**4.1 Genetic variation in aolipoproteins and TG levels**

As mentioned above (see Section 3.2), APOB is the backbone of atherogenic lipoproteins and is located on chromosome 2 (2p23-24). A rare monogenic autosomal recessive disorder called homozygous hypobetalipoproteinemia and rare autosomal codominant disorder called familial hypobetalipoproteinaemia (HHBL and FHBL, respectively: OMIM No. 107730), characterized by very low (<5th percentile of age- and sex-specific values) of plasma TG (and LDL-C) levels, which are caused by rare mutations in APOB (Burnett and Hooper, 2008; Di et al., 2009). Although common APOB polymorphisms have primarily been associated with LDL-C levels (Benn, 2009), GWAS has revealed that a common SNP in APOB, rs1042034, is associated with TG (Johansen and Hegele, 2011; Teslovich et al., 2010). Common polymorphisms in the APOA1/C3/A4/A5 gene cluster, located on chromosome 11 (11q23), have been associated with HDL-C levels (see Section 2.3) as well as TG levels (Teslovich et al., 2010; Willer et al., 2008). A SNP in the APOE gene, rs439401, has also been shown to be strongly associated with TG levels in a recent GWAS meta analyses (Johansen and Hegele, 2011; Teslovich et al., 2010).

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).

GWAS have confirmed associations between polymorphisms in viable candidate genes including APOB, APOE, LDLR and PCSK9, and have identified novel SNPs associated with LDL-C levels with strong biological plausibility including an inhibitor of lipase (ANGPTL3), see Section 4.1 and a transcription factor activating triglyceride synthesis (MLXIPL) see

Plasma triglycerides (TG) integrate multiple TG-rich lipoprotein particles, predominantly, intestinally synthesized chylomicrons in the postprandial state and hepatically synthesized VLDL in the fasted state. Therefore, not surprisingly, there is considerable overlap between genetic variants associated with HDL-C and LDL-C levels as well as TG levels. For example, the Global Lipids Genetics Consortium (GLGC) found that 15 of the 32 loci associated with TG levels were also jointly associated with HDL-C levels, explaining 9.6% of the total variation in plasma TG, which corresponded to 25–30% of the total genetic contribution to TG variability (Teslovich et al., 2010). However, the joint associations reported do not appear additionally adjusted for the other lipid phenotype. Furthermore, certain loci appear to be more strongly associated with one lipid phenotype over the other while others have similar effect sizes; and,

As mentioned above (see Section 3.2), APOB is the backbone of atherogenic lipoproteins and is located on chromosome 2 (2p23-24). A rare monogenic autosomal recessive disorder called homozygous hypobetalipoproteinemia and rare autosomal codominant disorder called familial hypobetalipoproteinaemia (HHBL and FHBL, respectively: OMIM No. 107730), characterized by very low (<5th percentile of age- and sex-specific values) of plasma TG (and LDL-C) levels, which are caused by rare mutations in APOB (Burnett and Hooper, 2008; Di et al., 2009). Although common APOB polymorphisms have primarily been associated with LDL-C levels (Benn, 2009), GWAS has revealed that a common SNP in APOB, rs1042034, is associated with TG (Johansen and Hegele, 2011; Teslovich et al., 2010). Common polymorphisms in the APOA1/C3/A4/A5 gene cluster, located on chromosome 11 (11q23), have been associated with HDL-C levels (see Section 2.3) as well as TG levels (Teslovich et al., 2010; Willer et al., 2008). A SNP in the APOE gene, rs439401, has also been shown to be strongly associated with TG levels in a recent GWAS meta analyses (Johansen

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

**4. Genetic variants in lipid metabolism and TG levels** 

**4.1 Genetic variation in aolipoproteins and TG levels** 

and Hegele, 2011; Teslovich et al., 2010).

genetic heterogeneity between loci clearly exists between major ethnic groups.

**3.4 GWAS and LDL-C Levels** 

Section 4.2 (Teslovich et al., 2010).


