**2. Ethnicity and hypercholesterolemia**

**1. Introduction**

132 Cholesterol Lowering Therapies and Drugs

Cholesterol is a sterol that presents one of the three major classes of lipids synthesized and utilized by animal cells to construct their cell membranes. It also serves as a precursor of the steroid hormones, bile acids and vitamin D, and is transported in the blood plasma within lipoproteins.These lipoproteins are classified according to theirdensity as (a) very‐low‐density lipoproteins(VLDLs),(b)low‐densitylipoproteins(LDLs),(c)intermediate‐densitylipoproteins (IDLs) and (d) high‐density lipoproteins (HDLs) [1]. Hypercholesterolemia (also often referred to as dyslipidemia) describes a condition characterized by elevated lipid (hyperlipidemia) or lipoprotein levels (hyperlipoproteinemia) (>240 mg/dL) in circulation [2]. Such elevated levels of lipoproteins, other than HDL (also called non‐HDL‐cholesterol), particularly the LDL‐ cholesterol,areassociatedwithanincreasedriskofcoronaryarterydisease(CAD)[3].Incontrast, increased HDL‐cholesterol levels are deemed protective [4]. An elevation in circulating non‐ HDL‐ and LDL‐cholesterol may be triggered by diet, obesity, genetic disorders or presence of other diseases, such as diabetes and dysfunctional thyroid [2, 5]. Hyperlipidemia is one of the most important players in developing cardiovascular disease leading to high mortality [6, 7]. Hence,managementofhyperlipidemianotonlymaintainshealthylipoproteinlevels,butis also

designed to avert the more deleterious consequences of CAD manifestation.

Hyperlipidemia affects humans globally with a prevalence of approximate 34 million in the USA. It occurs partly as an inheritable monogenic (Mendelian) disease, specifically the familial form, which affects 1 in 500 individuals globally, but more frequently so, as a result of an interaction of genetic changes with environmental factors, that may or may not be modifiable. Inheritable forms include the familial types, such as homozygous familial hypercholesterole‐ mia (HOFH) or familial hyperbetalipoproteinemia (FHBL), a disorder that impairs the body's capability to absorb and transport fats. This form of the disease is characterized by early signs of cholesterol infiltrates with premature CAD, accompanied by a building up of excess cholesterol in other tissues such as the skin, tendons and coronary arteries. This, in turn, is also accompanied by growths defined as tendon xanthomas, known to affect the Achilles tendons as well as tendons in hands and fingers [8]. Other forms of cholesterol deposits also exist, such as xanthelasmata under the eyelid skin and cornealis, accumulating at the edge of the clear front surface of the cornea. The complex form of hypercholesterolemia is triggered by some interplay between genetic variants with modifiable risk factors, such as lifestyle or diet and/or unmodifiable variables, such as age, ethnicity, gender and family history. Some of the modifiable predisposing factors such as diet, overweight and obesity are controllable by adopting a healthy eating plan, staying active and managing personal weight scale. However, patients with very high cholesterol levels, such as in familial hypercholesterolemia (FH), diet alone is often not adequate to achieve the desired lipid lowering effect, necessitating the use of lipid lowering medication to reduce its production and absorption [9], as well as other therapies including LDL apheresis or surgery. Several drug families are employed targeting different components of cholesterol metabolism. The success of treatment may vary in different communities, depending on a number of contributing factors, particularly ethnicity. Impor‐ tantly, while the influence of the unmodifiable risk traits is likely to be felt alike across ethnicities, their actual impact on disease will often be defined by the extent to which genetic

Blood lipid levels are highly heritable traits. Essentially, hypercholesterolemia occurs as a result of the low‐density lipoprotein receptor (LDLR) being unable to remove cholesterol effectively from circulation. This can be caused by mutations in one or more genes that regulate cholesterol metabolism and transportation. The greatest contribution to the manifestation of hypercho‐ lesterolemia and difficulties related to maintaining health circulating cholesterol levels are genetic changes in components of these pathways. While only a handful of Mendelian disease genes and founder mutations for the autosomal recessive form of the disease have been identified to date, there are many other genes that contribute to the complex form of the disease. Thus, whereas the Mendelian form is likely to exert the same impact globally, the manifestation of the complex trait will more often than not depend on the nature of the interactions between the predisposing genes and environmental factors, which may vary among various ethnicities. This, in turn, has a great impact on disease manifestation in a given society.

