**1. Introduction**

92 Dyslipidemia - From Prevention to Treatment

Watala C, Boncer M, Golanski J, Koziolkiewcz W, Trojanowski Z, Walkowiak B: Platelet

*Eur J Haematol* Vol.61, No.5, (November 1998), pp. 319–326, ISSN 1600-0609 Winocour, P.D., Watala, C. & Kinlough-Rathbone, R.L. (1992). Reduced membrane fluidity

*Med* Vol.120, No.6, (December 1992), pp. 921-928, ISSN 1532-6543

membrane lipid fluidity and intraplatelet calcium mobilization in type 2 diabetes.

and increased glycation of membrane proteins of platelets from diabetic subjects are not associated with increased platelet adherence to glycated collagen. *J Lab Clin* 

> 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 <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

Dyslipidemia: Genetics and Role in the Metabolic Syndrome 95

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,

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

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

**Size** 

(GP)

(GP) 735 (HBP)

(GP )

(GP)

(GP)

(GP)

**Results (Effect Size, p-value)** 

+1.9/+2.7 mg/dl (1/2copies); p=0.03 +1.9 /+5.0 mg/dl (1/2 copies); p=0.03

+0.7/+1.9 mg/dl (1/2 copies); p<0.02



**Reference** 

2004b)

(Shioji et al. 2004b)

(Hodoglugil et al. 2005)

(Porchay et al. 2006)

(Kathiresan et al. 2008)

2004b)

p=0.0455 (Shioji et al.

p=0.006 (Shioji et al.

2005) and from 0.24 to 0.63 for MetSyn (Lin et al., 2005; Sung et al., 2009).

provide our insights for future directions in this field.

**2. Genetic variants in lipid metabolism and HDL-C levels** 

SNPs in large studies that have been identified since their review.

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

ABCA1 C (-297)T rs2246298 0.25 (T) A 1625

ABCA1 G (-273)C rs1800976 0.40 (C) A 1626

ABCA1 G (-273)C rs1800976 0.38 (T) Tu 2332

ABCA1 G378C rs1800978 0.13 (C) W 5040

ABCA1 rs3890182 0.13 (A) W 5287

ABCA1 rs2275542 A <1880

LDL-C levels in the context of MetSyn yet LDL-C remains the primary target of therapy for the management of high blood cholesterol per the most recent guidelines from the NCEP ATPIII, which recommended drug therapy for LDL-C values ranging from ≥100 mg/dl to ≥190 mg/dl depending on the presence/absence of other coronary heart disease (CHD) risk factors (Grundy et al., 2004). When LDL becomes lipid depleted, small dense LDL (sdLDL) particles are formed, which have a lower affinity for the LDL receptor (LDLR), more susceptibility to oxidation and a higher affinity for macrophages; and, thus, sdLDL particles contribute to the atherosclerotic process (Austin et al., 1990; Littlewood and Bennett, 2003) and likely MetSyn (Kruit et al., 2010).

Dyslipidemia and MetSyn are common in developed nations and the prevalence of both are rising worldwide, which may be attributed, in part, to the rising rates of overweight and obesity (Alberti et al., 2009; Halpern et al., 2010). According to the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) in the United States (U.S.), which used the NCEP ATP III criteria, the age-adjusted prevalence of dyslipidemia defined by high TG or low HDL-C, was approximately 30.0% and 37.1%, respectively; and, the prevalence of MetSyn was approximately 23.7% (Ford et al., 2002). The prevalence of dyslipidemia and MetSyn generally increase with increasing age (Ford et al., 2002). However, in a more recent study that used the Health Survey for England (HSE) (2003-2006) survey data and NHANES (1999-2006) data with exclusion of persons over 80 years old, the prevalence of low HDL-C (defined in both males and females as <40 mg/dL) was 10.0% in England and 19.2% in the U.S. (Martinson et al., 2010). Thus, the prevalence can vary markedly depending on how these traits are defined (Cook et al., 2008). Interestingly, trends in the U.S. and England indicate during the past two decades an increase in the proportion of individuals diagnosed with high cholesterol (≥240 mg/dL) but who achieved therapeutic control (Roth et al., 2010). For example, in the U.S. in 2006, 54.0% of men (95% CI: 47.6–60.4) and 49.7% of women (95% CI: 44.3–55.0) with high total serum cholesterol were on cholesterol-lowering medication, as opposed to 10.8% of men (95% CI: 8.0–13.6) and 8.6% (95% CI: 6.7–10.6) of women in 1993 (Roth et al., 2010). In England, in 2006, 35.5% of men (95% CI: 32.8–38.3) and 25.7% of women (95% CI: 23.4–28.1) were on cholesterol-lowering medication as opposed to 0.6% of men (95% CI: 0.3–1.3) and 0.4% of women (95% CI: 0.1–0.7%) in 1993 (Roth et al., 2010). Thus, prevalence rates will also vary by whether or not relevant drug treatments have been considered and, perhaps, the list of relevant drugs should include cholesterol lowering therapies (e.g., statins) as well as other drugs (e.g., tamoxifen, glucocorticoids) known to alter TG and cholesterol levels (Garg and Simha, 2007).

