Classical risk factors for primary coronary artery disease from an aging perspective through Mendelian Randomization

Abstract

The significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian Randomization approaches to investigate the causal relationship between classical risk factors and primary CAD in different age groups. A Mendelian Randomization study was conducted in European-ethnicity individuals from the UK Biobank population. Analyses were performed using data of 22,313 CAD cases (71.6% men) and 407,920 controls (44.5% men). Using logistic regression analyses, we investigated the associations between standardized genetic risk score and primary CAD stratified by age of diagnosis. In addition, feature importance and model accuracy were assessed in different age groups to evaluate predictive power of the genetic risk scores with increasing age. We found age-dependent associations for all classical CAD risk factors. Notably, body mass index (OR 1.22 diagnosis < 50 years; OR 1.02 diagnosis > 70 years), blood pressure (OR 1.12 < 50 years; OR 1.04 > 70 years), LDL cholesterol (OR 1.16 < 50 years; OR 1.02 > 70 years), and triglyceride levels (OR 1.11 < 50 years; 1.04 > 70 years). In line with the Mendelian Randomization analyses, model accuracy and feature importance of the classical risk factors decreased with increasing age of diagnosis. Causal determinants for primary CAD are age dependent with classical CAD risk factors attenuating in relation with primary CAD with increasing age. These results question the need for (some) currently applied cardiovascular disease risk reducing interventions at older age.

Keywords: Aging; Coronary artery disease; LDL cholesterol; Mendelian Randomization; Risk factors.

Fig. 1

Feature importance and model performance dependent on the age of diagnosis. Analyses were performed using a balanced sample dependent on the age of diagnosis (for primary cases, cases of coronary artery disease) or age at study inclusion (for controls). The following age bins were used: 30–40 years (N = 210), 40–45 years (N = 711), 45–50 years (N = 1833), 50–55 years (N = 3828), 55–60 years (N = 6012), 60–65 years (N = 6376), and 65–80 years (N = 6336). a Presentation of the importance of the different features across age. b Performance measures of the combined genetic risk scores dependent on the age of diagnosis. Abbreviations: AUC, area under the curve; BMI, body mass index; BP, blood pressure; LDL, low-density lipoprotein; TG, triglycerides