#### **2.1. Ethnicity, race ancestry and disease**

Ethnicity and race have traditionally been related to biological and sociological factors, respectively. Accordingly, race presumes shared biological or genetic traits and is distinguish‐ able by the traits resulting from a shared genealogy due to geographical demarcations, while ethnicity connotes shared cultural traits and history, and possibly linguistic or religious traits. In terms of genetic undertones, therefore, individuals of the same racial background (ancestry) are likely to carry more common genetic architecture than those belonging to the same ethnicity. Hence, the impact of these two societal confounders on dyslipidemia manifestation may not always be the same. Besides, in multi‐cultural societies, such as in the USA or Southern Africa, many (ethnic) admixture groups have arisen in the course of time, from different ancestral lineage, and are often placed into the one or the other ethnical group. This adds some complexity to the estimation of the depth of genetic adulteration in racial genetic texture, rendering the ancestral delineation more complex. Accordingly, the impact of intra‐ethnical variations on disease might be over‐ or underestimated within a given community. Most importantly, the influence of ethnicity on the disease manifestation or therapeutic outcome is also often regulated by modifiable confounders as well as the depth of public awareness within a given society. Hence, the accuracy in the estimation of the depth of the influence of ethnicity on dyslipidemia and therapy thereof may depend on the constituent racial component of the given society.

#### **2.2. Ethnicity and genetics of hypercholesterolemia**

Genetically, hypercholesterolemia may occur in various forms depending on the type and genomic location of the causative mutation. This may directly be caused by a structural change in a gene involved in the transportation of the lipids. Thus, the monogenic (Mendelian) form, often manifest as familial hypercholesterolemia (FH), is triggered by changes in a single gene. To date, the monogenic form has been linked primarily to mutations in three genes, the LDLR [10–15], proprotein convertase sublitisin/kexin type 9 (PCSK9) [16–23] and apolipoprotein B (APOB) genes [24–28]. In most cases, individuals with FH will have inherited one or both altered copies of the gene from affected parents. In this case, the disease can be acquired in an autosomal recessive (presence of two copies of the mutated gene from both parents) such as the autosomal recessive hypercholesterolemia (ARH), or in a dominant (presence of only one copy of the mutated gene from either parent) form such as HOFH or heterozygous familial disease (HEFH). The recessive type tends to lead to the more severe form of the disease, which often appears in childhood. The HEFH is a very rare form of FH, affecting a small but noticeable percentage of individuals, yet constituting an important cause of early onset of CAD. The disease results from either biallelic pathogenic variants in one of the three genes or one pathogenic variant in each of two different genes. It is thought to account for 60–80% of FH.

However, the most common forms of hyperlipidemia are complex in nature, resulting primarily from an interaction between genetic changes and environmental factors [29]. Thus, apart from the three genes, *LDLR*, *APOB* and *PCSK9*, known to cause the monogenic disease, several others are also involved in the manifestation of the disease. The genes include the peroxisome proliferator‐activated receptor‐alpha (*PPAR-α*), cholesteryl ester transport protein (*CETP*), low‐density lipoprotein receptor adaptor protein 1 (*LDLRAP1*), apolipopro‐ tein (APO) A1 (APOA1), A4 and A5 complex (*APOA1/A4/A5*) and apolipoprotein E (*APOE*), 3‐hyroxy‐3‐methylglutaryl coenzyme A reductase (HMGR), lecithin cholesterolacyltransfer‐ ase (LCAT) and lipoprotein lipase (LPL), just to name a few. The genes associated with the different forms of dyslipidemia are summarized in **Table 1**.

