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Home > Learn > Heart Disease > Genes Can Cause Coronary Artery Disease
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Heart Disease
  Genes Can Cause Coronary
Artery Disease

By Stephanie Trelogan, MS

Reviewed by Christopher Friedrich, MD, PhD and Andy Avins, MD

 

There is no question that coronary artery disease (CAD) runs in families. We know that first-degree relatives of people who develop CAD at an early age are at a much higher risk for developing CAD than the general population. By better understanding the genetics of this disease, you can more accurately assess your risk and be on the lookout for early warning signs.

 
 
 

Inheritance Patterns

Researchers have identified more than 250 genes that may play a role in CAD. Although researchers are a long way from confirming whether even half of those genes are actually involved, we do know that CAD often results from the blended effects of multiple genes. These so-called polygenic effects mean that the genetics of CAD are extremely complicated, with many different genes influencing a person's risk. In most cases, CAD is not inherited in a clearly dominant or recessive manner. Instead, a person may have mutations in some genes that increase risk and mutations in other genes that decrease risk. On average, a person's risk level is approximately midway between those of the parents.

Rather than discuss all 250 genes that have been implicated, it makes sense to focus on several of the best-understood genes. As you examine the following information, keep in mind that this field is rapidly changing. The roles of many of these genes have not yet been fully defined.

For recent news about genes that are implicated in CAD, see Related News below.

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LDL Metabolism

Many genes linked to CAD are involved in how the body removes low density lipoprotein (LDL) cholesterol from the bloodstream. If LDL is not properly removed, it accumulates in the arteries and can lead to CAD.

  • LDL Receptor. The protein that removes LDL from the bloodstream is called the LDL receptor (LDLR). In 1985, Michael Brown and Joseph Goldstein were awarded a Nobel prize for determining that a mutation in this gene was responsible for familial hypercholesterolemia, or FH. People with FH have abnormally high blood levels of LDL. In FH, one or both of the LDLR genes has a mutation that makes the receptor inactive or inefficient. One in 500 people have a mutation in at least one of their LDLR genes.

    Unlike some diseases, where one specific mutation is responsible for the disease, many different mutations in the LDLR gene can lead to FH. In some people with this disorder, the receptor is simply not produced. In others, it binds LDL poorly or not at all. In the most severe cases, people with FH may actually have heart attacks in childhood.

    FH is inherited in a dominant manner. This means that you only have to inherit a defective LDLR allele from one parent in order to be at a very high risk for developing CAD. Even in people who have just one defective gene, the consequences are dramatic: LDL cholesterol levels are twice normal by the age of two, and CAD appears by age 30 to 60 in men and 50 to 80 in women. (For news about detecting people with familial hypercholesterolemia, see Related News below.)



  • Apolipoprotein E. As with LDLR, mutations in the apo E gene affect blood levels of LDL. More than 30 mutant forms of apo E have been identified. Interestingly, not all of these mutations are bad. People carrying the e4 version of the gene tend to have higher cholesterol levels than the general population, but levels in people with the e2 version are significantly lower. The apo E gene has also been implicated in Alzheimer's disease.
  • Apolipoprotein B-100. Apo B-100 is a component of LDL. Mutations of this gene result in LDL staying in the blood for longer than normal, leading to very high LDL levels. In people of Western European descent, one person in 500 has a mutation in the Apo B-100 gene. A mutation called ApoB3500 is the most common mutation found in people with a disease called familial defective apolipoprotein B-100.
  • Apolipoprotein(a). Apo(a) is a glycoprotein that combines with LDL to form a particle called Lp(a). Lp(a) is often found as a part of plaques on blood vessels. People with high Lp(a) levels (over 30 mg/dL) in their blood have a higher risk of developing CAD. The actual structure of Lp(a) varies greatly from person to person, so the genetics of mutations in the apo(a) gene are not well understood. Lp(a) levels are not part of routine lipid panels and must be specifically ordered. If you have a relative with high Lp(a) levels, be sure to ask your doctor to measure your own levels. Lp(a) levels may be reduced by treatment with niacin, or by hormone replacement therapy in postmenopausal women.

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Homocysteine Metabolism

High blood levels of homocysteine (a condition called hyperhomocystinemia) is known to be a risk factor for CAD. In almost all human tissues, normal cellular processes generate a waste product called homocysteine. Homocysteine is then cleared from the blood and recycled.

