Several studies have found that missense mutations increasing the activity of PCSK9 (i.e., gain-of-function mutations) result in an increase of LDL-C levels and CAD [22,32-34] whereas nonsense mutations reducing PCSK9 activity (i.e., loss-of-function mutations) have the opposite effect, lowering LDL-C levels and reducing risk of CAD [35-37]. The gene discussed is PCSK9; the disease is coronary artery disorder.