**2.2 Genetic variation in receptors and transporters and HDL-C levels**

Scavenger receptor class B, type 1 (SCARB1; SR-B1), which is highly expressed in liver and steroidogenic tissues (testes, ovaries, adrenal) (Cao et al., 1997), has been shown to participate in the uptake of HDL in animals by transferring cholesterol from the HDL-C particle and releasing the lipid-depleted HDL particle into the circulation (Acton et al., 1996; Miller et al., 2003). The human SCARB1 gene is located on chromosome 12 (12q24.31). Only a few studies have examined potential associations between SCARB1 polymorphisms and HDL-C levels (Table 1) (Boekholdt et al., 2006; Costanza et al., 2005; Hsu et al., 2003; Morabia et al., 2004; Osgood et al., 2003; Roberts et al., 2007). The most well studied polymorphism has been rs5888; however, the association with rs5888 and HDL-C levels was only significant among Caucasian (White, W) males in one study (Morabia et al., 2004), Amish females (Roberts et al., 2007) and Caucasian CVD patients (Boekholdt et al., 2006).

The LDL receptor (LDLR) and LDLR-related protein participate in the uptake of LDL and chylomicron remnants by hepatocytes (Kwan et al., 2007) and, therefore, may only indirectly affect HDL-C levels. The human LDLR is located on chromosome 19 (19p13.2). Although some common polymorphisms in LDLR have been associated with HDL-C levels (Table 1: (Costanza et al., 2005; Hegele et al., 1995; Yamada et al., 2008), their impact is likely greater on LDL-C levels (see Section 3.1).

The ATP-binding cassette transporter A1 (ABCA1), which is highly expressed in the liver, steroidogenic tissues and macrophages, plays a key role in 'reverse cholesterol transport' by mediating the efflux of cholesterol and phospholipids from macrophages to the nascent lipid-free, APOA-1 HDL particle (Cavelier et al., 2006; Miller et al., 2003). The human ABCA1 gene is located on chromosome 9 (9q31.1). Due to its functional importance, genetic variants in this gene have been well investigated but many of them are quite rare including the homozygous deletion that leads to Tangier's disease that is characterized by very low HDL-C levels (~5 mg/dl), orange colored tonsils, peripheral neuropathy and, sometimes, premature CHD (Garg and Simha, 2007). Several common polymorphisms have been fairly consistently associated with more modest changes in HDL-C levels but different variants appear to drive this association in different ethnic groups (Table 1) (Clee et al., 2001; Costanza et al., 2005; Frikke-Schmidt et al., 2004; Hodoglugil et al., 2005; Kathiresan et al., 2008b; Klos et al., 2006; Porchay et al., 2006; Shioji et al., 2004b; Whiting et al., 2005).
