**2.3 Genetic variation in apolipoproteins and HDL-C levels**

Apolipoprotein A-1 (APOA1; APOA-I) is a ligand required for HDL-C binding to its receptors including SCARB1 and ABCA1 and, is an important cofactor in 'reverse cholesterol transport' (Miller et al., 2003; Remaley et al., 2001; Rigotti et al., 1997). The

Parroxanonase 1 (PON1), inhibits the oxidation of LDL (Mackness et al., 1991) and, therefore, may only indirectly affect antioxidant properties of HDL-C. The human PON1 gene is located on chromosome 7 (7q21.3). Several SNPs in PON1 have been associated with HDL-C levels, most notably, two nonsynonymous SNPs, rs662 and rs3202100, which are in strong LD, but results are inconsistent across studies (Table 1) (Blatter Garin et al., 2006; Hegele et al., 1995; Manresa et al., 2006; Rios et al., 2007; van Aalst-Cohen et al.,

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

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

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;

Apolipoprotein A-1 (APOA1; APOA-I) is a ligand required for HDL-C binding to its receptors including SCARB1 and ABCA1 and, is an important cofactor in 'reverse cholesterol transport' (Miller et al., 2003; Remaley et al., 2001; Rigotti et al., 1997). The

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

2005).

(Boekholdt et al., 2006).

on LDL-C levels (see Section 3.1).

Shioji et al., 2004b; Whiting et al., 2005).

**2.3 Genetic variation in apolipoproteins and HDL-C levels** 

human APOA1 gene is located on chromosome 11 (11q23-24). APOA-I is a major constituent of HDL particles and deletions leading to complete APOA-I deficiency are rare but lead to HDL deficiency (HDL-C <10 mg/dl) and sometimes CHD (Garg and Simha, 2007). Several common polymorphisms in APOA-I have been associated with more modest reductions in HDL-C but results across studies are inconsistent (Table 1) (Brown et al., 2006; Kamboh et al., 1999b; Larson et al., 2002; Shioji et al., 2004a).

Apolipoprotein A-4 (APOA4; APOA-IV) is a potent activator of LCAT and modulates the activation of LPL and transfer of cholestryl esters from HDL to LDL (Kwan et al., 2007). The human APOA4 gene is located on chromosome 11 near APOA1 (11q23) and is part of what is known as the APOA1/C3/A4/A5 gene cluster. Polymorphisms in APOA4 have not been as well studied; however, the nonsynonymous SNP, rs5110 (Gln360His), has recently been associated with reduced HDL-C levels in Brazilian elderly (Ota et al., 2011) and coronary artery calcification (CAC) progression, a marker of subclinical atherosclerosis, in patients with Type I Diabetes Mellitus (T1DM) (Kretowski et al., 2006). The rs675 polymorphism has been associated with reduced HDL-C levels in females with T2DM (Qi et al., 2007).

Apolipoprotein A-5 (APOA5; APOA-V) is located predominantly on TG-rich chylomicrons and VLDL and activates LPL (Hubacek, 2005). The human APOA5 gene is located on chromosome 11 (11q23) in the APOA1/C3/A4/A5 gene cluster. Several APOA5 SNPs have been associated with reduced HDL-C levels; and, perhaps, the most well studied and consistent associations have been observed for rs651821 and rs662799 (Table 1) (Grallert et al., 2007; Hubacek, 2005; Klos et al., 2006; Lai et al., 2003; Qi et al., 2007; Talmud et al., 2002a; Yamada et al., 2008; Yamada et al., 2007).

Apolipoprotein C-3 (APOC3; APOC-III) is an inhibitor of LPL and is transferred to HDL during the hydrolysis of TG-rich lipoproteins (Kwan et al., 2007; Miller and Zhan, 2004). The human APOC3 gene is located on chromosome 11 (11q23) in the APOA1/C3/A4/A5 gene cluster. Although several APOC3 SNPs have been identified and investigated, associations between these SNPs and HDL-C levels have been quite inconsistent (Table 1) (Arai and Hirose, 2004; Brown et al., 2006; Corella et al., 2002; Hegele et al., 1995; Kamboh et al., 1999a; Lahiry et al., 2007; Pallaud et al., 2001; Qi et al., 2007; Russo et al., 2001).

Chylomicron remnants, VLDL and IDL particles are rich in apolipoprotein E (APOE) and APOE is a critical ligand for binding to hepatic receptors that remove these particles from the circulation (Kwan et al., 2007). Mutations in APOE are well known to modify LDL-C levels; however, their independent influence on HDL-C levels remains controversial (Sviridov and Nestel, 2007). Nevertheless, associations between APOE SNPs and HDL-C levels in large scale studies have been fairly consistent (Costanza et al., 2005; Frikke-Schmidt et al., 2000; Gronroos et al., 2008; Kataoka et al., 1996; Srinivasan et al., 1999; Volcik et al., 2006; Wilson et al., 1994; Wu et al., 2007).
