menstrual, reproductive, familial, genetic, and lifestyle factors seem to be important in this timing. Smoking, lower parity and poor socioeconomic status are associated with earlier menopause. However, a number of relationships have been inconsistent; others remain largely unexplored. Much remains to be learned about factors that affect follicular atresia and the onset and duration of perimenopause and the timing of the natural menopause. Knowledge about these relationships offers women and their health care providers enhanced understanding and choices to deal with menopause.

The menopause transition.

The menopause transition is a period of life during which a series of dynamic changes in physiology are taking place. There seems to be a transient increase in symptoms of many types, which are occasionally severe. There is a disproportionate burden of morbidity that seems to accrue to women of high body mass index and low socioeconomic status. Moreover, there are ethnic differences in hormones and symptoms that may reflect either basic biologic variation in hormone receptors and actions or the different social milieu that women in different ethnic groups experience. Current medical management of the perimenopause should include screen-ing for general health maintenance, avoidance of weight gain, and a holistic approach to symptoms.

Genetic analysis of the age at menopause by using estimating equations and Bayesian random effects models.

Multi-wave self-report data on age at menopause in 2182 female twin pairs (1355 monozygotic and 827 dizygotic pairs), were analysed to estimate the genetic, common and unique environmental contribution to variation in age at menopause. Two complementary approaches for analysing correlated time-to-onset twin data are considered: the generalized estimating equations (GEE) method in which one can estimate zygosity-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates; and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modelled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs sampling using the freeware package BUGS.