Natural loss-of-function mutations in PCSK9 (Cohen et al., 2006) and ANGPTL4 (Stitziel et al., 2016) resulted in notable protective effects in reduced LDL-cholesterol level and lower risk of premature coronary artery diseases (CAD) over large-population epidemiological studies (Fig. 6D and 6E). The gene discussed is PCSK9; the disease is coronary artery disorder.