Explore a Trait Assignment Heart Disease Scenario

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1 Explore a Trait Assignment Heart Disease Scenario 1. After reading the 23AndMe Facts on Heart Disease provided below, write a one-paragraph summary in your own words of the information provided. Include answers to the following questions: What is the difference between preliminary research and established research? How likely is heart disease to be inherited? What are the mutations that are currently tested for by 23AndMe for heart disease? If someone tested positive for one of these mutations, describe his/her increased risk for developing schizophrenia? What is the likelihood of developing heart disease if you test positive for these mutations? 2. Several research studies are referenced after the 23AndMe Facts on Heart Disease please summarize what is found in one of these research studies including a decision about how it would influence a person s decision to be tested. 3. Considering ethnic background, find a source that provides information tested in his ethnicity. 23AndMe Facts on Heart Disease: (Established Research based on 15 reported markers) Coronary Heart Disease Coronary heart disease (CHD), also called coronary artery disease, is a condition characterized by blockage of the arteries that supply the heart with blood. CHD can result in shortness of breath, chest pain (angina) and heart attack. It is a leading cause of death in both men and women worldwide. In the United States, about 1.2 million people will have a heart attack each year, and many of those heart attacks will be fatal. Healthy lifestyle choices play a major role in preventing CHD. If a heart attack does strike, prompt medical attention is vital. Delivering the Fluid of Life Your heart is the hardest working muscle in your body. Over the course of your lifetime it will beat about 3 billion times and pump a total of 60 million gallons of blood. Day in and day out, your heart keeps blood moving through your body, supplying the cells of your organs with nutrients and oxygen and taking away waste products. Your heart is divided up into four chambers that work in concert to move your blood in a continuous circuit throughout your body. The upper chambers are called atria and the lower chambers are called ventricles. Blood that has already made one journey through your body enters your heart through the right atrium. Once this chamber has filled up, the atrium contracts and a valve opens, sending the blood into the next chamber the right ventricle. The right ventricle then contracts, pumping the blood to your lungs. In the lungs, your red blood cells exchange waste carbon dioxide they picked up on their previous lap for fresh oxygen that they will deliver to your cells on their next trip around your body. After its trip to your lungs, blood returns to your heart, this time entering the left atrium. Once filled, this chamber contracts and pushes the blood into the final and largest chamber of your heart the left ventricle. The left ventricle produces the most powerful contraction of all in order to give your blood a final push on its way out into the rest of your body. Blood exiting your heart initially travels through a large artery called the aorta. Smaller arteries branch off from the aorta, like exits from a highway, each leading to a different part of the body. Some of the first arteries to branch from the aorta are the coronary arteries that supply blood to your heart. These arteries are critical because heart cells do not actually receive any oxygen or nutrients from the blood that pumps through the heart's chambers. A Clog in the Pipes As people age, the cells lining their arteries can become injured. These injuries allow fatty substances, cholesterol, cellular waste products, calcium, and other substances to build up in the walls of arteries in a process called atherosclerosis. As atherosclerosis progresses, fibrous plaques can form. Eventually these plaques can grow large enough to narrow an artery, restricting blood flow. If the plaques thicken to the point of filling an artery, they can completely block blood flow. Plaques can also rupture, and the ensuing repair process may form an artery-clogging clot. In either case, a blocked artery means that the blood supply to an organ or tissue is cut off. A blockage in any artery is serious, but if the coronary arteries are blocked and the heart is starved of blood for more than a few minutes, heart cells begin to die and get replaced by scar tissue. This is a heart attack, also called myocardial infarction (MI). The main symptoms are chest discomfort or pain; discomfort in other areas of the upper body such as the arms, back, neck, jaw, or stomach; and shortness of breath. Other symptoms may include breaking out in a cold sweat, nausea, or lightheadedness. The cell death caused by a heart attack can short out the contraction-generating electrical system of the heart. Without these pulses, the heartbeat can become dangerously irregular and the heart may stop pumping altogether- -a situation called cardiac arrest. It is critical that a person in this situation receives immediate medical attention. A heart attack that does not cause cardiac arrest can still have serious consequences. The formation of scar tissue can weaken the heart s ability to pump blood to the rest of the body efficiently, which may damage other organs and affect their ability to function properly.