  • MTHFR is one of the enzymes that clears homocysteine from the blood. In the US, about one in eight people have a mutation in the gene that makes MTHFR, which results in mild elevations in blood homocysteine. People with mutations in both of their MTHFR genes may have slightly higher homocysteine levels. Doctors treat hyperhomocystinemia with folate supplements.
  • Cystathione B-synthase, or CBS, is another enzyme involved in homocysteine metabolism. People who have mutations in both alleles of the CBS gene have a condition called homocystinuria, in which blood levels of homocysteine are so high that it can be detected in the urine. Homocystinuria is usually diagnosed in childhood; it typically causes mental retardation as well as heart disease.

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Blood Pressure Regulation

An enzyme called angiotensin Converting Enzyme (ACE) helps the body regulate blood pressure by causing blood vessels to constrict. Even though ACE has been studied extensively, many of the investigators have reported conflicting results. Several studies have implicated a particular mutation (called the ACE (I/D) polymorphism) in CAD. However, these studies involved small numbers of people and have yet to be repeated with larger groups.

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Other Genes

  • Apolipoprotein A1 is a protein that is packaged along with cholesterol in high density lipoprotein (HDL, the "good cholesterol"). Certain mutations in the apo A1 gene result in low apo A1 levels, low HDL levels, early heart attacks, and strokes. In general, overall HDL levels are a good indication of Apo A1 levels; Apo A1 is not usually measured separately.

    Scientists are especially interested in one particular mutation in Apo A1 found in some residents of Milan, Italy. The "Milano" mutation results in very low levels of HDL; however, this mutant HDL is exceptionally efficient at removing plaque from arteries. Thus, although these people have very low levels of HDL, they also have a low incidence of CAD. Pharmaceutical companies are currently trying to develop a compound that will mimic this genetic effect.
  • Glycoprotein IIb/IIIa is a protein that is present on the outer surface of certain blood components that play a critical role in blood clotting. A recent study found that this gene was mutated in half of patients under age 60 who were admitted to a hospital intensive care unit with CAD. Since heart attacks often result from the formation of blood clots, this is an interesting candidate gene for heart disease. New treatments that focus on glycoprotein IIb/IIIa are now available for heart attack patients.

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Genetic testing

In general, tests for specific genetic mutations are not performed in CAD. There are several reasons for this. First, it is not clear how much additional information this kind of information provides beyond the usual methods for assessing cardiac risk. Second, the best way you can avoid CAD is to modify your lifestyle to reduce environmental risk factors. This is especially true if you have a strong family history of CAD. While this subject is still under study, it is likely that people with a strong family history may be more susceptible to the effects of risk factors. If you have a strong family history of CAD, your main course of action is to vigorously reduce risk factors that you can control, such as smoking, blood pressure, diabetes, obesity, and cholesterol levels.

For some genes, indirect tests can be used to determine if there is a mutation. For example, it is much easier and less expensive to measure blood levels of homocysteine than it is to perform genetic testing. Most people with mild elevations of homocysteine respond well to treatment with folate supplements. If a person fails to respond to folate treatment, other causes of elevated homocysteine, such as vitamin B12 or vitamin B6 deficiency, should be tested. Cholesterol levels are another example. Regardless of the specific genetic cause of elevated cholesterol, the approach to testing and treatment is the same.

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Related News
In order to view these articles you will need to have a MyGeneticHealth account. If you are not already a member, selecting the article will automatically take you to a page where you can sign up.
Study finds genetic link to high cholesterol
Gene may predict success of heart failure drug
Family history useful in identifying risk for cardiovascular disease
Lp(a) levels and apoE4 allele predictive of coronary events in men
Gene variant linked to higher heart disease risk
Family heart disease? Your arteries may be clogged too
Genetic register facilitates identification of familial hypercholesterolemia patients
Obscure gene family linked to early heart disease
Company finds 6 proteins linked to heart disease

References

Higgins, M. (2000) Epidemiology and prevention of coronary heart disease in families. American Journal of Medicine, 108(5), 387-395.

Brown, M.S., et al. (1981) Regulation of plasma cholesterol by lipoprotein receptors. Science, 212, 628-635.

Rosenblatt, D.S. (1995) Inherited disorders of folate transport and metabolism. In C.R. Scriver et al. (Eds.), The Metabolic and Molecular Bases of Inherited Disease (pp.3111-3128). New York, NY: McGraw-Hill Book Co.

Ellsworth, D. L., et al. (1999) Coronary heart disease: at the interface of molecular genetics and preventive medicine. Am J Prev Med, 15(2), 122-133.


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