After adjusting for CHD, effect of LDLR on lifespan reduced from 0.164 (indirect effect, 95% CI 0.112 to 0.215, P = 4.37 × 10−10) to 0.127 (direct effect, 95% CI, 0.093 to 0.159, P = 6.24 × 10−5), indicating that major CHD events play a significant role as a mediator, accounting for 22.8% of the mediation effect for triggering the lipid-lowering effects of LDLR on extended human lifespan (Fig. 4B). Here, LDLR is linked to coronary artery disorder.