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

Dyslipidemia: Genetics and Role in the Metabolic Syndrome 113

Komurcu-Bayrak et al., 2007). Several SNPs in the LDLR have been associated with MetSyn (using AHA/NHLBI criteria) and LDL-C or HDL-C (Joy et al., 2008; Yamada et al., 2008).

**Size**

**Results**

p=2.1 x 10-3

**(p-value) Reference Comments** 

et al. 2007)

al. 2007)

et al. 2008)

al. 2007) (Pollex et al. 2006)

et al. 2008)

Bayrak et al. 2007)

(Grassi et al. 2011)

**(definition)** 

NCEP ATP III

NCEP ATP III

AHA/NHLBI

\*Women only NCEP ATP III

AHA/NHLBI

NCEP ATP III

NCEP ATPIII

**Number Ethn. Sample** 

APOA5 -1131T→C J 1788 p< 0.0009 (Yamada

APOA5 c.56C→G C 3124 p=0.026 (Grallert et

APOA5 -3A→G J 2417 p< 0.0001 (Yamada

APOC3 -455T→C O-C 515 p=0.029\* (Miller et

LDLR 2052TmC J 2417 p=0.0005 (Yamada

LPL S447X Tu 1586 p=0.04 (Komurcu-

Program Adult Treatment Panel III, IDF=International Diabetes Federation;

**6. Genetic variants in dyslipidemia and MetSyn: Future directions** 

how the effects of variation in one gene are modified in the presence of other genes.

Aggregate effects of multiple variants in genes affecting dyslipidemia and MetSyn related traits have included calculation of 'risk scores', which simply add the number of 'risk alleles' in a weighted or unweighted manner. For example, unweighted risk scores were constructed by summing the number of 'TG-raising' alleles at 32 loci and placed in 'risk bins' (categories) to show that higher risk scores were significantly associated with patients with hypertriglyceridemia (HTG) compared to controls (Johansen and Hegele, 2011; Teslovich et al., 2010). Increasing genotype risk scores comprised by summing risk alleles in 9 common SNPs were associated with decreasing HDL-C levels (Kathiresan et al., 2008a).

Table 4. Genetic Polymorphisms in Lipid Metabolism Associated with MetSyn. See Table 1 legend. WHO= World Health Organization; NCEP ATP III=National Cholesterol Education

AHA=American Heart Association; NHLBI=National Heart, Lung, and Blood institute.

Given the polygenic nature and multi-level complexity of Dyslipidemia and MetSyn, a better understanding of the genetic determinants of each intermediate (lower level) phenotype as well as the collective integration of these traits as unifying syndromes (higher/hierarchical level) is needed, which will require more elegant statistical modeling methods and, perhaps, a paradigm shift in the way in which we think about dissecting genetic and environmental factors in complex traits. As stated throughout this chapter, there is considerable overlap between genetic variants associated with HDL-C, LDL-C and TG levels as well MetSyn as a unifying trait. As a result, there is great need to understand not only the aggregate effects of multiple variants in each of these genes but to also understand

LPL rs295 Va 1407 OR= 0.7;

**Gene Polymorphism rs** 

Angiopoietin-like 3 protein (ANGPTL3) inhibits LPL catalytic activity but this process is reversible (Shan et al., 2009; Shimizugawa et al., 2002). A monogenic autosomal recessive disorder called familial combined hypolipidemia (FCH: OMIM No. 605019), characterized by very low TG levels, is genetically complex and poorly understood; however, mutations in ANGPTL3 are believed to play a role. Common polymorphisms in ANGPTL3, most notably, rs2131925, have been associated with more modest changes in TG levels (Johansen and Hegele, 2011; Keebler et al., 2009; Lanktree et al., 2009; Teslovich et al., 2010; Willer et al., 2008). Sequencing individuals in the Dallas Heart Study has identified several additional nonsynonymous ANGPTL3 variants affecting TG levels (Musunuru et al., 2010); however, these SNPs require further investigation in other populations.
