Genetic and Epigenetic Phenomena - Essay Example

?How may genetic and epigenetic phenomena influence cardiovascular risk by altering the pathophysiology of plasma lipoproteins? Introduction: In the current era of innovation and cutting edge technology, with the unraveling of the human genome and rapid advancements in technology, the sphere of human genomics has made considerable progress and the genetic and epigenetic basis of various diseases have been identified. One of the most prevalent group of diseases throughout the world nowadays is cardiovascular diseases (CVD) (Willer, et al., 2008, p. 161), which not only contribute towards significant morbidity and mortality but also incur significant healthcare related costs. An important risk factor for the development of cardiovascular diseases is dyslipidemia, whereby the plasma concentrations of different lipoprotein fractions, in particular, HDL and LDL, are deviated from the norm (Hegele, 2009, p. 111). Since approximately half of the variations in the plasma levels of HDL and LDL cholesterol are heritable (Kathiresan, et al., 2008, p. 1241), it is postulated that genetic influences play a significant role in the determination of plasma lipoprotein levels, especially HDL and LDL, which in turn are strongly correlated with the risk of cardiovascular disease and outcomes. Similarly, recent literature has also unveiled several epigenetic mechanisms whereby concentrations of different lipoproteins are altered. This paper discusses the relationship between the levels of different lipoproteins found in the human bloodstream and the risk for cardiovascular diseases. Moreover, the focus of this paper is to elucidate how genetic and epigenetic phenomena influence cardiovascular risk by altering the pathophysiology of plasma lipoproteins. The relationship between plasma lipoproteins and the risk for cardiovascular diseases: As discussed previously, CVDs are the leading preventable cause of death globally. It has been found that these diseases account for approximately 50% of the deaths in the developed world and are the most common cause of death in both developed and underdeveloped countries (Ebesunun, Agbedana, Taylor, & Oladapo, 2008, p. 282). In the United States alone, cardiovascular diseases have been shown to claim almost 1 million lives each year (Eichner, Dunn, Perveen, Thompson, Stewart, & Stroehla, 2002, p. 490). The domain of cardiovascular diseases encompasses various ailments such as hypertension, coronary artery disease, arrhythmias, cerebrovascular diseases such as stroke and peripheral arterial disease (Brunzell, et al., 2008, p. 811; Eichner, Dunn, Perveen, Thompson, Stewart, & Stroehla, 2002, p. 490). There are several established risk factors for cardiovascular diseases, both modifiable and non-modifiable, including and not limited to age, sex, smoking, diabetes, hypertension, obesity (in particular, central obesity) and dyslipidemia (Rizzo & Berneis, 2006, p. 1; Ordovas, 2009, p. 1509). Dyslipidemia, which is defined as an alteration in the plasma levels of lipids and lipoproteins, is an important risk factor for CVD (Hegele, 2009, p. 111). Lipoproteins are transporter macromolecules that are present in the human bloodstream and tend to serve the function of transporting insoluble plasma lipids, including cholesterol and triglycerides in the bloodstream (Hegele, 2009, p. 109). There are several different types of lipoproteins present in the plasma, which have been classified according to their density, particle size and the substances that they transport (Hegele, 2009, p. 110). Several studies have revealed that the most important determinants of cardiovascular risk are the levels of two important lipoproteins, viz. HDL and LDL and alterations in the levels of these lipoproteins can lead to several pathologies. While elevated LDL is found to increase CVD risk, elevated levels of HDL are found to confer protection against the likelihood of developing CVD. For example, it has been found that a 1mmol/l reduction in the plasma levels of LDL cholesterol leads to a 21% decline in the risk for major cardiovascular events during one’s lifespan (Hausenloy & Yellon, 2008, p. 590). Similarly, each 0.03 mmol/l increase in the plasma levels of HDL cholesterol leads to 2-3% risk reduction (Hausenloy & Yellon, 2008, p. 590). It has been elucidated that plasma LDL serves an important role in