Among the genes associated with dyslipidemia to date, the *LDLR* is understandably the most well defined. This gene encodes the LDLR protein which binds to low‐density lipoproteins (LDLs) particles, the primary carriers of cholesterol in the blood. This receptor resides on the outer surface of many cell types, particularly in the liver, where it picks up circulating LDL particles and transports them into the cell. Within the cell, the receptor is broken down in order to release cholesterol for utilization by the cell, storage or removal from the body. The LDLR is essential in regulating the amount of circulating cholesterol, whereby the speed at which the later gets eliminated from the system depends on the receptor expression. Hence, alteration in the structure of these receptors will lead to fundamental changes in the regulation of circulating cholesterol levels. Such mutations in the *LDLR* gene are thought to be the primary cause for FH, with a greater frequency in a population with founder mutations. Several such hyperlipidemia‐related variants have been identified thus far in this gene [10–15]. These mutations have different effects on the function of the protein. For example, some of them do so by reducing the number of LDLRs produced within the cells, while others disrupt the ability of the receptors to remove the LDLs from circulation. As a result, individuals harbouring *LDLR* mutations will have very high circulating cholesterol levels, ultimately leading to the familial form of the disease. Some of these mutations have been implicated in both the autosomal recessive (ARH) and dominant (ADH) forms of hypercholesterolemia, whereby in some ethnic populations, the ADH has been shown to exhibit allelic heterogeneity [11, 30]. Thus, genetic diversity has been described in FH [30, 31], pointing to the likelihood of differences in the extent to which these mutations may cause disease in different populations. This may be ascribable to differences in life style. It has also been suggested that the *LDLR* gene has a sexspecific pleiotropic effect, as is indicated by changes in the relationship between traits [32]. This suggests in turn that environmental factors, such as diet or even migration, may play a significant role in modulating the phenotype of heterozygous FH.

**2.2. Ethnicity and genetics of hypercholesterolemia**

134 Cholesterol Lowering Therapies and Drugs

different forms of dyslipidemia are summarized in **Table 1**.

Genetically, hypercholesterolemia may occur in various forms depending on the type and genomic location of the causative mutation. This may directly be caused by a structural change in a gene involved in the transportation of the lipids. Thus, the monogenic (Mendelian) form, often manifest as familial hypercholesterolemia (FH), is triggered by changes in a single gene. To date, the monogenic form has been linked primarily to mutations in three genes, the LDLR [10–15], proprotein convertase sublitisin/kexin type 9 (PCSK9) [16–23] and apolipoprotein B (APOB) genes [24–28]. In most cases, individuals with FH will have inherited one or both altered copies of the gene from affected parents. In this case, the disease can be acquired in an autosomal recessive (presence of two copies of the mutated gene from both parents) such as the autosomal recessive hypercholesterolemia (ARH), or in a dominant (presence of only one copy of the mutated gene from either parent) form such as HOFH or heterozygous familial disease (HEFH). The recessive type tends to lead to the more severe form of the disease, which often appears in childhood. The HEFH is a very rare form of FH, affecting a small but noticeable percentage of individuals, yet constituting an important cause of early onset of CAD. The disease results from either biallelic pathogenic variants in one of the three genes or one pathogenic variant in each of two different genes. It is thought to account for 60–80% of FH.

However, the most common forms of hyperlipidemia are complex in nature, resulting primarily from an interaction between genetic changes and environmental factors [29]. Thus, apart from the three genes, *LDLR*, *APOB* and *PCSK9*, known to cause the monogenic disease, several others are also involved in the manifestation of the disease. The genes include the peroxisome proliferator‐activated receptor‐alpha (*PPAR-α*), cholesteryl ester transport protein (*CETP*), low‐density lipoprotein receptor adaptor protein 1 (*LDLRAP1*), apolipopro‐ tein (APO) A1 (APOA1), A4 and A5 complex (*APOA1/A4/A5*) and apolipoprotein E (*APOE*), 3‐hyroxy‐3‐methylglutaryl coenzyme A reductase (HMGR), lecithin cholesterolacyltransfer‐ ase (LCAT) and lipoprotein lipase (LPL), just to name a few. The genes associated with the

Among the genes associated with dyslipidemia to date, the *LDLR* is understandably the most well defined. This gene encodes the LDLR protein which binds to low‐density lipoproteins (LDLs) particles, the primary carriers of cholesterol in the blood. This receptor resides on the outer surface of many cell types, particularly in the liver, where it picks up circulating LDL particles and transports them into the cell. Within the cell, the receptor is broken down in order to release cholesterol for utilization by the cell, storage or removal from the body. The LDLR is essential in regulating the amount of circulating cholesterol, whereby the speed at which the later gets eliminated from the system depends on the receptor expression. Hence, alteration in the structure of these receptors will lead to fundamental changes in the regulation of circulating cholesterol levels. Such mutations in the *LDLR* gene are thought to be the primary cause for FH, with a greater frequency in a population with founder mutations. Several such hyperlipidemia‐related variants have been identified thus far in this gene [10–15]. These mutations have different effects on the function of the protein. For example, some of them do so by reducing the number of LDLRs produced within the cells, while others disrupt the ability of the receptors to remove the LDLs from circulation. As a result, individuals harbouring *LDLR*