Both dyslipidemia and MetSyn increase the risk of Type II diabetes mellitus (T2DM) (Adiels et al., 2006; Kruit et al., 2010) and cardiovascular disease (CVD) morbidity (Alberti et al., 2009; Linsel-Nitschke and Tall, 2005) and CVD mortality (Lewington et al., 2007). Patients with MetSyn have a five-fold increase in the risk of developing T2DM and are at twice the risk of developing CVD over the next 5 to 10 years compared to individuals without the syndrome (Alberti et al., 2009). In the presence of both MetSyn and T2DM, the prevalence of CVD is markedly increased with an odds ratio (OR) of 3.04 [95% confidence interval (CI) of OR: 1.98-4.11] in comparison to those with none of these conditions (Athyros et al., 2004). The importance of MetSyn is exemplified by its ICD-9 code (277.7), which was initially established as a diagnosis of "Dysmetabolic Syndrome X" (Einhorn et al., 2003; Kahn et al., 2005). In summary, both dyslipidemia and MetSyn are substantial public health problems, which require a better understanding of their respective etiologies to develop more effective lifestyle and therapeutic interventions.

LDL-C levels in the context of MetSyn yet LDL-C remains the primary target of therapy for the management of high blood cholesterol per the most recent guidelines from the NCEP ATPIII, which recommended drug therapy for LDL-C values ranging from ≥100 mg/dl to ≥190 mg/dl depending on the presence/absence of other coronary heart disease (CHD) risk factors (Grundy et al., 2004). When LDL becomes lipid depleted, small dense LDL (sdLDL) particles are formed, which have a lower affinity for the LDL receptor (LDLR), more susceptibility to oxidation and a higher affinity for macrophages; and, thus, sdLDL particles contribute to the atherosclerotic process (Austin et al., 1990; Littlewood and Bennett, 2003)

Dyslipidemia and MetSyn are common in developed nations and the prevalence of both are rising worldwide, which may be attributed, in part, to the rising rates of overweight and obesity (Alberti et al., 2009; Halpern et al., 2010). According to the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) in the United States (U.S.), which used the NCEP ATP III criteria, the age-adjusted prevalence of dyslipidemia defined by high TG or low HDL-C, was approximately 30.0% and 37.1%, respectively; and, the prevalence of MetSyn was approximately 23.7% (Ford et al., 2002). The prevalence of dyslipidemia and MetSyn generally increase with increasing age (Ford et al., 2002). However, in a more recent study that used the Health Survey for England (HSE) (2003-2006) survey data and NHANES (1999-2006) data with exclusion of persons over 80 years old, the prevalence of low HDL-C (defined in both males and females as <40 mg/dL) was 10.0% in England and 19.2% in the U.S. (Martinson et al., 2010). Thus, the prevalence can vary markedly depending on how these traits are defined (Cook et al., 2008). Interestingly, trends in the U.S. and England indicate during the past two decades an increase in the proportion of individuals diagnosed with high cholesterol (≥240 mg/dL) but who achieved therapeutic control (Roth et al., 2010). For example, in the U.S. in 2006, 54.0% of men (95% CI: 47.6–60.4) and 49.7% of women (95% CI: 44.3–55.0) with high total serum cholesterol were on cholesterol-lowering medication, as opposed to 10.8% of men (95% CI: 8.0–13.6) and 8.6% (95% CI: 6.7–10.6) of women in 1993 (Roth et al., 2010). In England, in 2006, 35.5% of men (95% CI: 32.8–38.3) and 25.7% of women (95% CI: 23.4–28.1) were on cholesterol-lowering medication as opposed to 0.6% of men (95% CI: 0.3–1.3) and 0.4% of women (95% CI: 0.1–0.7%) in 1993 (Roth et al., 2010). Thus, prevalence rates will also vary by whether or not relevant drug treatments have been considered and, perhaps, the list of relevant drugs should include cholesterol lowering therapies (e.g., statins) as well as other drugs (e.g., tamoxifen, glucocorticoids) known to alter

Both dyslipidemia and MetSyn increase the risk of Type II diabetes mellitus (T2DM) (Adiels et al., 2006; Kruit et al., 2010) and cardiovascular disease (CVD) morbidity (Alberti et al., 2009; Linsel-Nitschke and Tall, 2005) and CVD mortality (Lewington et al., 2007). Patients with MetSyn have a five-fold increase in the risk of developing T2DM and are at twice the risk of developing CVD over the next 5 to 10 years compared to individuals without the syndrome (Alberti et al., 2009). In the presence of both MetSyn and T2DM, the prevalence of CVD is markedly increased with an odds ratio (OR) of 3.04 [95% confidence interval (CI) of OR: 1.98-4.11] in comparison to those with none of these conditions (Athyros et al., 2004). The importance of MetSyn is exemplified by its ICD-9 code (277.7), which was initially established as a diagnosis of "Dysmetabolic Syndrome X" (Einhorn et al., 2003; Kahn et al., 2005). In summary, both dyslipidemia and MetSyn are substantial public health problems, which require a better understanding of their respective etiologies to develop more effective

and likely MetSyn (Kruit et al., 2010).

TG and cholesterol levels (Garg and Simha, 2007).

lifestyle and therapeutic interventions.

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.
