Dyslipidemia: Genetics and Role in the Metabolic Syndrome

Dyslipidemia is characterized by an aggregation of lipoprotein abnormalities including low high density lipoprotein cholesterol (HDL-C), high serum triglycerides (TG) and increased small low density lipoprotein cholesterol (LDL-C). Lipoproteins, which contain lipids and proteins (apolipoproteins, APO) are responsible, primarily, for transporting water insoluble lipids (cholesterol, TG) in plasma from the intestines and liver, where they are absorbed and synthesized, respectively, to peripheral tissues (muscle, adipose) for utilization, processing and/or storage (Kwan et al., 2007). There are several subtypes of lipoproteins with specific functions including, from smallest to largest: 1) chylomicrons, which transport dietary TG from the intestines to the peripheral tissue and liver; 2) very LDL (VLDL) particles, which transport TG from the liver to peripheral tissues; 3) intermediate density lipoproteins (IDL), which are produced from VLDL particle metabolism and may be taken up by the liver or further hydrolyzed to LDL; and, 4) HDL, which is key in ‘reverse cholesterol transport’ or shuttling cholesterol from peripheral cells to the liver (Kwan et al., 2007). The Metabolic Syndrome (MetSyn) is a clustering of traits including dyslipidemia as well as hypertension (raised systolic and/or diastolic blood pressure), dysglycemia (high fasting glucose) and obesity (high body mass index (BMI) and/or waist circumference). Dyslipidemia is formally defined within the context of MetSyn. Various diagnostic definitions have been proposed for MetSyn by several organizations including the World Health Organization (WHO) (Alberti and Zimmet, 1998), European Group Insulin Resistance (EGIR) (Balkau and Charles, 1999), National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III, (2001), International Diabetes Federation (IDF, (Alberti et al., 2005), American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) (Grundy et al., 2006) and, with the most recent joint interim statement proposed by the AHA/NHLBI, IDF and other organizations (Alberti et al., 2009). Although the recommendations differ widely on the obesity component, the dyslipidemia component has been fairly consistently defined as having TG ≥ 150 mg/l, HDL-C 2.0 mmol/l (177 mg/dl). There is currently no recommended value for


Introduction
Dyslipidemia is characterized by an aggregation of lipoprotein abnormalities including low high density lipoprotein cholesterol (HDL-C), high serum triglycerides (TG) and increased small low density lipoprotein cholesterol (LDL-C).Lipoproteins, which contain lipids and proteins (apolipoproteins, APO) are responsible, primarily, for transporting water insoluble lipids (cholesterol, TG) in plasma from the intestines and liver, where they are absorbed and synthesized, respectively, to peripheral tissues (muscle, adipose) for utilization, processing and/or storage (Kwan et al., 2007).There are several subtypes of lipoproteins with specific functions including, from smallest to largest: 1) chylomicrons, which transport dietary TG from the intestines to the peripheral tissue and liver; 2) very LDL (VLDL) particles, which transport TG from the liver to peripheral tissues; 3) intermediate density lipoproteins (IDL), which are produced from VLDL particle metabolism and may be taken up by the liver or further hydrolyzed to LDL; and, 4) HDL, which is key in 'reverse cholesterol transport' or shuttling cholesterol from peripheral cells to the liver (Kwan et al., 2007).The Metabolic Syndrome (MetSyn) is a clustering of traits including dyslipidemia as well as hypertension (raised systolic and/or diastolic blood pressure), dysglycemia (high fasting glucose) and obesity (high body mass index (BMI) and/or waist circumference).Dyslipidemia is formally defined within the context of MetSyn.Various diagnostic definitions have been proposed for MetSyn by several organizations including the World Health Organization (WHO) (Alberti and Zimmet, 1998), European Group Insulin Resistance (EGIR) (Balkau andCharles, 1999), National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III, (2001), International Diabetes Federation (IDF, (Alberti et al., 2005), American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) (Grundy et al., 2006) and, with the most recent joint interim statement proposed by the AHA/NHLBI, IDF and other organizations (Alberti et al., 2009).Although the recommendations differ widely on the obesity component, the dyslipidemia component has been fairly consistently defined as having TG ≥ 150 mg/l, HDL-C <40 mg/dL (1.03 mmol/l, in males) or <50 mg/dL (1.29 mmol/l in females) or drug treatment for elevated TG or low HDL-C (NCEP ATP III: (2001), IDF: (Alberti et al., 2005), Joint Statement: (Alberti et al., 2009)).However, the WHO (Alberti and Zimmet, 1998) proposed slightly lower limits for HDL-C (male: < 0.9 mmol/l (35 mg/dl); female: < 1.0 mmol/l (39 mg/dl)) and the EGIR (Balkau and Charles, 1999) recommended dyslipidemia be defined by HDL-C < 1.0 mmol/l (39 mg/dl) or TG > 2.0 mmol/l (177 mg/dl).There is currently no recommended value for Heritability estimates suggest there is a strong genetic component to dyslipidemia and MetSyn.Heritability estimates for dyslipidemia range from 0.20 to 0.60 (Edwards et al., 1997;Goode et al., 2007;Herbeth et al., 2010;Kronenberg et al., 2002;Wang and Paigen, 2005) and from 0.24 to 0.63 for MetSyn (Lin et al., 2005;Sung et al., 2009).Multiple genetic variants in the form of single nucleotide polymorphisms (SNPs) (i.e., single DNA base changes) have been associated with manifestation of dyslipidemia and MetSyn.In this chapter, we review and summarize associations between common SNPs (i.e., those with a minor allele frequency (MAF) ≥0.05) in the most biologically plausible candidate genes and HDL-C, LDL-C and TG levels as well as MetSyn as a single, unifying trait.Previous estimates suggest all common variants together explain less than 10 percent of HDL-C levels in the general population (Kronenberg et al., 2002); however, more elegant statistical modeling methods that combine SNPs in a more biologically meaningful way may be needed to better understand the collective role of genetic variants in manifestation of dyslipidemia, MetSyn and other complex metabolic traits.As a result, at the end of this chapter, we review studies that have undertaken more complex modeling strategies to understand the aggregate effects of SNPs in manifestation of dyslipidemia and MetSyn and provide our insights for future directions in this field.

