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Background Chronic kidney disease (CKD) has an apparent sex disparity, with a more rapid progress in men than in women. Whether the well-established sex-specific evolutionary biology trade-off between reproduction and longevity might inform CKD has not previously been considered. Relevant evidence from randomized controlled trials (RCTs) is not available. Methods We used a bi-directional Mendelian randomization study to obtain unconfounded estimates using the UK Biobank. Single nucleotide polymorphisms (SNPs) that strongly ( p value < 5 × 10 −8 ) predicted testosterone in a sex-specific manner were applied to 179,916 white British men (6016 CKD cases) and 212,079 white British women (5958 CKD cases) to obtain sex-specific associations with CKD, albuminuria, and estimated glomerular filtration rate (eGFR). We also used multivariable MR to control for sex hormone binding globulin (SHBG). For validation, we similarly examined their role in hemoglobin and high-density lipoprotein cholesterol (HDL-c). We also assessed the role of kidney function in serum testosterone, by applying eGFR-related SNPs to testosterone in the UK Biobank. Results Genetically predicted testosterone was associated with CKD in men (odds ratio (OR) for bioavailable testosterone 1.17 per standard deviation, 95% confidence interval (CI) 1.03 to 1.33) based on 125 SNPs but not in women (OR 1.02, 95% CI 0.92 to 1.14 for total testosterone) based on 254 SNPs. Multivariable MR allowing for SHBG showed consistent patterns. Genetically predicted bioavailable testosterone in men and women and genetically predicted total testosterone in women increased hemoglobin and lowered HDL-c, as seen in RCTs. Genetically predicted eGFR was not related to serum testosterone in men or in women. Conclusions Genetically predicted testosterone was associated with CKD and worse kidney function in men, whilst not affected by kidney function. Identifying drivers of testosterone and the underlying pathways could provide new insights into CKD prevention and treatment.

Background Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. Methods A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using “(“testosterone” or “androgen”) and trial and (“random*”)” with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. Results Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding ( P -value for interaction 0.03), but not with baseline testosterone level ( P -value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). Conclusions The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.

Alcohol is widely used but recognized as a risk factor for several adverse health outcomes based on observational studies. How alcohol affects lifespan remains controversial, with no trial to make such an assessment available or likely. We conducted a Mendelian randomization (MR) to assess the effect of alcohol on lifespan in men and women, including a possible role of smoking and education. Strong ( p  < 5e − 8 ), independent (r 2  < 0.001) genetic predictors of alcohol consumption in 2,428,851 participants of European ancestry from the Sequencing Consortium of Alcohol and Nicotine use (GSCAN) consortium genome wide association study (GWAS) were applied to sex-specific GWAS of lifespan (paternal and maternal attained age) and age at recruitment to the UK Biobank. We used multivariable MR to allow for smoking and education, with systolic and diastolic blood pressure as control outcomes. Inverse variance weighted was the primary analysis with sensitivity analysis. Alcohol consumption decreased lifespan overall (− 1.09 years (logged alcoholic drinks per week), − 1.89 to − 0.3) and in men (− 1.47 years, − 2.55 to − 0.38), which remained evident after adjusting for smoking (− 1.81 years, − 3.3 to − 0.32) and education (− 1.85 years, − 3.12 to − 0.58). Estimates from sensitivity analysis were similar, and when using the genetic variant physiologically associated with alcohol use. Alcohol consumption was associated with higher blood pressure as expected. Our study indicates that alcohol does not provide any advantages for men or women but could shorten lifespan. Appropriate interventions should be implemented.

IntroductionObservational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be confounded. We conducted a two sample Mendelian randomisation study using summary statistics from genome-wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function.MethodsWe obtained genetic instruments for forced expiratory volume in 1 s (FEV1: 260) and forced vital capacity (FVC: 320) from publicly available UK Biobank summary statistics (n=421 986) and applied to GWAS summary statistics for coronary artery disease (CAD) (n=184 305), stroke (n=446 696), atrial fibrillation (n=1 030 836) and heart failure (n=977 320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes, with various sensitivity analyses. Bidirectional Mendelian randomisation was used to assess reverse causation.ResultsFEV1 and FVC were inversely associated with CAD (OR per SD increase, 0.72 (95% CI 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (95% CI 0.82 to 1.00)) and some stroke subtypes. FEV1 and FVC were inversely associated with type 2 diabetes and systolic blood pressure. Sensitivity analyses produced similar findings although the association with CAD was attenuated after adjusting for height (eg, OR for 1SD FEV10.95 (0.75 to 1.19), but not for stroke or type 2 diabetes. There was no strong evidence for reverse causation.ConclusionHigher lung function likely protect against CAD and stroke.

