Postmenopausal hormone therapy and cardiovascular risk

Introduction and aims: Postmenopausal hormone therapy (HT) is the most effective treatment for menopausal symptoms, but its safety has been debated during the past 15 years. Previous observational studies showed benefits from HT, whereas subsequent large randomized clinical trials showed an increased risk for cardiovascular disease (CVD) and other chronic diseases; the pivotal difference between these studies was the average age at HT initiation. Subsequent re-analyses of these observational studies and the randomized clinical trials, which considered age at HT initiation and years since menopause onset, showed less dissimilar results. This phenomenon gave support to the timing hypothesis, stating that HT, if initiated early in relation to menopause onset, may exert vascular protection, whereas there may be negative consequences if initiated late. This stresses the need for further studies. There is also limited knowledge about whether oestrogen type, route of administration, and duration of HT are important for the association between HT and cardiovascular risk, while considering the timing of HT initiation. In the present thesis, the aim was to assess how HT associates with the risk of CVD in menopausal women, with a specific focus on the role of timing of HT initiation, and with consideration of oestrogen types and combinations, routes of administration, and duration of use. Material and methods: The present thesis was based on observational data from a case- control study and pooled individual participant data from five population based cohorts. HT was categorized as early or late initiation in relation to the onset of menopause. Different groups of HT regimens and durations were considered. Coronary heart disease, stroke (composite end point), and haemorrhagic stroke end points were assessed from population registers. To assess the association between HT and CVD we performed logistic regression for the case-control study and Laplace regression for the pooled cohort data. The reference category was never use. Single and multivariable confounding control was performed for an array of factors. Results: After multivariable-adjustment, early HT initiation was not associated with an increased risk of coronary heart disease, nor for stroke. These results held regardless of oestrogen regimen or combination (oestrogen-progestin), route of administration, and the duration. However, a specific analysis of haemorrhagic stroke revealed an increased risk if single conjugated equine oestrogens were used. Late HT initiation was associated with increased risk for coronary heart disease when the therapy was composed of equine oestrogens combined with a progestin. Risk of stroke and haemorrhagic stroke, on the other hand, were increased when single equine oestrogens were initiated late. Late initiation of combined HT was associated with an increased haemorrhagic stroke risk. Interpretation: HT did generally not increase the risk of CVD when initiated close to the onset of menopause. The results contribute to the scientific basis that may guide clinicians who handle patients seeking treatment for climacteric symptom control. The results should however not change current practice that recommends against the use of HT for prevention of CVD

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity

The Genetic Basis of Hypertriglyceridemia

PURPOSE OF REVIEW: Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia. RECENT FINDINGS: More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. SUMMARY: The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities

Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity

Physical inactivity and increased sedentary time are associated with excess weight gain in observational studies. However, some longitudinal studies indicate reverse causality where weight gain leads to physical inactivity and increased sedentary time. As observational studies suffer from reverse causality, it is challenging to assess the true causal directions. Here, we assess the bidirec- tional causality between physical inactivity, sedentary time, and adiposity by bidirectional Mendelian randomization analysis. We used results from genome-wide association studies for accelerometer- based physical activity and sedentary time in 91,105 individuals and for body mass index (BMI) in 806,834 individuals. We implemented Mendelian randomization using CAUSE method that accounts for pleiotropy and sample overlap using full genome-wide data. We also applied inverse variance- weighted, MR-Egger, weighted median, and weighted mode methods using genome-wide signif- icant variants only. We found evidence of bidirectional causality between sedentary time and BMI: longer sedentary time was causal for higher BMI [beta (95% CI) from CAUSE method: 0.11 (0.02, 0.2), p = 0.02], and higher BMI was causal for longer sedentary time (0.13 (0.08, 0.17), p = 6.3 x 10-4). Our analyses suggest that higher moderate and vigorous physical activity are causal for lower BMI (moderate: –0.18 (-0.3,–0.05), p = 0.006; vigorous: –0.16 (-0.24,–0.08), p = 3.8 × 10-4), but indicate that the association between higher BMI and lower levels of physical activity is due to hori- zontal pleiotropy. The bidirectional, causal relationship between sedentary time and BMI suggests that decreasing sedentary time is beneficial for weight management, but also that targeting adiposity may lead to additional health benefits by reducing sedentary time.

Baseline characteristics of the postmenopausal women included in the present study of the Combined cohorts of menopausal women—Studies of register-based health outcomes in relation to hormonal drugs (COMPREHEND) material.

<p>Baseline characteristics of the postmenopausal women included in the present study of the Combined cohorts of menopausal women—Studies of register-based health outcomes in relation to hormonal drugs (COMPREHEND) material.</p