Genetic variants in lipid metabolism and HDL-C levels
As mentioned above, HDL-C is important for "reverse cholesterol transport" or the shuttling of cholesterol from peripheral cells to the liver.Many of the genetic variants associated with HDL-C levels have been summarized nicely in a recent comprehensive review by Boes et al. (Boes et al., 2009).In Table 1, we include common SNPs tabulated in Boes et al. (2009) review of large studies (ethnic group sample sizes ≥500) as well as common SNPs in large studies that have been identified since their review.

Genetic variation in enzymes involved in lipid metabolism and HDL-C levels
Perhaps, the most notable gene in the HDL-C synthesis and metabolism pathways, whose variants have been consistently associated with HDL-C, is the cholesterol ester transfer protein (CETP), which is a key plasma protein that mediates the transfer of esterfied cholesterol from HDL to APOB containing particles in exchange for TG.Although complete loss of CETP function is rare and can yield HDL-C levels up to five times higher than normal (Klos and Kullo, 2007), three common polymorphisms (Table 1: TaqIB (rs708272); -629C>A (rs1800775); Ile405Val (rs5882)) can all modestly inhibit CETP activity and have been consistently associated with higher HDL-C levels (Bernstein et al., 2003;Blankenberg et al., 2004;Boekholdt et al., 2005;Boekholdt and Thompson, 2003;Borggreve et al., 2005;Eiriksdottir et al., 2001;Freeman et al., 2003;Kathiresan et al., 2008a;Klerkx et al., 2003;Tai et al., 2003b;Thompson et al., 2008).The CETP gene is located on chromosome 16 (16q21).

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).

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 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).

Genetic variants in lipid metabolism and LDL-C levels
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).

Genetic variation in proteases and LDL-C levels
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 and LDL-C Levels
GWAS 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 Section 4.2 (Teslovich et al., 2010).

Genetic variants in lipid metabolism and TG levels
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, genetic heterogeneity between loci clearly exists between major ethnic groups.

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) 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.

Genetic variation in enzymes and transcription factors and TG levels
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 Hegele, 2011;Teslovich et al., 2010;Wang et al., 2008;Willer et al., 2008).

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;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).

Genetic variants in dyslipidemia and MetSyn: Future directions
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 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).
We have used the multivariate statistical framework of structural equation modeling (SEM) to evaluate multiple genetic determinants of MetSyn and aggregate effects of individual genes by modeling MetSyn as a second-order factor together with multiple putative candidate genes represented by latent constructs, which we mathematically defined by multiple SNPs in each gene (Nock et al., 2009b).Using this approach with the Framingham Heart Study (Offspring Cohort, Exam 7; Affymetrix 50k Human Gene Panel) data, we found that the CETP gene had a very strong association with the Dyslipidemia factor but little effect on MetSyn directly.Furthermore, we found that the effects of the CSMD1 gene diminished when modeled simultaneously with six other candidate genes, most notably CETP and STARD13.Work to identify the genetic determinants of 'Syndrome Z', modeled as a higher-order, unifying syndrome defined by 5 first-order factors (dyslipidemia, insulin resistance, obesity, hypertension, sleep disturbance) (Nock et al., 2009a) using the latent gene construct SEM approach is underway.The use of other forms of 'causal modeling' (edge/node; integrative genetics) has been proposed (Lusis et al., 2008), particularly, to improve our understanding of differential effects by gender as well as to better understand how maternal nutrition and epigenetics affect MetSyn.Furthermore, a complex model for the genetic determinants of MetSyn associated phenotypes was recently proposed and, using gene enrichment analysis and protein-protein interaction network approaches, the retinoid X receptor and farnesoid X receptor (FXR) were identified as key players in MetSyn given their multiple interactions with metabolism, cell proliferation and oxidative stress (Sookoian and Pirola, 2011).However, more elegant kinetic models may be required to understand the true influence of genetic variants on Dsylipidemia and MetSyn given the presence of multiple feedback loops and reversible reactions (Bakker et al., 2010;Gutierrez-Cirlos et al., 2011).

Acknowledgement
This work was supported, in part, by the National Institutes of Health/National Cancer Institute Grant [K07CA129162] awarded to NLN.

Table 2 .
Genetic Polymorphisms Associated with LDL-C.See Table 1 legend.

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

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.