Genetic evidence for causal relationships between age at natural menopause and the risk of ageing-associated adverse health outcomes.

BACKGROUND: A later age at natural menopause (ANM) has been linked to several ageing-associated traits including an increased risk of breast and endometrial cancer and a decreased risk of lung cancer, osteoporosis and Alzheimer disease. However, ANM is also related to several proxies for overall health that may confound these associations. METHODS: We investigated the causal association of ANM with these clinical outcomes using Mendelian randomization (MR). Participants and outcomes analysed were restricted to post-menopausal females. We conducted a one-sample MR analysis in both the Women's Health Initiative and UK Biobank. We further analysed and integrated several additional data sets of post-menopausal women using a two-sample MR design. We used ≤55 genetic variants previously discovered to be associated with ANM as our instrumental variable. RESULTS: A 5-year increase in ANM was causally associated with a decreased risk of osteoporosis [odds ratio (OR) = 0.80, 95% CI (0.70-0.92)] and fractures (OR = 0.76, 95% CI, 0.62-0.94) as well as an increased risk of lung cancer (OR = 1.35, 95% CI, 1.06-1.71). Other associations including atherosclerosis-related outcomes were null. CONCLUSIONS: Our study confirms that the decline in bone density with menopause causally translates into fractures and osteoporosis. Additionally, this is the first causal epidemiological analysis to our knowledge to find an increased risk of lung cancer with increasing ANM. This finding is consistent with molecular and epidemiological studies suggesting oestrogen-dependent growth of lung tumours.

Broad clinical manifestations of polygenic risk for coronary artery disease in the Women's Health Initiative.

Background: The genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized. Methods: We measured polygenic risk for CAD using the meta genomic risk score, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women's Health Initiative and applied a phenome-wide association study framework to assess associations between the PRS and a broad range of blood biomarkers, clinical measurements, and health outcomes. Results: Polygenic risk for CAD is associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors. Analysis of adjudicated outcomes shows a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. We find associations between increased polygenic risk for CAD and decreased risk for incident breast and lung cancer, with replication of the breast cancer finding in an external cohort. Genetic correlation and two-sample Mendelian randomization suggest that breast cancer association is likely due to horizontal pleiotropy, while the association with lung cancer may be causal. Conclusion: Polygenic risk for CAD has broad clinical manifestations, reflected in biomarkers, clinical measurements, behaviors, and diagnoses. Some of these associations may represent direct pathways between genetic risk and CAD while others may reflect pleiotropic effects independent of CAD risk.

Alcohol use and cardiometabolic risk in the UK Biobank: A Mendelian randomization study.

Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.

Decreasing human body temperature in the United States since the industrial revolution.

In the US, the normal, oral temperature of adults is, on average, lower than the canonical 37°C established in the 19th century. We postulated that body temperature has decreased over time. Using measurements from three cohorts--the Union Army Veterans of the Civil War (N = 23,710; measurement years 1860-1940), the National Health and Nutrition Examination Survey I (N = 15,301; 1971-1975), and the Stanford Translational Research Integrated Database Environment (N = 150,280; 2007-2017)--we determined that mean body temperature in men and women, after adjusting for age, height, weight and, in some models date and time of day, has decreased monotonically by 0.03°C per birth decade. A similar decline within the Union Army cohort as between cohorts, makes measurement error an unlikely explanation. This substantive and continuing shift in body temperature-a marker for metabolic rate-provides a framework for understanding changes in human health and longevity over 157 years.

Comparison of two methods - regression predictive model and intake shift model - for adjusting self-reported dietary recall of total energy intake of populations.

Daily dietary intake data derived from self-reported dietary recall surveys are widely considered inaccurate. In this study, methods were developed for adjusting these dietary recalls to more plausible values. In a simulation model of two National Health and Nutrition Examination Surveys (NHANES), NHANES I and NHANES 2007-2008, a predicted one-third of raw data fell outside a range of physiologically plausible bounds for dietary intake (designated a 33% failure rate baseline). To explore the nature and magnitude of this bias, primary data obtained from an observational study were used to derive models that predicted more plausible dietary intake. Two models were then applied for correcting dietary recall bias in the NHANES datasets: (a) a linear regression to model percent under-reporting as a function of subject characteristics and (b) a shift of dietary intake reports to align with experimental data on energy expenditure. After adjustment, the failure rates improved to <2% with the regression model and 4-9% with the intake shift model - both substantial improvements over the raw data. Both methods gave more reliable estimates of plausible dietary intake based on dietary recall and have the potential for more far-reaching application in correction of self-reported exposures.

Urinary triclosan is associated with elevated body mass index in NHANES.

BACKGROUND: Triclosan-a ubiquitous chemical in toothpastes, soaps, and household cleaning supplies-has the potential to alter both gut microbiota and endocrine function and thereby affect body weight. METHODS: We investigated the relationship between triclosan and body mass index (BMI) using National Health and Nutrition Examination Surveys (NHANES) from 2003-2008. BMI and spot urinary triclosan levels were obtained from adults. Using two different exposure measures-either presence vs. absence or quartiles of triclosan-we assessed the association between triclosan and BMI. We also screened all NHANES serum and urine biomarkers to identify correlated factors that might confound observed associations. RESULTS: Compared with undetectable triclosan, a detectable level was associated with a 0.9-point increase in BMI (p<0.001). In analysis by quartile, compared to the lowest quartile, the 2nd, 3rd and 4th quartiles of urinary triclosan were associated with BMI increases of 1.5 (p<0.001), 1.0 (p = 0.002), and 0.3 (p = 0.33) respectively. The one strong correlate of triclosan identified in NHANES was its metabolite, 2,4-dichlorophenol (ρ = 0.4); its association with BMI, however, was weaker than that of triclosan. No other likely confounder was identified. CONCLUSIONS: Triclosan exposure is associated with increased BMI. Stronger effect at moderate than high levels suggests a complex mechanism of action.