Genetic and Epigenetic Phenomena Influence on Cardiovascular Risk - Research Paper Example

Genetic and epigenetic phenomena influence on cardiovascular risk by altering the pathophysiology of plasma lipoproteins? Cardiovascular diseases arethe primary cause of death in the modern world, and globally more people die from cardiovascular diseases and complications of cardiovascular morbidity than from any other cause. Mortality from cardiovascular diseases is believed to be the leading cause of death in the future and these trends are believed to persist and rise by year 2030 (WHO 2011). Cardiovascular diseases are linked to a number of risk factors that contribute to their high incidence in industrialized countries, risks like elevated blood pressure, smoking, obesity, diabetes mellitus, metabolic syndrome, and dyslipidemia as one of the major factor that is contributing to cardiovascular morbidity and mortality (NCEP 2002). The prevalence of cardiovascular diseases is also increasing because of the trend of aging of the population (Rayner and Petersen 2008). One of the most important risk factor for cardiovascular diseases is high cholesterol and saturated fat that is incorporated in significant amounts in everyday diet (Emberson et al. 2003). Programs for saturated fat reduction in the diet in the general population has lead to significant improvement of cholesterol levels in the population of Finland for example, where the program for saturated fat reduction in everyday’s diet lead to significant reduction of the incidence of cardiovascular diseases (Laatikainen et al. 2005). Introduction of effective treatment of dyslipidemia is another factor that can significantly reduce the incidence of morbidity and mortality of cardiovascular diseases. Based on the data from World health organization 80 percents of all deaths due to cardiovascular diseases are concentrated in the low and middle income countries, and this is believed to be due to lack of access to effective medical care treatment, including effective programs for healthy diet and reducing saturated fat in the diet, but also due to lack of effective anti-hyperlidemic drugs (WHO 2011). However data from a number of studies show that effectiveness of different statins is variable and influenced by genetic and environmental factors. Mounting evidences show that genetic variations influence the level of blood lipids within one individual, but also the personal diet has important influence of the effectiveness of statins and other pharmaceuticals (Kajinami et al. 2005). The metabolism of lipids in the organism is complex and is managed by multiple organs and systems. The main lipids in the human organism are the free and esterified cholesterol and triglycerides. Reabsorption of triglycerides starts in enterocytes with the transporters of fatty acids. In the enterocytes fatty acids are then reconstructed into triglycerides and organized with C ester and apolipoproten B48 into chylomicrons by microsomal trygliceride transfer protein (MTTP). This protein is important in normal transport and resorption of triglycerides. Defects in this protein can lead to inherited disease characterized with very low levels of low density lipoproteins LDL called abetalipoproteinemia (Tarugi et al. 2007). But also genetic variations of this protein which is very important in production of chylomicrons in the intestine and VLDL in the liver, are found to be important in the incidence of dyslipidemia in diabetes mellitus type 2 patients (Chen et al 2003). In the study conducted by Chen et al 2003, using gene sequencing they studied the influence of MTTP gene polymorphism and its influence on the triglyceride levels in diabetic patients. It was found that the so called MTTP-493 TT variation of the gene was associated with increased triglyceride and VLDL levels and smaller LDL particle size. In this study we can see that a gene variation is found to be directly connected to elevated triglycerides levels in the blood. But the second important finding in this study was the fact that the same group of individuals had findings of smaller size LDL particles, finding that we will discuss further in the text, and a finding that is also associated with increased cardiovascular disease. After the process of formation of chylomicrons they enter the vein system through the lymphatic ducts. Chylomicrons are predominantly composed of triglycerides (up to 85%), small percentage of cholesterol and apolipoproteins (mainly apolipoprotein B48). When they enter the blood stream HDL particles donate apolipoprotein C-II and apolipoprotein E and with this process the chylomicron is considered to be mature. These chylomicrons then interact with the lipoprotein lipase enzyme which hydrolyzes the triglycerides into glycerol and fatty acids that are then utilized by the peripheral tissues and cells. The chylomicron remnants then enter the liver in a process of receptor mediated endocytosis. Apolipooroten E is again very important factor in this process (Have 1984). The gene responsible for translating apolipoproten E is located on 19-th chromosome and it is polymorphic gene found in 3 most common isoforms: apolipoproten E2, E3 and E4 (Singh et al. 2006). These allelic isofomrs differ between each other in only one amino acid on positions 130 and 176, but they differ significantly on their physiologic characteristics (Ghebranious et al. 2005). In a number of studies apolipoprotein E2 isomorf is associated with hyperipoproteinemia type 3 and individuals with E2/E2 genotype are at increased risk for developing cardiovascular disease. It is interesting to note that only approximately 2 percents of the E2/E2 cariers develop hypelipoproteinemina 3 (however over 95 percent of individuals with huperlipoproteinemia 3 have this genotype) which means that other genes are also responsible for the manifestation of the disease (Breslow et al. 1982). Apolipoprotein isomorf E4 carriers are also associated with increased levels of circulating total cholesterol and LDL particles in the blood. This is believed to be the main cause for recognized increased risk for developing cardiovascular disease in ApoE4 carriers (Humphries et al. 2001). However this effect of apolipoprotein E4 is found to be influenced by many factors, like gender, personal diet, age etc. For example in a study conducted by Ilveskoski et al. 1999 is was found that this risk for cardiovascular diseases in ApoE4 carriers was present only in individuals bellow age 53. This only confirms the fact that the influence of apolipoprotein E4 is corrected by other genetic, epigenetic, environmental and other factors (Ilveskoski et al. 1999). It is found that E3/E3 homozygote’s are considered to have normal risk-level for developing cardiovascular risk and are present in 60 to 90 percents of the general population, and 65 percents of the Caucasian population is