Importance of Clinical, Laboratory, and Genetic Risk Factors for Incident CAD

Prior work suggests modifiable cardiovascular risk factors (CRFs) account for 80% to 90% of the risk for incident myocardial infarction. The contributions of genetic and other novel CRFs have not been simultaneously assessed in contemporary data sets.

In the United Kingdom Biobank, CRFs were identified and Cox proportional hazards models with traditional CRFs (hypertension, diabetes, dyslipidemia, waist-to-hip ratio, diet, exercise, alcohol, and socioeconomic deprivation) and contemporary/genetic CRFs (Lp(a) [lipoprotein(a)], hsCRP [high-sensitivity C-reactive protein], familial hypercholesterolemia variants, and polygenic risk score for coronary artery disease) were constructed for coronary artery disease. Coronary artery disease was defined as a first-time myocardial infarction diagnosis or coronary revascularization. R² was calculated for each model, and the percent contribution of each individual CRF was calculated by the R² percent decrease after its removal.

Among 299 707 individuals, the mean (SD) age was 56.2 (8.1) years, and 166 533 (55.6%) were women. Over a median (interquartile range) follow-up of 11.0 (9.6-12.5) years, 17 409 (5.8%) of participants developed myocardial infarction. R² increased from the base model (R², 0.021 [0.020-0.022]), to the clinical model (R², 0.045 [0.043-0.046]), to the contemporary/genetic model (R², 0.053 [0.052-0.055]). The most powerful individual CRFs were hypertension (R² loss, 15.2% [14.5-17.1]) and polygenic risk score for coronary artery disease (R² loss, 12.4% [10.8-13.3]), followed by dyslipidemia (R² loss, 3.4% [2.6-3.5]), diabetes (R² loss, 2.2% [1.5-2.0]), hsCRP (R² loss, 1.8% [1.5-2.0]), and Lp(a) (R² loss, 1.5% [1.2-1.8]).

Novel CRFs like polygenic risk score for coronary artery disease, hsCRP, and Lp(a) have similar importance, comparable to traditional CRFs such as hypertension, dyslipidemia, and diabetes, for incident myocardial infarction, highlighting important identifiable residual risk factors.