ADH, autosomal dominant hypercholesterolemia; ApoB, apolipoprotein B; APOER, apolipoprotein receptor; CETP, cholesteryl ester transport protein; FDB, familial defective apoB-100; Chol, cholesterol; Chr; chromosomal position; FH, familial hypercholesterolemia; FHBL, familial hyperbetalipoproteinemia; HALP, hypoalphalipoproteinemia; HBLP, hypobetalipoproteinemia; HDLC, high-density lipoprotein-cholesterol; HMG-CoA; 3-hyroxy-3-methylglutaryl coenzyme A reductase; HLP, hyperlipoproteinemia; hTG, hypertriglyceridemia; LCAT, lecithin cholesterol acyltransferase; LDLR, low-density lipoprotein receptor; LDLRAP1, low-density lipoprotein receptor adaptor protein 1; LPL, lipoprotein; PCSK9, proprotein convertase sublitisin/kexin type 9; PPAR-α, peroxisome proliferator-activated receptor-alpha; VLDL, very-low-density lipoprotein.

**Table 1.** Gene polymorphisms currently known to contribute to hypercholesterolemia.

One other important gene involved in HL is that encoding the apolipoprotein B (apoB) proteins. This gene encodes two versions of the protein: a shorter version (apoB‐48) and a longer version (apoB‐100). Both isoforms are involved in transporting fat‐like particles, including cholesterol, in the blood. They are synthesized primarily in two organs, whereby the apoB‐48 is produced in the intestines, while the apoB‐100 is synthesized primarily in the liver. The former functions as a component of the chylomicron lipoproteins and is important for the absorption of certain fat‐soluble vitamins, such as the vitamins A and E. The apoB‐100, on the other hand, constitutes a component of other forms of lipoproteins, specifically the VLDLs, IDLs and LDLs, all of which are involved in the transportation of fats and cholesterol in the blood. Accordingly, apoB facilitates the LDL binding to their receptors in the liver cell surface. This in turn enables the transportation of these lipoproteins into the cell, where they are broken down to facilitate the release of cholesterol. Thus, mutations in the *APOB* gene can cause familial hyperbetalipoproteinemia (FHBL) or hypercholesterolemia by triggering the produc‐ tion of abnormally short forms of the protein, and therefore a reduction or lack of dietary fat and cholesterol transportation and ultimately the body's ability to absorb fats and fat‐soluble vitamins from the diet. The severity of the disease depends on the length of the abnormal protein. Accordingly, a resultant protein that is longer than the apoB‐48 will not hamper its production; hence, it should still be capable of forming chylomicrons. On the other hand, a similar product of the apoB‐100 in the liver will not be able to produce LPLs efficiently. Hence, protein products that are shorter than the apoB are associated with more severe symptoms than in cases where some normal apoB‐48 is produced. *APOB* mutations may also trigger the familial ligand‐defective apoB‐100 (FDB) [27] and ADH conditions [26]. These states are characterized by the presence of very high circulating cholesterol levels and therefore increased risk of disease. The impact of genetic changes in *APOB* on hypercholesterolemia is, however, less described than that of the *LDLR* gene. Besides, there has been some inconsistences in reports on the impact of some of these mutations in different populations [10], pointing to its variation by ethnicity [33, 34].

The proprotein convertase sublitisin/kexin type 9 (PCSK9) functions by enhancing the regulation of circulating cholesterol levels, thereby possibly controlling the number of LDLRs on the cell surface. It probably acts by breaking down the LDLRs before they reach the cell surface. A few hypercholesterolemia‐related mutations have been reported in the PCSK9 to date [16, 35], and have been linked mainly to ADH [20–23]. Accordingly, the mutations responsible for the disease are termed 'gain‐of‐function' mutations as they enhance the protein activity or lead to the protein acquiring new atypical functions. Serum lipoprotein Lp(a) is thought to be elevated in FH as a result of such PCSK9 gain‐of‐function mutations [18, 19], for example. The overactive protein significantly reduces the number of LDLRs on the surface of the liver cells, possibly by triggering faster breakage of the LDLRs. Thus, the attenuated production of the receptors leads to more cholesterol accumulation, and therefore the possi‐ bility of the disease occurring. Other mutations in the gene defined as 'loss‐of‐function' mutations reduce blood cholesterol levels (hypocholesterolemia) by decreasing the PSCK9 activity or reducing its amount in the cell. These mutations lead to an increase in the number of LDLRs on the surface of liver cells. Harbouring of such mutation has been linked to a significantly lower than average risk of developing heart disease. Furthermore, elevated PCSK9 levels are thought to be detrimental for patients carrying either non‐FH or HEFH [36], since they tend to correlate with LDL‐cholesterol levels [37].

