PCSK9, MST1, and RPS6K1 predominantly mediated the detrimental effect of sedentary behavior on CAD, while the effect of smoking was mainly mediated by RGMB, PCSK9, ITPKA, RPS6KA1, and AGER, which partially aligned with the observed association pattern between obesity and CAD. Here, ITPKA is linked to coronary artery disorder.