**3.3 Genetic variation in proteases and LDL-C levels**

Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a serine protease that degrades hepatic LDLR in endosomes (Maxwell et al., 2005). The human PCSK9 gene is located on chromosome 1 (1p32.3). A mutation in PCSK9 results in an autosomal dominant form of hypercholesterolemia (OMIM No. 607786) with clinical features similar to FH patients (Garg and Simha, 2007). Over 50 variants in PCSK9 have been shown to affect circulating levels of cholesterol; however, most of these are relatively rare (see Davignon et al., 2010) for a complete list). The number of common polymorphisms in PCSK9 is substantially less with only a few SNPs having been associated with changes in LDL-C levels (Table 2) (Chen et al., 2005; Evans and Beil, 2006; Huang et al., 2009; Teslovich et al., 2010; Willer et al., 2008).
