Important points One form of cardiovascular disease is coronary artery disease that results from a build up of cholesterol and other fats in the blood causing the formation of plaques. Plaque deposits on the walls of blood vessels and may cause them to block Familial hypercholesterolaemia (FH) is an inherited tendency to have high cholesterol, and this may lead to coronary artery disease; it accounts for about 5%-10% of coronary artery disease that occurs before the age of 55 In the body, the cholesterol is transported to the cells via the blood in small particles called lipoproteins. The most common form of FH involves the LDLR gene which contains the instructions for the body to make the low-density lipoprotein (LDL) receptor (R) which enables the absorption of the low-density lipoprotein into the cell When the LDLR gene is faulty, the protein produced does not work properly, leading to a build up of cholesterol and other fats in the blood that form the plaques that are deposited on the walls of the blood vessels and makes the individual susceptible (predisposed) to coronary artery disease If a person has one faulty LDLR gene copy and the other partner LDLR gene copy is working, they are carriers of the faulty LDLR gene: they are unaffected genetic carriers for familial hypercholesterolaemia (FH) and will develop FH if triggering factors that include diet and lifestyle factors are also present Genetic carriers for FH are susceptible (predisposed) to developing high levels of cholesterol which can lead to coronary artery disease - About 1 in 500 people in Australia are genetic carriers for FH - FH is more frequent, and there is greater frequency of unaffected genetic carriers, in people whose ancestry is Christian Lebanese, Afrikaans (Dutch descent) and French Canadian - About 50% of men will develop coronary artery disease before the age of 50 and 100% by the age of 70; about 12% of women will develop coronary artery disease by age 50 and 74% by age 70 The pattern of inheritance of the LDLR faulty gene copy in families causing predisposition to FH is described as autosomal dominant inheritance - When one of the parents is a genetic carrier for FH, in every pregnancy they have 1 chance in 2 (or 50% chance) of having a child who is at increased risk for FH - When both parents are genetic carriers for FH, in every pregnancy, there is 1 chance in 4 or 25% chance that their child will receive the faulty LDLR gene copy from both parents. Having two copies of the faulty LDLR gene is exceedingly rare (about 1 in a million people) but is a severe health problem Genetic testing at an appropriate age can assist family members to determine if they have inherited the faulty gene for FH that has been identified in their family - To date, about 1000 changes have been identified in the LDLR gene but most are family-specific which makes the search for unknown mutation challenging and expensive Genetic counselling (see Genetics Fact Sheet 3) can provide the most up-to-date information about genetic testing Cardiovascular disease (cardio refers to the heart and vascular refers to the blood circulation system) is the general term given to conditions that include: Problems with the blood vessels that supply the heart muscle (coronary artery disease) High blood pressure (hypertension) Problems with the blood vessels that supply the brain (stroke) Abnormalities in the structure of the heart affecting the valves and muscle of the heart (eg cardiomyopathy) and other heart defects ; when these are present at birth they are called congenital heart defects Problems with the electrical system in the heart that controls the heart beat (arrhythmias) Problems with other arteries in the body, such as the aorta (the main artery that leads from the heart) In some cases, the information in the genes contributes to the development of cardiovascular disease. This is more likely when: There are a number of affected members of a family Symptoms of the condition occur at an early age In most cases where there is a family history of cardiovascular disease, the genetic component appears to be a susceptibility factor, rather than a major genetic cause. That is, the disease is a multifactorial condition (see Genetics Fact Sheet 11) where both inherited genetic predisposition to develop the condition and environmental triggers are involved. What is inherited predisposition to cardiovascular disease? Our genes are part of chromosomes and provide the information for our bodies to grow and develop, and to work properly throughout our life (see Genetics Fact Sheet 1). When the information in the genes is changed in some way, the information sent to the cells may be different. A gene that contains a variation in the information that stops it working properly is described as faulty. The variation that makes the gene faulty is called a mutation. The information contained in the faulty gene, and its product, is impaired (see Genetics Fact Sheets 4 & 5). Genetic predisposition means that a person has inherited from a parent a faulty gene copy that does not cause a problem directly but makes them more susceptible to developing the condition later in life when particular environmental factors that trigger the condition are present (see Genetics Fact Sheet 11). We all have two copies of the genes in our cells and when one copy of the gene is faulty, it may not cause a problem as the other gene copy still sends the right message to the cells to make the gene product. Even if the variation in the information in the gene is major, other genes in the cell may still enable the cell to function normally. www.genetics.edu.au Centre for Genetics Education 1
