**3.1 Genetic variation in enzymes, receptors and transporters and LDL-C levels**

LDL-C is a widely accepted risk factor for atherosclerotic cardiovascular diseases. The most marketed drugs for lowering LDL-C are statins, which inhibit hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate limiting enzyme in cholesterol synthesis that is normally suppressed (Endo, 1992). The human HMGCR gene is located on chromosome 5 (5q13.3-14). Only a few common HMGCR polymorphisms have been associated with LDL-C levels including rs3846662, which was identified through GWAS (Table 2) (Burkhardt et al., 2008; Hiura et al., 2010; Polisecki et al., 2008; Teslovich et al., 2010).

As mentioned above, the LDL receptor (LDLR) regulates the uptake of LDL and chylomicron remnants by hepatocytes (Kwan et al., 2007) and, the human LDLR gene is located on chromosome 19 (19p13.2). Familial (or monogenic) hypercholesterolemia (FH: OMIM No. 143890), which is due to mutations in LDLR occurring at a frequency of approximately 1 in 500 (heterozygotes) to 1 in 1,000,000 (homozygotes), is one of the most common inherited metabolic diseases and results in a reduced number of LDL receptors and, in heterozygotes, a 2- to 3-fold increase in LDL–C levels and, in homozygotes, complete loss of LDLR function and a greater than 5-fold increase in LDL-C (Garg and Simha, 2007). A few common polymorphisms in LDLR have been identified and associated with more modest changes in LDL-C levels, most notably, rs6511720, which was highly significantly associated with LDL-C in a recent meta analysis (Table 2) (Teslovich et al., 2010; Willer et al., 2008).

ATP-binding cassette transporters G5 and G8 (ABCG5/8) regulate the efflux of cholesterol back into the intestinal lumen and, in hepatocytes, the efflux of cholesterol into bile (Graf et al., 2003). The human ABCG5/8 gene cluster is located on chromosome 2 (2p21). A rare autosomal recessive mutation in ABCG5/8 leads to sitosterolemia characterized by xanthomas, premature atherosclerosis and other features (Berge et al., 2000). Only a couple of common variants in ABCG5/8 have been associated with LDL-C levels and a recent meta-analysis failed to find associations between ABCG5/G8 polymorphisms including, ABCG8 rs6544718, and plasma lipid levels (Table 2) (Jakulj et al., 2010; Teslovich et al., 2010)

### **3.2 Genetic variation in lipoproteins and LDL-C levels**

Apolipoprotein B (APOB; main isoform: ApoB-100) is responsible for the recognition and uptake of LDL by LDLR, which clears approximately 60-80% of the LDL in 'normal' individuals with the remaining taken up by LRP or SCARB1 (Kwan et al., 2007). The human APOB gene is located on chromosome 2 (2p23-24). Familial defective APOB (FDB: OMIM No. 144010) is an autosomal codominant disorder due to mutations in APOB that are a bit more rare than FH mutations at approximately 1 in 500 to 1 in 700 resulting in lower LDL-C levels than in FH patients (Garg and Simha, 2007). Common polymorphisms have also been identified and associated with more modest changes in LDL-C (Table 2) (Haas et al., 2011; Teslovich et al., 2010; Waterworth et al., 2010; Willer et al., 2008).

As mentioned above, APOE is a critical ligand for binding chylomicron remnants, VLDL and IDL particles to hepatic receptors to remove these particles from the circulation (Kwan et al., 2007). The human APOE gene is located on chromosome 19 (19q13.2). The structural APOE gene is polymorphic with three common alleles, designated as ε2, ε3 and ε4 which encode for E2, E3 and E4 proteins, respectively. Although several APOE polymorphisms have been identified, the APOE ε4 allele has been the most consistently associated with CHD and LDL-C levels (Table 2) (Anoop et al., 2010; Chang et al., 2010; Eichner et al., 2002; Teslovich et al., 2010; Willer et al., 2008).

LDL-C is a widely accepted risk factor for atherosclerotic cardiovascular diseases. The most marketed drugs for lowering LDL-C are statins, which inhibit hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate limiting enzyme in cholesterol synthesis that is normally suppressed (Endo, 1992). The human HMGCR gene is located on chromosome 5 (5q13.3-14). Only a few common HMGCR polymorphisms have been associated with LDL-C levels including rs3846662, which was identified through GWAS (Table 2) (Burkhardt et al.,

As mentioned above, the LDL receptor (LDLR) regulates the uptake of LDL and chylomicron remnants by hepatocytes (Kwan et al., 2007) and, the human LDLR gene is located on chromosome 19 (19p13.2). Familial (or monogenic) hypercholesterolemia (FH: OMIM No. 143890), which is due to mutations in LDLR occurring at a frequency of approximately 1 in 500 (heterozygotes) to 1 in 1,000,000 (homozygotes), is one of the most common inherited metabolic diseases and results in a reduced number of LDL receptors and, in heterozygotes, a 2- to 3-fold increase in LDL–C levels and, in homozygotes, complete loss of LDLR function and a greater than 5-fold increase in LDL-C (Garg and Simha, 2007). A few common polymorphisms in LDLR have been identified and associated with more modest changes in LDL-C levels, most notably, rs6511720, which was highly significantly associated with LDL-C

ATP-binding cassette transporters G5 and G8 (ABCG5/8) regulate the efflux of cholesterol back into the intestinal lumen and, in hepatocytes, the efflux of cholesterol into bile (Graf et al., 2003). The human ABCG5/8 gene cluster is located on chromosome 2 (2p21). A rare autosomal recessive mutation in ABCG5/8 leads to sitosterolemia characterized by xanthomas, premature atherosclerosis and other features (Berge et al., 2000). Only a couple of common variants in ABCG5/8 have been associated with LDL-C levels and a recent meta-analysis failed to find associations between ABCG5/G8 polymorphisms including, ABCG8 rs6544718, and plasma lipid levels (Table 2) (Jakulj et al., 2010; Teslovich et al., 2010)