One other important gene involved in HL is that encoding the apolipoprotein B (apoB) proteins. This gene encodes two versions of the protein: a shorter version (apoB‐48) and a longer version (apoB‐100). Both isoforms are involved in transporting fat‐like particles, including cholesterol, in the blood. They are synthesized primarily in two organs, whereby the apoB‐48 is produced in the intestines, while the apoB‐100 is synthesized primarily in the liver. The former functions as a component of the chylomicron lipoproteins and is important for the absorption of certain fat‐soluble vitamins, such as the vitamins A and E. The apoB‐100, on the other hand, constitutes a component of other forms of lipoproteins, specifically the VLDLs, IDLs and LDLs, all of which are involved in the transportation of fats and cholesterol in the blood. Accordingly, apoB facilitates the LDL binding to their receptors in the liver cell surface. This in turn enables the transportation of these lipoproteins into the cell, where they are broken down to facilitate the release of cholesterol. Thus, mutations in the *APOB* gene can cause familial hyperbetalipoproteinemia (FHBL) or hypercholesterolemia by triggering the produc‐ tion of abnormally short forms of the protein, and therefore a reduction or lack of dietary fat and cholesterol transportation and ultimately the body's ability to absorb fats and fat‐soluble vitamins from the diet. The severity of the disease depends on the length of the abnormal protein. Accordingly, a resultant protein that is longer than the apoB‐48 will not hamper its production; hence, it should still be capable of forming chylomicrons. On the other hand, a similar product of the apoB‐100 in the liver will not be able to produce LPLs efficiently. Hence, protein products that are shorter than the apoB are associated with more severe symptoms than in cases where some normal apoB‐48 is produced. *APOB* mutations may also trigger the familial ligand‐defective apoB‐100 (FDB) [27] and ADH conditions [26]. These states are characterized by the presence of very high circulating cholesterol levels and therefore increased risk of disease. The impact of genetic changes in *APOB* on hypercholesterolemia is, however, less described than that of the *LDLR* gene. Besides, there has been some inconsistences in reports on the impact of some of these mutations in different populations [10], pointing to its

The proprotein convertase sublitisin/kexin type 9 (PCSK9) functions by enhancing the regulation of circulating cholesterol levels, thereby possibly controlling the number of LDLRs on the cell surface. It probably acts by breaking down the LDLRs before they reach the cell surface. A few hypercholesterolemia‐related mutations have been reported in the PCSK9 to date [16, 35], and have been linked mainly to ADH [20–23]. Accordingly, the mutations responsible for the disease are termed 'gain‐of‐function' mutations as they enhance the protein activity or lead to the protein acquiring new atypical functions. Serum lipoprotein Lp(a) is thought to be elevated in FH as a result of such PCSK9 gain‐of‐function mutations [18, 19], for example. The overactive protein significantly reduces the number of LDLRs on the surface of the liver cells, possibly by triggering faster breakage of the LDLRs. Thus, the attenuated production of the receptors leads to more cholesterol accumulation, and therefore the possi‐ bility of the disease occurring. Other mutations in the gene defined as 'loss‐of‐function' mutations reduce blood cholesterol levels (hypocholesterolemia) by decreasing the PSCK9 activity or reducing its amount in the cell. These mutations lead to an increase in the number of LDLRs on the surface of liver cells. Harbouring of such mutation has been linked to a significantly lower than average risk of developing heart disease. Furthermore, elevated

variation by ethnicity [33, 34].

136 Cholesterol Lowering Therapies and Drugs

The PPAR‐α, −β/γ are ligand‐activated transcription factors serving as the primary regulators of several activities including glucose, fatty acid and lipoprotein metabolism, energy balance, cell proliferation and differentiation, inflammation and atherosclerosis. Thereby, the PPAR‐α activates the lipoprotein lipase (LPL) to ultimately reduce the formation of VLDL‐cholesterol and triglycerides as well as increasing HDL‐cholesterol. The genes have been collectively implicated in hypertriglyceridemia [38], possibly through gene‐gene interactive mechanisms, and may modulate the risk of CAD by influencing both fasting and postprandial lipid concentrations [39]. Together with the PPAR‐γ, the PPAR‐α has also been implicated in HL [40–43] and low HDL levels [44, 45].

