What Is Polygenic Hypercholesterolemia?

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Polygenic hypercholesterolemia (PH) is a genetic condition that causes high cholesterol. It is characterized by increased levels of low density lipoprotein (LDL) cholesterol with near-normal levels of serum triglyceride concentrations.

PH specifically describes a condition in which several relatively small genetic defects combine to produce elevated cholesterol levels, as opposed to just one single dominant genetic defect, as in a monogenic condition such as familial hypercholesterolemia (FH).

PH tends to be less severe than FH, but still needs to be monitored and treated, as elevated LDL cholesterol levels can increase your risk of heart disease and stroke.

This article will review the symptoms, risk factors, and treatment options for polygenic hypercholesterolemia.

Cholesterol test

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Polygenic Hypercholesterolemia Symptoms

Polygenic hypercholesterolemia is usually asymptomatic, so the condition is detected during routine screening. In rare cases. the following symptoms may appear:

  • Xanthomas, or fatty yellow deposits under the skin: These can be found on the skin of the hands, elbows, buttocks, and knees.
  • Xanthelasmas, or cholesterol deposits in the eyelids 
  • Chest pain: This can be the first sign of coronary artery disease, prompting one to seek a healthcare professional for help. 
  • Early and sudden cardiac or cardiovascular events such as heart attack or stroke in severe cases

What Causes PH?

Polygenic hypercholesterolemia is the most common cause of elevated serum cholesterol concentrations because it is influenced by multiple factors such as a high-fat diet, obesity, a sedentary lifestyle, and genetic alterations.

The majority of people with an acquired form of hypercholesterolemia have multiple genetic mutations that contribute to the development of altered LDL metabolism.

In a polygenic disease (a disease due to changes in many genes), the contribution of any single genetic change is very small. However, the combination of many can lead to significantly elevated LDL levels.

Polygenic hyperlipidemia can present as severely as FH, but often presents in milder or more variable forms than FH. This is because the number of changes inherited by any one family member is always different.

Lifestyle factors also play a major role in the development of disease, so healthcare professionals will likely ask you about factors that can increase your risk. These include cigarette smoking, diabetes mellitus, eating patterns, and a sedentary lifestyle.

How PH Is Diagnosed

PH is a clinical diagnosis that is usually made without having to get genetic testing. Your healthcare provider will look at the results of your lipid panel (a blood test that analyzes fat in the blood), as well as your family history and physical exam, to make a diagnosis.

PH is characterized by moderately elevated levels of LDL cholesterol (140–300 mg/dL) with serum triglyceride concentrations within the normal range.

Clinically, it is often difficult to differentiate between PH and FH, but genetic tests can be useful in making the distinction between the two. The majority of hypercholesterolemia cases test negative for mutations in LDLR, APOB, and PCSK9—the predominant mutations in FH.

However, high cholesterol levels may still run in families. In these cases, genetic testing for multiple variants in LDL metabolism often points to PH. If left untreated, PH significantly increases the risk of developing coronary heart disease.

Understanding Your Treatment Options

Treatment for individuals with polygenic hypercholesterolemia focuses on promoting a healthier, more active lifestyle, such as adopting a heart-healthy, low-sodium, low-fat diet like the DASH diet and increasing physical activity.

In addition to making these important lifestyle changes, people with PH typically also need prescription cholesterol-lowering medication, such as statins.

Statin drugs are the staple of pharmacological treatment because they help to quickly lower your risk of heart attack and stroke with minimal side effects.

The most commonly used statins are:

  • Mevacor (lovastatin)
  • Pravachol (pravastatin)
  • Zocor (simvastatin)
  • Lescol (fluvastatin)
  • Lipitor (atorvastatin)
  • Livalo (pitavastatin)
  • Crestor (rosuvastatin)

Other cholesterol-lowering medicines include:

  • Bile acid-sequestering resins: These medications block the absorption of fat by the stomach by binding them to bile acids. This decreases the retention of cholesterol. Bile acid sequestering resins also increase LDL receptors.
  • Zetia (ezetimibe): Studies have shown that the use of Zetia (ezetimibe) results in an additional 15% to 20% reduction in LDL cholesterol regardless of the therapeutic approach used.
  • Fibrates: These medications—such as Lopid (gemfibrozil) or Triglide/Fibricor (fenofibrate)—are often prescribed to those who can’t take statins. In addition to lowering cholesterol, this class of drugs also serves as potent triglyceride-lowering medications.
  • Nicotinic acid: This is a B-vitamin that has been shown to reduce LDL cholesterol levels by 10% to 20%, reduce triglycerides by 20% to 50%, and raise HDL cholesterol by 15% to 35%.
  • PCSK9 inhibitors: This newer class of medications has provided some hope for those who are unable to get their cholesterol under control by other means. Some commonly used drugs are Praluent (alirocumab) and Repatha (evolocumab).

Polygenic hypercholesterolemia can be exacerbated by risk factors such as diabetes mellitus and obesity, so treating these underlying conditions is key to reducing cholesterol and CAD risk. 

Summary

Polygenic hypercholesterolemia is a common genetic condition that causes elevated levels of “bad” LDL cholesterol. This condition is the result of many genes that work together to influence LDL metabolism.

Lifestyle factors can exacerbate the condition and increase your risk of cardiovascular disease, so it’s important to eat a healthy diet and stay active to protect your heart. Your healthcare provider may also recommend cholesterol-lowering medication.

A Word From Verywell

Polygenic hypercholesterolemia usually presents with no symptoms. When it finally appears as a heart attack or stroke, it might be too late.

To avoid these devastating consequences, it is important to get routine cholesterol screening, especially if you have a family history of high cholesterol or early heart disease. 

It is never too early to seek guidance from a healthcare professional, as they can help you figure out how to live the most heart-healthy life possible. If you have chest pain or trouble breathing, seek immediate medical attention.

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5 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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