In some cases variations can occur during life in the other gene copy or to the other genes, caused by as yet largely unknown environmental factors. In other cases it is not clear how the environmental factors interact with the inherited faulty gene copy. It is therefore important to both determine the genetic basis of cardiovascular conditions in order to be able to identify those who may wish to know of their susceptibility as well as determine the environmental triggers. This Fact Sheet discusses a form of cardiovascular disease in which genes are known to be involved: an inherited tendency to have high cholesterol that leads to coronary artery disease. Genetics Fact Sheet 54 discusses the role of genetics in predisposition to cardiomyopathies Genetics Fact Sheet 55 discusses the role of genetics in predisposition to cardiovascular conditions where there is a problem with the electrical control of the heartbeat Genetics Fact Sheet 56 discusses the genetic aspects of hypertension, congenital heart defects and inherited conditions of connective tissue with cardiovascular effects Coronary artery disease and high cholesterol The arteries are blood vessels that supply blood, oxygen and nutrients to the body from the heart. Coronary artery disease occurs when the walls of the arteries become heavily lined, and sometimes eventually blocked, with a fatty substance often containing cholesterol. The build up of cholesterol may: Cause chest pain or discomfort (angina) Sometimes result in blood clots forming in the narrowed artery and blood supplies to the heart becoming limited. This may lead to chronic heart pain, causing varying degrees of disability or even heart attack (when the heart muscle is starved of essential oxygen and nutrients, leading to damage). Some heart attacks may cause sudden death. The importance of cholesterol Cholesterol is essential for the normal function and structure of the body: it is used in making bile for digestion, it is a component of several hormones and it is used in making membranes which are part of the cell s structure. About 50% of the cholesterol comes from a person s diet. When the amount of cholesterol in the blood is much higher than is needed for use by the cells, there is an increased chance that it will combine with other materials and cells, forming plaques that are deposited on the walls of the blood vessels (Figure.1). The build-up of cholesterol leading to the formation of plaques leads to narrowing the passages through which the blood flows to the heart and other organs. It is just like when a water pipe becomes so clogged that eventually water can no longer flow through it. What causes the build-up of cholesterol? The cholesterol is transported to the cells through the blood in small particles called lipoproteins. There are many different lipoproteins but there are two types involving cholesterol: High-density lipoproteins (HDL) - Works by taking cholesterol out of the cells and taking it back to the liver - Often called the good type of cholesterol as it protects against the hardening of the arteries Low-density lipoproteins (LDL) - Works by attaching to the surface of the cell by a special receptor which enables the absorption of the LDL into the cell. Once inside the cell, the cholesterol is released, ready to be used by the cell - Often called the bad type of cholesterol Both types are essential in the body for good health: it is the proportion of low to high density lipoproteins (LDL:HDL) that a individual has that determines if they are at risk of developing coronary artery disease. There are a number of factors that influence the formation of plaques in the arteries: Diet high in animal fats Smoking High blood pressure Obesity Lack of exercise Diabetes Whether a person is male or female Age A person s genetic make-up. Genes and cholesterol Genes contain the instructions for the way in which cholesterol and other fats are taken into the cells. The LDLR gene contains the instructions for the body to make the low-density lipoprotein (LDL) receptor (R) that enables the absorption of the LDL into the cell. When the LDL-receptor is not working properly (it is faulty) it leads to a build up of cholesterol and other fats in the blood. As a result, plaques form and the person is susceptible (predisposed) to coronary artery disease. The LDLR gene is located on chromosome 19. There are two copies of chromosome number 19 in every body cell and therefore two copies of the gene that codes for the low-density