the formation of an atherosclerotic plaque via activating several inflammatory pathways and also interferes with arterial relaxation (Hegele, 2009, p. 111). LDL cholesterol, which has been found to be the most abundant lipoprotein in the human body, contributing almost 60-70% of the total cholesterol in the human body, is the major atherogenic lipoprotein, particularly when it is present in levels above 100mg/dL (National Heart, Lung, and Blood Institute: National Institutes of Health, 2002). Similarly, studies have established an independent relationship between the levels of HDL-Cholesterol and the risk of coronary artery disease whereby lower levels of HDL have been found to incur a greater risk of CAD (i.e. an inverse relationship) (Steeg, et al., 2008, p. 635). HDL-Cholesterol has been found to be protective in nature with regard to CVD by virtue of its anti-oxidant, anti-inflammatory and anti-thrombotic properties and thus, levels of HDL-Cholesterol lower than 1mmol/l have been found to be associated with a significant risk of cardiovascular diseases (Hausenloy & Yellon, 2008, p. 590). In addition, it has been found that the most important lipoprotein fractions/fragments which contribute towards the risk of premature cardiovascular disease are Lp(a) and apolipoprotien B (apoB) (Ebesunun, Agbedana, Taylor, & Oladapo, 2008, p. 283). Till date, the strongest independent predictor of cardiovascular risk has been found to be the ratio between apolipoprotein B to apolipoprotein A-I, which are directly correlated with the levels of plasma LDL and HDL, respectively (Hegele, 2009, p. 111). Genetic influences on lipoprotein levels and the risk for CVD: Genome wide studies have helped in elucidating the genetic determinants of plasma levels of lipids and lipoproteins. It has been found that plasma lipid levels have fairly high heritability, with the highest heritability estimates for HDL and LDL cholesterol, being between 40-60% and 40-50% respectively. Moreover, triglycerides have also been found to have about 35-48% heritability (Ordovas, 2009, p. 1510). These findings reflect the contribution of genetic influences to plasma levels of lipids and lipoproteins and underscore the importance of the impact of genetic aberrations on the etiology of several diseases associated with altered concentrations of the aforementioned substances, such as atherosclerosis. Till date, several different genetic loci have been identified which are important contributors in the determination of serum lipoprotein levels. These include ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9 (Willer, et al., 2008, p. 161). It has also been elucidated that any genetic variants leading to increased LDL levels are also strongly associated with an increased risk for cardiovascular diseases (Willer, et al., 2008, p. 161). Amongst these genetic variants, the single nucleotide polymorphisms which have been implicated in the determination of serum LDL concentration include APOB, PCSK9, LDLR, APOE, FADS2,3, SORT1, CILP2 and HMGCR (Kathiresan, et al., 2008, p. 1241; Hegele, 2009, p. 114; Willer, et al., 2008, p. 162). While all other single nucleotide polymorphisms (SNPs) in the aforementioned genes lead to increased levels of LDL cholesterol in the bloodstream, loss of function mutations in PCSK9 have been found to protective in nature with regard to CVD risk, in that they lead to decreased levels of serum LDL by causing increased levels of LDL receptor expression, which causes greater removal of LDL from the plasma (Cohen, Boerwinkle, Mosley, & Hobbs, 2006, p. 1265). An important observation which highlights the role of genetics in the determination of LDL levels is that all single gene disorders resulting in elevated LDL levels, five of which have been identified till date, are associated with an increased risk of premature coronary artery disease amongst individuals (Cohen, Boerwinkle, Mosley, & Hobbs, 2006, p. 1264). Another important factor which is partly genetically determined is the LDL size. It has been elucidated that a particular subgroup of individuals who display a triad of low HDL, high levels of triglycerides and elevated levels of small, dense LDL, which is designated as the “atherogenic lipoprotein phenotype” are at a significantly higher risk for CVD (Rizzo & Berneis, 2006, p. 2). The size of LDL particles (i.e. the small, dense type) has been shown to be