Apolipoprotein B (APOB; main isoform: ApoB-100) is responsible for the recognition and uptake of LDL by LDLR, which clears approximately 60-80% of the LDL in 'normal' individuals with the remaining taken up by LRP or SCARB1 (Kwan et al., 2007). The human APOB gene is located on chromosome 2 (2p23-24). Familial defective APOB (FDB: OMIM No. 144010) is an autosomal codominant disorder due to mutations in APOB that are a bit more rare than FH mutations at approximately 1 in 500 to 1 in 700 resulting in lower LDL-C levels than in FH patients (Garg and Simha, 2007). Common polymorphisms have also been identified and associated with more modest changes in LDL-C (Table 2) (Haas et al., 2011;

As mentioned above, APOE is a critical ligand for binding chylomicron remnants, VLDL and IDL particles to hepatic receptors to remove these particles from the circulation (Kwan et al., 2007). The human APOE gene is located on chromosome 19 (19q13.2). The structural APOE gene is polymorphic with three common alleles, designated as ε2, ε3 and ε4 which encode for E2, E3 and E4 proteins, respectively. Although several APOE polymorphisms have been identified, the APOE ε4 allele has been the most consistently associated with CHD and LDL-C levels (Table 2) (Anoop et al., 2010; Chang et al., 2010; Eichner et al., 2002;

**3.1 Genetic variation in enzymes, receptors and transporters and LDL-C levels** 

**3. Genetic variants in lipid metabolism and LDL-C levels** 

2008; Hiura et al., 2010; Polisecki et al., 2008; Teslovich et al., 2010).

in a recent meta analysis (Table 2) (Teslovich et al., 2010; Willer et al., 2008).

**3.2 Genetic variation in lipoproteins and LDL-C levels** 

Teslovich et al., 2010; Waterworth et al., 2010; Willer et al., 2008).

Teslovich et al., 2010; Willer et al., 2008).



Dyslipidemia: Genetics and Role in the Metabolic Syndrome 111

**Size**

(Meta)

(Meta)

(Meta)

(Meta)

(Meta)

rs12286037 0.94 (C) Va 9,738 25.82 mg/dl;

rs2000571 0.17 (G) Va 3,209 6.93 mg/dl;

rs486394 0.28 (A) Va 3,597 1.50 mg/dl;

APOE rs439401 0.40 (C) C 4.192 p=2.2×10-5 (Liu et al. 2011) APOE rs439401 0.64 (C) Va Meta p=5.5x10-30 Johansen et al.

LIPC/HL rs261342 0.22 (G) Va Meta p=2.0x10-13 Johansen et al.

LPL S447X rs328 0.90 (C) EA 24,258 p=4.16E-30 (Dumitrescu

LPL rs326 0.18 (G) C 4,192 p=2.3×10-6 (Liu et al. 2011)

**Results (Effect** 


p=5.4x10-8

+16.95mg/dl; p=7x10-240

p=1.6x10-22

p=2.7x10-10

p=8.7x10-5

p=0.0073

p=2.9x10-5


p=1.6x10-14

p=0.0029

p=5x10-4

0.19) mmol/l

mmol/l

mmol/l



p=5x10-8

p=9.0×10-59

**Size, p-value) Reference** 

(Teslovich et al. 2010)

(Willer et al. 2008)

(Teslovich et al. 2010)

(Willer et al. 2008)

(Willer et al. 2008)

(Willer et al. 2008)

(Willer et al. 2008)

(2010)

(Willer et al. 2008)

(2010)

(Teslovich et al. 2010)

(Willer et al. 2008)

(Willer et al. 2008)

(Willer et al. 2008)

et al. 2011)

(Sagoo et al. 2008)

(Sagoo et al. 2008)

(Sagoo et al. 2008)

(Teslovich et al. 2010)

(Teslovich et al. 2010)

(Willer et al. 2008)

(Johansen et al. 2011)

**z Polym. rs Number MAF Ethn. Sample** 

ANGPTL3 rs1748195 0.70 (G) Va 9,559 7.12 mg/dl;

APOA5 rs662799 0.05 (A) Va 3,248 16.88 mg/dl

LIPC/HL rs4775041 0.67 (G) Va 8,462 3.62 mg/dl;

LPL rs10503669 0.90 (A) Va 9,711 11.57 mg/dl;

LPL rs2197089 0.58 (A) Va 3,202 3.38 mg/dl;

LPL rs6586891 0.66 (A) Va 3,622 4.60 mg/dl;

LPL S447X rs328 0.10 (X) Va 43,242 -0.15 (-0.12- -

LPL D9N rs1801177 0.03 (N) Va 21,040 0.14 (0.08-0.20)

LPL N291S rs368 0.03 (S) Va 27,204 0.19 (0.12-0.26)

MLXIPL rs17145738 0.84 (T) Va 9,741 8.21 mg/dl;

MLXIPL rs7811265 0.81 (A) Va Meta 7.91 mg/dl

Table 3. Genetic Polymorphisms Associated With TG Levels. See Table 1 legend.

LPL rs12678919 0.12 (G) E 96,598

LRP1 rs11613352 0.23 (T) E 96,598

MLXIPL rs17145738 0.12 (T) E 96,598

ANGPTL3 rs2131925 0.32 (G) E 96,598

APOA5 rs964184 0.13 (G) E 96,598

APOA5/A 4/C3/A1

APOA5/A 4/C3/A1

APOA5/A 4/C3/A1
