Educational Attainment as the Primary Socioeconomic Determinant of Heart Failure: A Multivariable Mendelian...

Socioeconomic status (SES), intelligence, and cognitive function have been associated with heart failure (HF) risk in observational studies, but their causal relationships remain unclear.

The purpose of this study was to determine whether SES components, intelligence, and cognitive function have independent causal effects on HF risk and to identify modifiable mediators underlying these associations.

We conducted 2-sample Mendelian randomization (MR) analyses using summary statistics from large genome-wide association studies in populations of European ancestry. Genetic instruments for SES (education, income, Townsend Deprivation Index), intelligence, and cognitive function were identified. Multivariable MR was used to assess independent effects. A 2-step MR mediation analysis was conducted to identify and quantify lifestyle and clinical mediators linking educational attainment to HF.

Educational attainment showed a robust inverse association with HF risk (OR per 1 SD [4.2 years] = 0.68; 95% CI: 0.55-0.83), independent of income and deprivation. Intelligence, cognitive function, income, and deprivation were not independently associated with HF after adjusting for education. Among 88 candidate mediators, 12 met criteria for causal mediation, including smoking, sleep duration, body mass index, body fat percentage, triglyceride level, hypertension, metabolic disorders, hypercholesterolemia, coronary artery disease, myocardial infarction, stroke, and atrial fibrillation. Myocardial infarction mediated the largest proportion of the education-HF association (61.4%), followed by body mass index and body fat (43.1% and 45.7%, respectively).

Educational attainment is the primary causal component of SES affecting HF risk. These effects are mediated through modifiable lifestyle and cardiovascular factors, highlighting education as a key intervention target for HF prevention.