E3/E3 homozygote (Corbo and Scacchi 1999) (Eichner et al. 2002). The remaining population is homozygote or heterozygote in different percentages. For example 19 percents of the Caucasian population are E3/E4 heterozygotes, 4 percents are E2/E4 heterozygotes, 2 percents E2 homozygote’s ect (Eichner et al. 2002). This only shows that different percentages of the general population are influenced by this genetic burden for dyslipidemia. Triglycerides that enter the liver are then again packaged along with cholesterol and apolipoprotein B100 into very low density lipoproteins (VLDL). The triglycerides in VLDL particles are hydrolyzed by lipoprotein lipase that is producing free fatty acids and VLDL ruminants called (IDL). They are additionally hydrolyzed by the hepatic lipase thereby producing low density lipoproteins (LDL). LDL particles are important in transport of the cholesterol to the peripheral tissues and cells in the body. When a cell needs cholesterol (for membrane repair for example) et expresses LDL receptors (LDLR) which is a binding place for LDL particles. It is found that the size of the LDL particles in humans can be categorized in two groups: larger and buoyant LDL particles (A pattern) and smaller and denser LDL particles or B pattern (Berneis and Krauss 2002). It is important that it was found that the pattern A correlates with higher HDL levels (or so called good cholesterol) and lower triglycerides level in the blood as opposite to pattern B where lower levels of HDL and higher level of triglycerides are found in the blood. Interestingly this type of small LDL particles combined with low HDL levels and elevated triglycerides is called “atherogenic phenotype” and is believed that is a marker for increased coronary heart disease risk. Pattern B is also common finding in metabolic syndrome, and it is believed that this is the reason for increased cardiovascular disease risk in metabolic syndrome (Austin et al. 1990). Small LDL particle size is increasingly recognized as a important risk factor for cardiovascular diseases as we will discuss further (Rizzo and K. Berneis 2006). There are many factors that are mentioned trying to explain why smaller size LDL particles are associated with increased risk for cardiovascular disease. One of them is that denser LDL particles are more easily resorbed by arterial tissues compared to larger LDL particles (Bjornheden et al. 1996). By other theories smaller LDL particle is more oxidation susceptible with decreased efficacy of antioxidant concentrations (Tribble et al. 2001). Other theories are available also. Now regarding the genetic component, pattern B phenotype is found in about 30 percents of adults below age 20 and up to 20 % in postmenopausal women. It is found that LDL size has geneticall influence with a hereditability between 35 and 45 percents, with complex polygenic inheritance (Austin 1992). But what is important non genetic factors are also found to be important in the level of expression of this phenotype, meaning that epigenic mechanism is also involved in the appearance of B pattern of LDL size, factors like abdominal type of obesity, usage of contraceptives, a diet constituted with low fat and high carbohydrate intake etc. (Rizzo et al. 2003) (Dreon et al. 1997). LDL particles are recognized as a major risk factor for atherosclerosis and cardiovascular disease. Apolipoprotein B is important constituent of LDL particles and is used as a receptor for endocytosis of LDL particles by the peripheral tissues, including arteries. It is important to note that one LDL particle has only one apolipoprotein B. This is why measurement apolipoprotein B in the blood is found to be better predictor of cardiovascular risk than the level of LDL cholesterol (Sniderman 2004). Apolipoprotein B is important factor in adherence of LDL particles on the arterial walls. By some authors in the process of atherosclerosis more important is the process of adherence of the LDL particles (mediated by apolipoproten B) on the arterial subendotelial space than the process of endocytosis of LDL particles. These trapped LDL particles in the subendotelial spaces in the arterial walls are than subjected to a process of oxidation by oxidative products from the cells of the arterial wall (Morelet al. 1984). This process leads to inflammation and activation of macrophages that lead to even further oxidation of LDL particles and formation of ”foam cells” and other processes characteristic for the formation of atherosclerotic plaque (Sparrow et al. 1989). Regarding the importance of LDL particle size and the genetic involvement in this phenotype we can conclude that this is an example of direct genetic influence on morbidity of atherosclerosis and cardiovascular diseases in pattern B individuals. The metabolism of cholesterol in the human organism is also subjected to individual variations regarding to specific genetic isomorfs. Cholesterol enters the enterocytes in the intestines through the Niemann-Pick C1-like 1 transporter and is organized in chylomicrons. There are studies that show that genetic variations in the Niemann-Pick C1-like 1 transporter influence the levels of triglycerides and cholesterol in the blood where dysfunctional Niemann-Pick C1-like 1 transporter or some of the isomorfs of this transporter leads to increased liver synthesis of cholesterol (Riikka-Liisa et al. 2010). Cholesterol is also synthesized in the liver with 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) enzyme. It is found that genetic variations in the function of this enzyme modify the effects of statins on blood levels of cholesterol and LDL particles (Chasman et al. 2004). This is why there is significant difference on the compliance of statin therapy among different individuals (Shear et al. 1992). Based on all of the above we can conclude that genetic factors have significant influence in the cardiovascular rick due to increased lipoproteins in the blood. Because of the genetic variations among individuals the treatment of dyslipidemia is also effective in different levels between different individuals. Based on the genetic differences between individuals we can even advise different approaches in the treatment of dyslipidemia. For example it is found that restriction of dietary intake of cholesterol resulted in significant reduction of blood cholesterol levels in apolipoprotein E4 carriers, but not in other isomorphs of apolipoprotein E (Masson et al. 2003). This means that in the future the treatment of the resistant dyslipidemias must take into account the genetic burden of the individual, and we must include the knowledge of specific genetic factor in the treatment of dyslipidemia. The physiology of cholesterol and triglycerides is far from completely understood. New mechanisms of regulation are recognized on a daily basis. 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