lipoprotein. Everyone therefore has 2 copies of the LDLR gene in their body cells. A familial tendency to high cholesterol (Familial Hypercholesterolaemia FH) In some families there is an inherited tendency to have very high levels of cholesterol. This genetic condition is called familial hypercholesterolaemia (FH). The most common form of FH is due to a individual being born with a variation in their LDLR gene that makes the gene faulty (see Genetics Fact Sheets 4 & 5). Variations in the LDLR gene lead to a reduction in the number of the LDL receptors on the cell s surface or an alteration in the receptor structure. Figure.1: Diagrammatic representation of a blood vessel becoming clogged with a build-up of plaques. www.genetics.edu.au Centre for Genetics Education 2
If an individual has one faulty LDLR gene copy and the other partner LDLR gene copy is working, they are carriers of the faulty LDLR gene: they are unaffected genetic carriers for FH. Genetic carriers for FH are susceptible (predisposed) to developing high levels of cholesterol which can lead to coronary artery disease Just having a faulty LDLR gene is not enough for high cholesterol to develop Other environmental factors such as a lifestyle and diet associated with coronary artery disease must also be present for the condition to develop (see Genetics Fact Sheet 11). Other genes identified in causing FH It is likely that there will be a number of different genes associated with the lipoproteins that will be identified as involved in genetic predisposition to coronary artery disease. For example, the genes that contain the information for the lipoproteins themselves, called the APO genes: - Apolipoprotein B(APOB) codes for the main protein of the low density lipoprotein referred to above (LDL); the APOB gene is located on chromosome number 2 - Variations in the APOB gene can lead to high levels of cholesterol, and susceptibility to cardiovascular disease - The symptoms are indistinguishable from classic FH, although cholesterol levels are generally not as elevated Research is continuing to define the genetic contribution of the APO genes to cardiovascular disease. Another form of FH is due to changes in a different gene which is passed down through families following an autosomal recessive pattern of inheritance (see Genetics Fact Sheet ). This form of FH is generally less severe and more variable, with greater responsiveness to therapy. FH in Australia Accounts for about 5% -10% of coronary artery disease that occurs before the age of 55 It is estimated that, of the roughly 40,000 cases of FH in Australia, about 20% are diagnosed and less than 10% are being adequately treated. Less than 5% however, have been formally identified About 1 in 500 people are genetic carriers for FH Having two copies of the faulty LDLR gene (see below) is exceedingly rare (about 1/1,000,000 people) but is a severe health problem FH is more frequent, and there is greater frequency of unaffected genetic carriers, in people whose ancestry is: - Christian Lebanese, 1 in 70 - Afrikaans (Dutch descent), 1 in 70 - French Canadian, 1 in 70 What is the pattern of inheritance of FH due to the faulty LDLR gene in families? FH is a genetic condition (see Genetics Fact Sheet 2). Therefore it is passed from parents to children in their genes. Two factors influence the pattern of inheritance of the faulty LDLR gene causing FH in families. 1. The LDLR gene is located on chromosome 19, an autosome (one of the numbered chromosomes) 2. The effect of the variation in the LDLR gene is dominant over the information in the working copy of the gene on the partner chromosome 19 (see Genetics Fact Sheets 1, 4 & 5) Figure.2: Autosomal dominant inheritance where one parent has the faulty LDLR gene copy that predisposes them to FH. The faulty gene copy is represented by D ; the working copy by d. Figure.3: Autosomal dominant inheritance where both parents have the faulty LDLR gene copy. The faulty gene copy is represented by D ; the working copy by d. When both parents pass the faulty LDLR gene copy to a child, he/she is at very high risk for developing heart disease during their life and may develop it quite early. www.genetics.edu.au Centre for Genetics Education 3
The pattern of inheritance in families of the faulty LDLR gene causing susceptibility to high cholesterol (FH) is therefore described as autosomal dominant inheritance (see Genetics Fact Sheet 9). In Figures.2 and.3 the autosomal dominant faulty LDLR gene causing FH is represented by D ; the working copy by d. As shown in Figure.2, where one of the parents has FH (or is predisposed to high cholesterol) due to the faulty LDLR gene, there are four possible combinations of the genetic information that is passed on by the parents. This means that, in every pregnancy, there is: 1 chance in 2 (ie. 2 chances in 4) or 50% chance that their child will inherit a copy of the faulty LDLR gene and will therefore be susceptible to having high cholesterol and developing coronary artery disease An equal chance (ie. 1 chance in 2) or 50% that their child