BACKGROUND: Education, intelligence, and cognition are associated with hypertension, but which one plays the most prominent role in the pathogenesis of hypertension and which modifiable risk factors mediate the causal effects remains unknown. METHODS: Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted 2-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, or cognition on hypertension (FinnGen study, 70 651 cases/223 663 controls; UK Biobank, 77 723 cases/330 366 controls) and blood pressure (International Consortium of Blood Pressure, 757 601 participants), and used 2-step Mendelian randomization to evaluate 25 potential mediators of the association and calculate the mediated proportions. RESULTS: Meta-analysis of inverse variance weighted Mendelian randomization results from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was associated with 44% (95% CI: 0.40–0.79) decreased hypertension risk and 1.682 mm Hg lower systolic and 0.898 mm Hg lower diastolic blood pressure, independently of intelligence and cognition. While the causal effects of intelligence and cognition on hypertension were not independent of education, 6 out of 25 cardiometabolic risk factors were identified as mediators of the association between education and hypertension, ranked by mediated proportions, including body mass index (mediated proportion: 30.1%), waist-to-hip ratio (22.8%), body fat percentage (14.1%), major depression (7.0%), high-density lipoprotein cholesterol (4.7%), and triglycerides (3.4%). These results were robust to sensitivity analyses. CONCLUSIONS: Our findings illustrated the causal, independent impact of education on hypertension and blood pressure and outlined cardiometabolic mediators as priority targets for prevention of hypertension attributable to low education.

Objective The aim of this study was to investigate the associations of diabesity with incident cardiovascular disease (CVD) and subclinical atherosclerosis. Methods The prospective cohort study included 8,006 participants without baseline CVD. Diabesity was categorized as (i) normal glucose tolerance (NGT) with nonobesity; (ii) NGT with obesity; (iii) prediabetes with nonobesity; (iv) prediabetes with obesity; (v) diabetes with nonobesity; and (vi) diabetes with obesity. The hazard ratios (HRs) for incident CVD and odds ratios (ORs) for subclinical atherosclerosis associated with diabesity categories were examined. Results Compared with the category of NGT with nonobesity, the categories of NGT with obesity (HR 1.68; 95% CI: 1.10–2.57), diabetes with nonobesity (HR 1.42; 95% CI: 1.08–1.88), and diabetes with obesity (HR 1.78; 95% CI: 1.24–2.55) were associated with higher risks of CVD. Prediabetes with or without obesity conferred no excess risk for CVD but higher risks for subclinical atherosclerosis. The diabetes with obesity category was associated with the highest risk for elevated pulse pressure (OR 3.07; 95% CI: 2.06–4.58) and albuminuria (OR 3.39; 95% CI: 2.31–4.99), and diabetes with or without obesity showed comparable ORs for elevated brachial–ankle pulse wave velocity. Conclusions The association patterns between diabesity and CVD risks support the value of diabesity as a prevention target for CVD.

Purpose Observational studies have associated obesity with chronic kidney disease (CKD) and arterial stiffness, but the causality remains unclear. We aimed to investigate the causality of obesity with CKD and arterial stiffness using Mendelian randomization (MR) analysis. Methods We genotyped 14 body mass index (BMI)-associated variants validated in East Asians in 11384 Chinese adults. A genetic risk score based on the 14 variants and the 14 individual single nucleotide polymorphisms were respectively used as instrumental variables (IVs). CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m 2. Arterial stiffness was defined as brachial-ankle pulse wave velocity >1550 cm/s. Results Using the genetic risk score as the IV, we demonstrated causal relations of each 1-standard deviation increment in BMI with CKD (odds ratio [OR]: 2.36; 95% confidence interval [CI]: 1.11-5.00) and arterial stiffness (OR: 1.71; 95% CI: 1.22-2.39). Using the 14 single nucleotide polymorphisms individually as IVs, each 1-standard deviation increment in BMI casually associated with CKD (OR: 2.58; 95% CI: 1.39-4.79) and arterial stiffness (OR: 1.87; 95% CI: 1.24-2.81) in the inverse-variance weighted analysis, and MR-Egger regression revealed no evidence of horizontal pleiotropy (Both P for intercept≥0.34). The causality between obesity and CKD was validated in two-sample MR analysis among Europeans (681275 of Genetic Investigation of ANthropometric Traits and 133413 of CKD Genetics). Conclusions This study provided novel insights into causality of obesity with CKD and arterial stiffness, highlighting the importance of weight management for primary prevention and control of subclinical vascular diseases.