Great progress has been made in reducing cardiovascular mortality over the past 50 years. Nevertheless, prevalence is rising in some settings and remains higher in men than in women, even with the same level of established risk factors. To gain new insights, researchers are now considering cardiovascular disease in relation to the well known evolutionary biology model of growth and reproduction trading off against longevity, with trials of calorie restriction underway. However, calorie restriction has not been as successful as expected in primates and it is increasingly realised that effects on the reproductive axis might also be important. In this paper, the modulation of the reproductive axis using existing agents that have such properties—tachykinin neurokinin 3 receptor antagonists—is proposed as a way of reducing cardiovascular disease and combating a leading cause of global morbidity and mortality.

Statins have been suggested as a potential treatment for immune-related diseases. Conversely, statins might trigger auto-immune conditions. To clarify the role of statins in allergic diseases and auto-immune diseases, we conducted a Mendelian randomization (MR) study. Using established genetic instruments to mimic statins via 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition, we assessed the effects of statins on asthma, eczema, allergic rhinitis, rheumatoid arthritis (RA), psoriasis, type 1 diabetes, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Crohn’s disease and ulcerative colitis in the largest available genome wide association studies (GWAS). Genetically mimicked effects of statins via HMGCR inhibition were not associated with any immune-related diseases in either study after correcting for multiple testing; however, they were positively associated with the risk of asthma in East Asians (odds ratio (OR) 2.05 per standard deviation (SD) decrease in low-density lipoprotein cholesterol (LDL-C), 95% confidence interval (CI) 1.20 to 3.52, p value 0.009). These associations did not differ by sex and were robust to sensitivity analysis. These findings suggested that genetically mimicked effects of statins via HMGCR inhibition have little effect on allergic diseases or auto-immune diseases. However, we cannot exclude the possibility that genetically mimicked effects of statins via HMGCR inhibition might increase the risk of asthma in East Asians.

Background Asialoglycoprotein receptor 1 (ASGR1) is emerging as a potential drug target to reduce low-density lipoprotein (LDL)-cholesterol and coronary artery disease (CAD) risk. Here, we investigated genetically mimicked ASGR1 inhibitors on all-cause mortality and any possible adverse effects. Methods We conducted a drug-target Mendelian randomization study to assess genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and 25 a priori outcomes relevant to lipid traits, CAD, and possible adverse effects, i.e. liver function, cholelithiasis, adiposity and type 2 diabetes. We also performed a phenome-wide association study of 1951 health-related phenotypes to identify any novel effects. Associations found were compared with those for currently used lipid modifiers, assessed using colocalization, and replicated where possible. Results Genetically mimicked ASGR1 inhibitors were associated with a longer lifespan (3.31 years per standard deviation reduction in LDL-cholesterol, 95% confidence interval 1.01 to 5.62). Genetically mimicked ASGR1 inhibitors were inversely associated with apolipoprotein B (apoB), triglycerides (TG) and CAD risk. Genetically mimicked ASGR1 inhibitors were positively associated with alkaline phosphatase, gamma glutamyltransferase, erythrocyte traits, insulin-like growth factor 1 (IGF-1) and C-reactive protein (CRP), but were inversely associated with albumin and calcium. Genetically mimicked ASGR1 inhibitors were not associated with cholelithiasis, adiposity or type 2 diabetes. Associations with apoB and TG were stronger for ASGR1 inhibitors compared with currently used lipid modifiers, and most non-lipid effects were specific to ASGR1 inhibitors. The probabilities for colocalization were > 0.80 for most of these associations, but were 0.42 for lifespan and 0.30 for CAD. These associations were replicated using alternative genetic instruments and other publicly available genetic summary statistics. Conclusions Genetically mimicked ASGR1 inhibitors reduced all-cause mortality. Beyond lipid-lowering, genetically mimicked ASGR1 inhibitors increased liver enzymes, erythrocyte traits, IGF-1 and CRP, but decreased albumin and calcium.