2 Risk Factors for Heart Attacks Anything that promotes the formation or rupture of atherosclerotic plaques is a risk factor for heart attack. Lifestyle and environmental factors play a major role, though genetic factors are also important, as CHD and heart attacks are known to cluster in families. High blood pressure, high cholesterol, and diabetes are all conditions that can contribute to atherosclerosis. Lifestyle choices that lead to these disorders as well as genetic predispositions to them are therefore risk factors for CHD and heart attack. Ethnicity also affects one's chances of having a heart attack. Men of European ancestry are more likely to have a heart attack than women of European ancestry. Women of African ancestry, however, are more likely to have a heart attack than men of African ancestry. Smoking, excessive alcohol use, and not getting enough exercise can damage arteries and lead to atherosclerosis. High blood levels of C-reactive protein, the amino acid homocysteine, or fibrinogen are also known to be associated with clogged arteries and heart attacks. Average 24.4 out of 100 women of European ethnicity will develop Coronary Heart Disease between the ages of 45 and 79. Genes vs. Environment Heritability for coronary heart disease ranges from 39% to 56%, depending on the exact subtype of heart disease. This means that genetic factors and environmental factors contribute about equally to risk for coronary heart disease. There is also evidence that genetic factors may contribute slightly more to risk of death from coronary heart disease in men than they do in women. Genetic factors that play a role in coronary heart disease include both unknown factors and known factors such as the SNPs we describe here. Other factors that increase your risk include being older, being male, being African-American, smoking, having high blood cholesterol or high blood pressure, physical inactivity, being overweight, having diabetes, alcohol use, and stress. I. Gene or region: 9p21 region SNP: rs Numerous SNPs associated with coronary heart disease risk have been identified in a region on chromosome 9 known as 9p21. 23andMe reports your results for a SNP that is one of the most strongly associated SNPs in this region. The reported SNP is not in a known gene, but it could affect a gene in a neighboring stretch of DNA. It might also have been discovered because it serves as a signpost for a nearby, unidentified SNP. The SNP 23andMe reporter is located near two genes, CDKN2A and CDKN2B. These genes both encode tumor suppressor proteins that are involved in regulating cell proliferation, cell aging, and cell death. These processes are important in the formation of the atherosclerotic plaques characteristic of coronary heart disease. The SNP is also located near a gene that encodes a large RNA molecule with unknown function. More studies are needed to determine what role, if any, it may play in the development of CHD. Another gene close to this SNP is MTAP, which encodes a protein that recycles certain cellular waste products into the amino acid methionine. Methionine is also produced when cells break down excess homocysteine (a molecule that has been shown to be a risk factor for atherosclerosis and heart attack). It is possible that a change in MTAP function--perhaps caused by a genetic variant--could disrupt the methionine balance in cells, in turn affecting homocysteine levels and affecting risk for CHD. Multiple studies have shown this SNP to be associated with CHD in populations of European ancestry. This association has also been replicated in East Asian (Chinese) and South Asian populations. The association has been studied in an African American population, however more studies are needed to confirm the association in populations of African descent. Researchers have also reported that diet may influence the association between SNPs at the 9p21 locus and CHD. A combined ethnicity study found that individuals who had two copies of the risk version of SNPs in this region and regularly consumed raw vegetables and fruit were not at higher risk for heart attack compared to individuals who had two copies of the protective version of SNPs in this region and ate a similar diet. Individuals who had two copies of the risk version of SNPs in this region and did not regularly consume raw vegetables and fruit, however, were at higher risk for heart attack. (Read more about this finding on our blog.) Broadbent HM et al. (2008). Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum. Mol. Genet. 17(6): Preuss M et al. (2010). Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study: A Genome-wide association meta-analysis involving more than cases and controls. Circ Cardiovasc Genet 3(5): Clarke R et al. (2009). Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361(26):