As the name denotes, the function of cholesteryl ester transfer protein (CETP) is to transfer neutral lipids, such as cholesteryl ester, forming cholesterol among lipoprotein particles. Specifically, it controls the net influx of cholesteryl ester from HDL to triglyceride‐rich VLDL and the equimolar transport of triglyceride from VLDL to HDL. Thus, it regulates the reverse cholesterol transport through which the lipid is removed from peripheral tissue and returned to the liver for elimination. Defects such as *CETP Taq1B* polymorphism in the encoding gene have been implicated in harbouring of low HDL‐cholesterol [46, 47] and hypertriglyceridemia [48].

The low‐density lipoprotein receptor adaptor protein 1 (*LDLRAP1*) acts essentially by influencing the function of the LDLRs. Hence, mutations in this gene would either prevent the cell from making functional receptors or alter their function. It probably interacts with the LDLRs thereby removing them together with the attached LDLs from the cell surface to the interior of the cell to facilitate the breaking down of the latter and the release of cholesterol. In the absence of a functional LDLRA1 protein, LDLR particles cannot be transported into the cell, even if they bind normally to them. This triggers the retention of the lipids in circulation, therefore leading to abnormally high cholesterol levels. Mutations in the gene have been associated with ARH [49–52]. This is thought to be a result of the gene producing an abnormally small, non‐functional version of the protein or preventing the cell from making the functional protein.

The apolipoprotein A‐1 promotes cholesterol efflux from tissue to the liver for excretion. It is also a co‐factor for lecithin cholesterol acyltransferase (LCAT), which is responsible for the formation of the majority of cholesteryl esters. Some recent reports indicate that the increase in HDL‐cholesterol on statin treatment may also be influenced by *APOA1* genotypes. The *APOA1* gene is closely linked to three other apolipoprotein genes, *APOA4*, *APOA5* and *APOC3* in a cluster form of *APOA1/C3/A4/A5* on chromosome 11. This complex has been associated with hypertriglyceridemia in various ethnic groups [53, 54]. The *APOA4* gene is a major component of HDL and chylomicrons, but not so much associated with VLDL. It is thought to be a potent activator of LCAT. It may play a role in chylomicrons and VLDL secretion and catabolism, and is needed by the apoC‐II for efficient activation of LPL. The apo A5 regulates plasma triglyceride levels by acting both as a potent stimulator of triglyceride hydrolysis by apoC II‐mediated LPL activity and as an inhibitor of hepatic VLDL production. However, its activation of LCAT is weak and does not enhance the efflux of cholesterol from macrophag‐ es. The *APOA5* gene polymorphism has been associated with hypertriglyceridemia and hyperlipoproteinemia type 5 [54].

The apolipoprotein E (*APOE*) polymorphism is regulated through three common alleles, epsilon 2, 3 and 4, coding for proteins that differ in lipoprotein receptor binding activity or their catabolism. This lipoprotein contains two different polypeptides apoB‐100 and the (lipoprotein) Lp(a) glycoprotein. The latter exhibits a genetic polymorphism that is regulated by a series of autosomal alleles at a single locus and is associated with lipoprotein plasma concentrations. This suggests that the same gene locus is involved in determining Lp(a) glycoprotein phenotypes and its plasma concentrations. Hence, variability in apolipoprotein genes related to the normal variance of lipoprotein concentrations play a major genetic role in multi‐factorial forms of HL such as hTG, familial type III HL, polygenic HL [55] and ADH [24].