will inherit the working copy of the gene from his/her affected parent as well as a working copy from his/her unaffected parent. In this case, the child will not be any more susceptible to coronary artery disease than the average person. While Figure.2 shows the father as the parent carrying the faulty LDLR gene, the same situation would arise if it was the mother. The risk that a child who carries the faulty LDLR gene will develop high cholesterol and coronary artery disease during their lifetime is different for males and females. Without treatment to control the high cholesterol (see later) About 50% of males who are genetic carriers for FH will develop coronary artery disease before the age of 50 and 100% by the age of 70 About 12% of the females who are genetic carriers for FH will develop coronary artery disease by age 50 and increases to 74% by age 70 As shown in Figure.3, where both parents have the faulty LDLR gene, there are again four possible combinations of the genetic information that is passed on by the parents. This means that, in every pregnancy, there is 1 chance in 4 or 25% chance that their child will inherit the working copy of the LDLR gene from both parents. In this case, the child will not be any more susceptible to coronary artery disease than the average person 1 chance in 2 (2 chances in 4) or 50% chance that the child will inherit the faulty LDLR gene copy and a working copy and be a genetic carrier for FH just like the parents 1 chance in 4 or 25% chance that their child will inherit the faulty LDLR gene copy from both parents. Having two copies of the faulty LDLR gene has much greater impact on the cholesterol levels and can cause childhood onset of coronary artery disease What can be done about familial hypercholesterolaemia (FH)? Without treatment, individuals affected with FH will have deposits of cholesterol in a number of different body tissues and are at very high risk of coronary artery disease and heart attack. If detected early, it can be treated by lifestyle modification (avoiding the known environmental factors that are associated with coronary artery disease) and drugs that lower the amount of harmful cholesterol in the blood. Effective treatment for both men and women greatly reduces their risk. Testing to determine if a high cholesterol level is associated with FH is therefore very important for those in population groups at higher risk such as Australians of Christian Lebanese, Afrikaans of Dutch descent. Children of an affected parent should be screened when a cholesterol-lowering diet can be safely implemented and advice given about avoidance of smoking Drug therapy is only used in children severely affected families Simply testing cholesterol levels may not provide sufficient information, as normal cholesterol levels do not necessarily rule out being a carrier for an FH-causing faulty gene. Genetic testing at an appropriate age can assist family members to determine if they have inherited the faulty gene for FH already identified in the family To date, over 1000 variations (mutations) have been identified in the LDLR gene but most are family-specific which makes the search for unknown mutation challenging and expensive Genetic counselling (see Genetics Fact Sheet 3) can provide the most up-to-date information about genetic testing (see Genetics Fact Sheet 21). Research is continuing into the benefits of childhood detection, treatment and lifestyle strategies, such as diet, for those who are carriers of the faulty gene for FH. Other Genetics Fact Sheets referred to in this Fact Sheet: 1, 2, 3, 4, 5,, 9, 11, 21, 54, 55, 56 www.genetics.edu.au Centre for Genetics Education 4
Information in this Fact Sheet is sourced from: Watts GF, Sullivan DR et al for the FamilialHypercholesterolaemia Australasia Network (2012) A New Model of Care for Familial Hypercholesterolaemia: What is the Role of Cardiology? Heart, Lung and Circulation 21: 543 550 Australian Institute of Health and Welfare (AIHW). Chronic diseases and associated risk factors in Australia, 2001. [online] Canberra. Available from: http://www.aihw.gov.au/publications/phe/cdarfa01/index.html [Accessed Nov 2012] Burnett J, et al. (2005). Familial hypercholesterolaemia: a look back, a look ahead. Medical Journal of Australia, 12: 552-5 Hooper AJ, Nguyen LT, Burnett TR et al (2012) Genetic analysis of familial hypercholesterolaemia in Western Australia. Atherosclerosis 224:430 434 Harper, P.S. (2010) Practical Genetic Counselling (7th revised Edition), Butterworth and Heinemann Read A, Donnai D. (2011) New Clinical Genetics. 2nd Edition Bloxham, Oxfordshire: Scion Publishing Ltd Trent RJ (2012) Molecular medicine: genomics to personalized healthcare. Elsevier Inc Edit history November 2012 Author/s: A/Prof Kristine Barlow-Stewart Previous editions: 2007, 2004, 2002, 2000, 199, 1996 Acknowledgements previous editions: Bronwyn Butler; Prof John Emery; Dr Stephen Li; A/Prof Sylvia Metcalfe; Gayathri Parasivam; Dr Tony Roscioli; Mona Saleh; Prof David Sullivan; Dr David Wilcken www.genetics.edu.au Centre for Genetics Education 5