PCSK9 variants have been identified in each of these domains, some of which associate with significant changes in circulating LDLC levels; PCSK9 variants that associate with hypercholesterolemia or ADH [22-26] are termed ‘gain of function’, while PCSK9 ‘loss of function’ variants associate with hypocholesterolemia and reduced risk of coronary artery disease [27-33]. This evidence concerns the gene PCSK9 and familial hypercholesterolemia.