Although FH is thought to be monogenic to a greater part, some inter‐ethnical differences have been reported in the prevalence of the disease. In the USA, for example, dyslipidemia is thought to be highly prevalent among Hispanics (Latinos), with Cubans appearing to be particularly at risk, possibly explained by socio‐economic status and acculturation [56], while increased African ancestry has been apparently linked to a decrease in triglyceride and LDLC as well as increased HDLC levels [57]. Also, lower odds for combined hyperlipidemia have been demonstrated for African‐Americans compared to whites, despite higher body mass index (BMI) and abnormal adiposity, while Hispanics had slightly higher and Asian no difference odds to whites [58]. These differences may to a greater part be due to variations in the genetic modifiers among ethnic groups, a subject that continues to be unravelled. Similarly, the prevalence of the CEPT polymorphism appears to vary among ethnic groups as suggested by a Singaporean study reporting highest prevalence in Indian and lowest in the Malays with the Chinese showing an intermediate value, while African‐American veterans exhibited higher blood pressure, LDL‐cholesterol and protein A1c levels than Whites [59]. Differences have also been reported in the distribution of the *APOA5* gene variants in various ethnic groups in China [54] and Singapore [59]. These variations have been partly linked to the existence of population admixture [60]. It has also been observed that some polymorphic gene locus controls the concentrations of Lp(a) lipoprotein complex in plasma which may vary very widely between individuals. Hence, variability in apolipoprotein genes related to the normal variance of lipoprotein concentrations play a major genetic role in multi‐factorial forms of HL such as hTG, familial type III HL and polygenic HL [55], as well as ADH [24]. Furthermore, the effects of the *APOE* alleles on the phenotypic variance of plasma lipoprotein concentrations have been found to differ significantly among ethnic groups. This has been explained by the fact that APOE polymorphism encodes different proteins with different binding properties. However, to date, most of the large‐scale studies have been performed primarily in individuals of European descent, but many other ethnic groups have not been exhaustively studied yet. Importantly, due to lack of studies in such populations, we might be missing important data relevant in the influence of ethnicity of the manifestation of the disease. For example, it is quite likely that because of consanguinity among ethnic Arab populations, their prevalence would rank among the highest in the world. Therefore, data needs to be collected on such populations to define more precisely the impact of ethnicity on the relationship between gene polymor‐ phism and HL manifestation, which is likely to be unique for that particular ethnic group. Nonetheless, these data furnish support to the notion of the inter‐ethnic variations in lipid traits being linked to genetic variants that exhibit differences in frequencies in individuals of African, Asian and European ancestry [61]. Besides, differences in lifestyle, such as leisure time, smoking and pedantic life style, for example, will also exert an impact on the disease manifestation, as demonstrated by the different levels of awareness of health risks among urban population compared to rural ones. Therefore, their ultimate effect on disease manifes‐ tation may vary between different ethnic groups, even within a given society.

#### **2.3. Confounders for ethnicity interactions with hyperlipidemia disease**

activation of LCAT is weak and does not enhance the efflux of cholesterol from macrophag‐ es. The *APOA5* gene polymorphism has been associated with hypertriglyceridemia and

The apolipoprotein E (*APOE*) polymorphism is regulated through three common alleles, epsilon 2, 3 and 4, coding for proteins that differ in lipoprotein receptor binding activity or their catabolism. This lipoprotein contains two different polypeptides apoB‐100 and the (lipoprotein) Lp(a) glycoprotein. The latter exhibits a genetic polymorphism that is regulated by a series of autosomal alleles at a single locus and is associated with lipoprotein plasma concentrations. This suggests that the same gene locus is involved in determining Lp(a) glycoprotein phenotypes and its plasma concentrations. Hence, variability in apolipoprotein genes related to the normal variance of lipoprotein concentrations play a major genetic role in multi‐factorial forms of HL such as hTG, familial type III HL, polygenic HL [55] and ADH [24].

Although FH is thought to be monogenic to a greater part, some inter‐ethnical differences have been reported in the prevalence of the disease. In the USA, for example, dyslipidemia is thought to be highly prevalent among Hispanics (Latinos), with Cubans appearing to be particularly at risk, possibly explained by socio‐economic status and acculturation [56], while increased African ancestry has been apparently linked to a decrease in triglyceride and LDLC as well as increased HDLC levels [57]. Also, lower odds for combined hyperlipidemia have been demonstrated for African‐Americans compared to whites, despite higher body mass index (BMI) and abnormal adiposity, while Hispanics had slightly higher and Asian no difference odds to whites [58]. These differences may to a greater part be due to variations in the genetic modifiers among ethnic groups, a subject that continues to be unravelled. Similarly, the prevalence of the CEPT polymorphism appears to vary among ethnic groups as suggested by a Singaporean study reporting highest prevalence in Indian and lowest in the Malays with the Chinese showing an intermediate value, while African‐American veterans exhibited higher blood pressure, LDL‐cholesterol and protein A1c levels than Whites [59]. Differences have also been reported in the distribution of the *APOA5* gene variants in various ethnic groups in China [54] and Singapore [59]. These variations have been partly linked to the existence of population admixture [60]. It has also been observed that some polymorphic gene locus controls the concentrations of Lp(a) lipoprotein complex in plasma which may vary very widely between individuals. Hence, variability in apolipoprotein genes related to the normal variance of lipoprotein concentrations play a major genetic role in multi‐factorial forms of HL such as hTG, familial type III HL and polygenic HL [55], as well as ADH [24]. Furthermore, the effects of the *APOE* alleles on the phenotypic variance of plasma lipoprotein concentrations have been found to differ significantly among ethnic groups. This has been explained by the fact that APOE polymorphism encodes different proteins with different binding properties. However, to date, most of the large‐scale studies have been performed primarily in individuals of European descent, but many other ethnic groups have not been exhaustively studied yet. Importantly, due to lack of studies in such populations, we might be missing important data relevant in the influence of ethnicity of the manifestation of the disease. For example, it is quite likely that because of consanguinity among ethnic Arab populations, their prevalence would rank among the highest in the world. Therefore, data needs to be collected on such populations