3 Helgadottir A et al. (2007). A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316(5830): Horne BD et al. (2008). Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease. Circ Cardiovasc Genet 1(2): Coronary Artery Disease Consortium et al. (2009). Large scale association analysis of novel genetic loci for coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 29(5): Samani NJ et al. (2007). Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357(5): Wellcome Trust Case Control Consortium (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145): Wang F et al. (2011). Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat. Genet. 43(4): De Bree A et al. (2002). Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacol. Rev. 54(4): Kim WY et al. (2006). The regulation of INK4/ARF in cancer and aging. Cell 127(2): Do R et al. (2011). The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study. PLoS Med 9(10):e II. Gene or region: PHACTR1 SNP: rs This SNP is located in an intron of the PHACTR1 gene. While the role of this gene in CHD isn t known, this SNP is associated with heart attack risk and calcification of the coronary artery. More research is required to understand the functional role of this gene in heart disease. III. Gene or region: CXCL12 SNP: rs This SNP is not located in any known genes, however a recent study has shown that the risk version (C) of this SNP increases the activity of a nearby gene called CXCL12, which codes for a protein involved in the immune system. CXCL12 is often found in and/or regulates cells associated with CHD, such as white blood cells. Further studies are necessary to determine how CXCL12 and this SNP may be affecting risk for CHD. Coronary Artery Disease Consortium et al. (2009). Large scale association analysis of novel genetic loci for coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 29(5): Mehta NN et al. (2011). The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels. Eur. Heart J. 32(8): IV. Gene or region: SMARCA4 SNP: rs This SNP is located in an intron of the SMARCA4 gene. The role of SMARCA4 in CHD is unknown, however this SNP is very near the low-density lipoprotein receptor (LDLR) gene. LDLR and other SNPs in this area are associated with higher levels of LDL cholesterol, which is also associated with higher risk of coronary heart disease. Kathiresan S et al. (2008). Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40(2): V. Gene or region: MRPS6 SNP: rs This SNP is located near the MRPS6 gene. It is not currently known how this SNP or this gene is involved in CHD.

4 VI. Gene or region: MIA3 SNP: rs This SNP is located in an intron of the MIA3 gene, which encodes a protein thought to play a role in cell growth. It is not currently known how this SNP or this gene is involved with CHD. VII. Gene or region: WDR12 SNP: rs This SNP is located in the WDR12 gene. It is not currently known how this SNP or this gene is involved in CHD. VIII. Gene or region: MRAS SNP: rs This SNP is equivalent to rs , which is located near the MRAS gene. It is not currently known how this SNP or this gene is involved in CHD. Citation Erdmann J et al. (2009). New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41(3): IX. Gene or region: LPA SNP: rs This SNP is located in the LPA gene, which encodes apolipoprotein(a), the protein component of the lipoprotein(a), or Lp(a), particle. The exact function of Lp(a) is not well known, however a high level of Lp(a) is a known risk factor for CHD. This SNP causes a change in the protein that results in an increase in Lp(a) levels. There is also suggestive evidence that low-dose aspirin therapy may help reduce CHD risk in individuals with the CC genotype at this SNP. However, the aspirin therapy study had a limited sample size and more research is necessary to confirm this finding. Chasman DI et al. (2009). Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 203(2): X. Gene or region: ZC3HC1 SNP: rs This SNP is located within the ZC3HC1 gene and changes the sequence of the resulting protein. It is not currently known how this SNP or this gene is involved in CHD. XI. Gene or region: ABO SNP: rs This SNP is located near the ABO gene, which is the basis for the blood type system by the same name. The gene encodes a glycotransferase enzyme, which when deficient is responsible for the O blood group (non-a, non-b). As the A and B blood groups are associated with increased risk of coronary artery thrombosis, the O blood group may protect against heart attack. Although very little is known about how this SNP or gene affects risk for CHD, this SNP is also associated with levels of LDL and total cholesterol, which may contribute to overall risk for CHD.

5 XII. Gene or region: CNNM2 SNP: rs This SNP is located in the CNNM2 gene. It is not currently known how this SNP or this gene is involved in CHD. XIII. Gene or region: APOA5 SNP: rs This SNP is located near the ZNF259 and APOA5 genes. APOA5 encodes an apolipoprotein that is involved in the regulation of triglyceride levels in the blood. Defects in APOA5 are a cause of lipoprotein disorders characterized by abnormal levels of triglycerides and LDL and increased risk for CHD. The specific effect (if any) of this SNP on APOA5 is currently unknown. This SNP is also associated with levels of HDL and total cholesterol, which may contribute to overall risk for CHD. Pennacchio LA et al. (2002). Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. Hum. Mol. Genet. 11(24): XIV. Gene or region: COL4A2 SNP: rs This SNP is located in the COL4A2 gene, which encodes a collagen protein that confers stability to cellular membranes. A fragment of this collagen protein also inhibits blood vessel growth (also known as angiogenesis) and tumor growth. It is not currently known how this SNP or this gene is involved in CHD. Kamphaus GD et al. (2000). Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J. Biol. Chem. 275(2): XV. Gene or region: HHIPL1 SNP: rs This SNP is located in the HHIPL1 gene. It is not currently known how this SNP or this gene is involved in CHD.

Lecture 8 Cardiovascular Health Lecture 8 1. Introduction 2. Cardiovascular Health 3. Stroke 4. Contributing Factors

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