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guidelines lowered the hypertension threshold to ≥ 130/80 mmHg, but the role of diastolic BP remains contested. This two-sample mendelian randomisation study used replicated genetic variants predicting systolic and diastolic BP applied to the UK Biobank and large genetic consortia, including of cardiovascular diseases and parental lifespan, to obtain total and direct effects. Systolic and diastolic BP had positive total effects on CVD (odds ratio (OR) per standard deviation 2.15, 95% confidence interval (CI) 1.95, 2.37 and OR 1.91, 95% CI 1.73, 2.11, respectively). Direct effects were similar for systolic BP (OR 1.83, 95% CI 1.48, 2.25) but completely attenuated for diastolic BP (1.18, 95% CI 0.97, 1.44), although diastolic BP was associated with coronary artery disease (OR 1.24, 95% CI 1.03, 1.50). Systolic and diastolic BP had similarly negative total (− 0.20 parental attained age z-score, 95% CI − 0.22, − 0.17 and − 0.17, 95% CI − 0.20, − 0.15, respectively) and direct negative effects on longevity. Our findings suggest systolic BP has larger direct effects than diastolic BP on CVD, but both have negative effects (total and direct) on longevity, supporting the 2017 ACC/AHA guidelines lowering both BP targets.

Background l -carnitine is emerging as an item of interest for cardiovascular disease (CVD) prevention and treatment, but controversy exists. To examine the effectiveness and safety of l -carnitine, we assessed how genetically different levels of l -carnitine are associated with CVD risk and its risk factors. Given higher CVD incidence and l -carnitine in men, we also examined sex-specific associations. Methods We used Mendelian randomization to obtain unconfounded estimates. Specifically, we used genetic variants to predict l -carnitine, and obtained their associations with coronary artery disease (CAD), ischemic stroke, heart failure, and atrial fibrillation, as well as CVD risk factors (type 2 diabetes, glucose, HbA1c, insulin, lipid profile, blood pressure and body mass index) in large consortia and established cohorts, as well as sex-specific association in the UK Biobank. We obtained the Wald estimates (genetic association with CVD and its risk factors divided by the genetic association with l -carnitine) and combined them using inverse variance weighting. In sensitivity analysis, we used different analysis methods robust to pleiotropy and replicated using an l -carnitine isoform, acetyl-carnitine. Results Genetically predicted l -carnitine was nominally associated with higher risk of CAD overall (OR 1.07 per standard deviation (SD) increase in l -carnitine, 95% CI 1.02 to 1.11) and in men (OR 1.09, 95% CI 1.02 to 1.16) but had a null association in women (OR 1.00, 95% CI 0.92 to 1.09). These associations were also robust to different methods and evident for acetyl-carnitine. Conclusions Our findings do not support a beneficial association of l -carnitine with CVD and its risk factors but suggest potential harm. l -carnitine may also exert a sex-specific role in CAD. Consideration of the possible sex disparity and exploration of the underlying pathways would be worthwhile.

Observationally, the association of basal metabolic rate (BMR) with mortality is mixed, although some ageing theories suggest that higher BMR should reduce lifespan. It remains unclear whether a causal association exists. In this one-sample Mendelian randomization study, we aimed to estimate the casual effect of BMR on parental attained age, a proxy for lifespan, using two-sample Mendelian randomization methods. We obtained genetic variants strongly (p-value < 5 × 10 –8 ) and independently (r 2  < 0.001) predicting BMR from the UK Biobank and applied them to a genome-wide association study of parental attained age based on the UK Biobank. We meta-analyzed genetic variant-specific Wald ratios using inverse-variance weighting with multiplicative random effects by sex, supplemented by sensitivity analysis. A total of 178 and 180 genetic variants predicting BMR in men and women were available for father’s and mother’s attained age, respectively. Genetically predicted BMR was inversely associated with father’s and mother’s attained age (years of life lost per unit increase in effect size of genetically predicted BMR, 0.46 and 1.36; 95% confidence interval 0.07–0.85 and 0.89–1.82), with a stronger association in women than men. In conclusion, higher BMR might reduce lifespan. The underlying pathways linking to major causes of death and relevant interventions warrant further investigation.