**5. Genetic variants in dyslipidemia and the Metabolic Syndrome (MetSyn)**

As mentioned in the Introduction (see Section 1.0), MetSyn is a clustering of traits including dyslipidemia as well as obesity, hypertension and insulin resistance/dysglycemia. Undoubtedly, there is complex interplay between genetic determinants of each of these traits and 'environmental' factors including those related to lifestyle (diet, exercise, sleep) and those related to toxin exposure. Due to space limitations, we focus only on the genetic determinants of dyslipidemia that overlap with MetSyn defined as a single, unifying trait and refer the reader to other reviews for genetic determinants of the other traits involved in MetSyn (Joy et al., 2008; Monda et al., 2010; Pollex and Hegele, 2006; Sharma and McNeill, 2006) and their interactions with lifestyle factors (Adamo and Tesson, 2008; Garaulet et al., 2009; Ordovas and Shen, 2008; Phillips et al., 2008) and toxins (Andreassi, 2009).

Lipoprotein related genes with common SNPs associated with MetSyn (as defined by NCEP ATP III and AHA/NHLBI criteria) and HDL-C, LDL-C or TG levels include APOA5 and APOC3 (Table 4) (Grallert et al., 2007; Joy et al., 2008; Miller et al., 2007; Pollex et al., 2006; Pollex and Hegele, 2006; Yamada et al., 2008). Enzymes involved in lipid metabolism with genetic polymorphisms that have also been associated with MetSyn (using the NCEP ATPIII criteria) appear limited to the nonsynonymous SNP in LPL, rs328 (Table 4) (Joy et al., 2008;

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,

As mentioned above (see Section 2.1), LPL is an enzyme that hydrolyzes TG-rich particles in peripheral tissues (muscle, macrophages, adipose) generating FFA and glycerol for energy metabolism and storage (Goldberg, 1996). More than 100 mutations in LPL have been identified (Murthy et al., 1996); however, only a few common nonsynonymous SNPs have been consistently associated with TG levels including rs1801177, rs328 and rs268 (Mailly et al., 1995; Rip et al., 2006; Sagoo et al., 2008; Teslovich et al., 2010; Willer et al., 2008). Two SNPs, rs1801177 and rs328, have also been consistently associated with CHD; however, there is fairly strong LD between these SNPs, at least in Caucasians (Sagoo et al., 2008). MLX interacting protein like (MLXIPL) locus encodes a transcription factor of the Myc/Max/Mad superfamily which activates, in a glucose-dependent manner, carbohydrate response element binding protein (CREBP) that is expressed in lipogenic tissues coordinating the subsequent activation of lipogenic enzymes such as fatty acid synthase (FAS) to convert dietary carbohydrate to TG (Iizuka and Horikawa, 2008). The human MLXIPL gene is located on chromosome 7 (7q11.23). Although initially identified through GWAS, the rs1745738 polymorphism has been replicated in other studies (Johansen and

these SNPs require further investigation in other populations.

**4.2 Genetic variation in enzymes and transcription factors and TG levels** 

Hegele, 2011; Teslovich et al., 2010; Wang et al., 2008; Willer et al., 2008).

**5. Genetic variants in dyslipidemia and the Metabolic Syndrome (MetSyn)** 

2009; Ordovas and Shen, 2008; Phillips et al., 2008) and toxins (Andreassi, 2009).

As mentioned in the Introduction (see Section 1.0), MetSyn is a clustering of traits including dyslipidemia as well as obesity, hypertension and insulin resistance/dysglycemia. Undoubtedly, there is complex interplay between genetic determinants of each of these traits and 'environmental' factors including those related to lifestyle (diet, exercise, sleep) and those related to toxin exposure. Due to space limitations, we focus only on the genetic determinants of dyslipidemia that overlap with MetSyn defined as a single, unifying trait and refer the reader to other reviews for genetic determinants of the other traits involved in MetSyn (Joy et al., 2008; Monda et al., 2010; Pollex and Hegele, 2006; Sharma and McNeill, 2006) and their interactions with lifestyle factors (Adamo and Tesson, 2008; Garaulet et al.,

Lipoprotein related genes with common SNPs associated with MetSyn (as defined by NCEP ATP III and AHA/NHLBI criteria) and HDL-C, LDL-C or TG levels include APOA5 and APOC3 (Table 4) (Grallert et al., 2007; Joy et al., 2008; Miller et al., 2007; Pollex et al., 2006; Pollex and Hegele, 2006; Yamada et al., 2008). Enzymes involved in lipid metabolism with genetic polymorphisms that have also been associated with MetSyn (using the NCEP ATPIII criteria) appear limited to the nonsynonymous SNP in LPL, rs328 (Table 4) (Joy et al., 2008;


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).

Table 4. Genetic Polymorphisms in Lipid Metabolism Associated with MetSyn. See Table 1 legend. WHO= World Health Organization; NCEP ATP III=National Cholesterol Education Program Adult Treatment Panel III, IDF=International Diabetes Federation; AHA=American Heart Association; NHLBI=National Heart, Lung, and Blood institute.