hyperlipoproteinemia type 5 [54].

138 Cholesterol Lowering Therapies and Drugs

As stated above, in the majority of cases, HL is a product of an interaction of a combination of lifestyle choices with structural alterations in a multiple of genes, rather than a result of a single inherited condition. The disease penetrance will be dependent on the prevalence of various risk factors, including diet, exercise and tobacco smoking, but more importantly gender and age. The latter are also important determinants of the influence of dyslipidemia and other diseases, such as diabetes and obesity, on the manifestation of CAD. Ultimately, the impact of these interactions on dyslipidemia varies by ethnicity. The impact of ethnicity on HL mani‐ festation is, in turn, also greatly influenced by these lifestyle confounders, particularly the modifiable variables, such as obesity, diet and lifestyle. According to the World Health Organisation (WHO), obesity is a condition in which the body accumulates fat to the extent that the health and well‐being of the individual are adversely affected [62]. The primary causes for this disorder are sedentary lifestyle and high‐fat energy‐rich diets. This is a result of fundamental adaptive changes involving the societal and behavioural patterns of modern communities, attributable mainly to increased urbanization and industrialization at the cost of the fading or disappearing traditional ways of living. These traits are themselves signifi‐ cantly influenced by other risk factors, such as BMI, which exhibits great inter‐ethnical variability. To begin with, BMI is determined by the distribution of the body fat, which in turn depends on age and sex. The average body fat is known to differ among ethnic populations, as suggested by studies demonstrating that most Asian ethnicities have higher average body fat percentage than whites of the same age and BMI [63–65], for example. These variations appear to be a result of the distribution of body fat for a given BMI. A study in the Singaporean population established differences among its ethnic subpopulations in the association of the CETP variants, Taq1B and ‐629C>A, with plasma HDL‐cholesterol in which the BMI was uniformly linked to disease [59]. The adverse health outcomes associated with these variations are often accompanied by additional complexities, especially since the depth of their relation‐ ships can also differ by ethnicity. To add to the intricacy of the problem, the relationship of BMI and such adverse health outcomes involves additional complexities of displaying intra‐ ethnical variations. For example, among white populations, Europeans have been reported to have a higher percentage of body fat at a given BMI than whites in the USA [63, 66], and a study in the Chinese showed lower average BMI levels among rural compared to urban populations [64, 67]. Thus, the BMI levels may also differ considerably among subpopulations within an ethnic group because of prevailing environmental and lifestyle conditions. Given the variations in the ratios of body fat for a given BMI [64–66], some of these studies have led to the notion that Asians may be predisposed to a greater risk of clinical events, such as acquiring hypertension and cardiovascular disease, despite having lower BMI levels than Caucasians [63, 67–70]. Taken together, these data imply that the global impact of obesity on hyperlipidemia is similar across ethnicity, while that of the BMI may differ considerably even within an ethnic group, since the relationship between BMI and percentage of body fat depends on age and sex, and differs across ethnic groups [63, 65]. Gender has also been implicated, whereby for example, female veterans have been shown to display higher LDL‐cholesterol than males [71]. Hence, the penetrance of their influence is ultimately dependent on their distribution by ethnicity. Differences in lipid profiles, prevalence of dyslipidemia and their risk factors can also be explained as product of combined effects of lifestyle and genetic factors [72]. Such inter‐ethnical differences in the prevalence of obesity, cholesterol, hypertension and diabetes have similarly been ascribed to socio‐economic effects and lifestyle changes [73]. The direct influence of the different risk traits on dyslipidemia can also vary within an ethnic group in presence of racial admixturing. All these variations will affect the appropriateness of managing dyslipidemic disorders in an ethnicity‐dependent fashion.
