Key Points Question What is the role of body mass index, systolic blood pressure and smoking in mediating the effect of education on cardiovascular disease risk? Finding We find consistent evidence that body mass index, systolic blood pressure and smoking mediate the effect of education, explaining up to 18%, 27% and 33% respectively. Including all three risk factors in a model together explains around 40% of the effect of education. Meaning Intervening on body mass index, systolic blood pressure and smoking would lead to reductions in cases of CVD attributable to lower levels of education. Over half of the effect of education on risk of cardiovascular disease is not mediated through these risk factors. Importance Lower levels of education are causally related to higher cardiovascular risk, but the extent to which this is driven by modifiable risk factors also associated with education is unknown. Objective To investigate the role of body mass index, systolic blood pressure and smoking in explaining the effect of education on risk of cardiovascular disease outcomes. Design Multivariable regression analysis of observational data and Mendelian randomization (MR) analysis of genetic data. Setting UK Biobank and international genome-wide association study consortia. Participants Predominantly individuals of European ancestry. Main outcomes and measures The effects of education (per 1-standard deviation increase, equivalent to 3.6 years) on coronary heart disease, cardiovascular disease (all subtypes), myocardial infarction and stroke risk (all measured in odds ratio, OR), and the degree to which this is mediated through body mass index, systolic blood pressure and smoking. Results Each additional standard deviation of education associated with 13% lower risk of coronary heart disease (OR 0.87, 95% confidence interval [CI] 0.84 to 0.89) in observational analysis and 37% lower risk (OR 0.63, 95% CI 0.60 to 0.67) in Mendelian randomization analysis. As a proportion of the total risk reduction, body mass index mediated 15% (95% CI 13% to 17%) and 18% (95% CI 14% to 23%) in the observational and Mendelian randomization estimates, respectively. Corresponding estimates for systolic blood pressure were 11% (95% CI 9% to 13%) and 21% (95% CI 15% to 27%), and for smoking, 19% (15% to 22%) and 33% (95% CI 17% to 49%). All three risk factors combined mediated 42% (95% CI 36% to 48%) and 36% (95 % CI 16% to 63%) of the effect of education on coronary heart disease in observational and Mendelian randomization respectively. Similar results were obtained when investigating risk of stroke, myocardial infarction and all-cause cardiovascular disease. Conclusions and relevance BMI, SBP and smoking mediate a substantial proportion of the protective effect of education on risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of CVD attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.

What explains the effect of education on cardiovascular disease? Applying Mendelian randomization to identify the consequences of education inequality