inherited either in a dominant fashion as a single-gene trait or in a co-dominant fashion (Austin, King, Vranizan, & Krauss, 1990, p. 495; Rizzo & Berneis, 2006, p. 2). The heritability for LDL size has been found to range from 35-45%, based on the pattern of inheritance (Rizzo & Berneis, 2006, p. 2). The same LDL phenotype has also been found to be the predominant LDL type in individuals with the genetically determined familial lipoprotein metabolism disorders such as familial combined hyperlipidaemia, hyper-beta-lipoproteinaemia and hypo-alpha-lipoproteinaemia (Berneis & Rizzo, 2004 cited in Rizzo & Berneis, 2006, p.2). Epigenetics and its role in determination of lipoprotein concentrations: The term Epigenetics refers to “chromatin-based pathways important in the regulation of gene expression and includes three distinct, but highly interrelated, mechanisms: DNA methylation, histone density and posttranslational modifications, and RNA-based mechanisms (Yan, Matouk, & Marsden, 2010, p. 916).” Recently, epigenetic mechanisms have gained widespread popularity as their elucidation has helped in filling several gaps which previously existed in our knowledge regarding the heritability of several diseases, in particular chronic diseases such as cancers and cardiovascular diseases. The role of several epigenetic mechanisms in the causation of atherosclerosis has been elucidated. One of the most important lipoprotein-induced epigenetic mechanisms that contribute towards the etiology of atherosclerosis is DNA methylation (Lund & Zaina, 2007, p. 699). DNA methylation refers to modification in the chromatin structure due to the methylation of specific bases in the DNA, for example methylation of cytosine in CpG dinucleotides, which is the most common form of DNA methylation in mammals, (Barros & Offenbacher, 2009, p. 401). Studies have revealed that this lipoprotein induced DNA methylation is an epigenetic alteration which occurs early in the course of atherosclerosis and is a key determinant of the future risk of developing cardiovascular diseases (Lund & Zaina, 2007). The lipoprotein fragments which have been implicated to potentially play a role in DNA methylation include Apolipoprotein A-1and Apolipoprotein B, both of which have been shown to have chromatin binding capability (Zaina, Dossing, Lindholm, & Lund, 2005). Another important epigenetic mechanism which has been found to influence the levels of different lipoproteins in the plasma is genetic imprinting (Lawson, Zelle, Fawcett, Wang, & Pletchser, 2010, p. 16). Genetic imprinting refers to the phenomenon whereby the alleles of a particular gene locus are expressed in a non-equivalent fashion, i.e. one of the alleles from either parent (i.e. either maternal or paternal) is preferentially expressed as compared to the other, which is repressed (Barros & Offenbacher, 2009, p. 403). Moreover, other mechanisms such as polar dominance imprinting and bipolar dominance imprinting are also important epigenetic contributors to variations in serum lipoprotein levels (Lawson, Zelle, Fawcett, Wang, & Pletchser, 2010, p. 16). Thus, epigenetic mechanisms have enabled scientists to establish the link between the expressed genotype and the observed phenotype. Conclusions: Thus, the concentration of various lipoproteins in the bloodstream is an important determinant of the future likelihood of developing cardiovascular disease. Several genetic and epigenetic mechanisms are responsible for determining the levels of lipoproteins in the human bloodstream, and genome wide association studies have enabled us to unravel some of these mechanisms. The most important epigenetic implicated in the pathophysiology of cardiovascular diseases is DNA methylation, while the common genetic aberrations include single nucleotide polymorphisms and single gene disorders resulting in the familial lipoprotein metabolism disorders. These findings have several implications for the treatment and prevention of cardiovascular diseases as they open new arenas for intervention at a molecular level by altering patterns of genetic expression, to control the risk for development of cardiovascular ailments. Figure 1: Relationship between Genetic and Epigenetic factors, Plasma Lipoprotein levels and risk for CVD References: Austin, M. A., King, M.-C., Vranizan, K. M., & Krauss, R. M. (1990). 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