What is Polygenic Hypercholesterolemia?
Hypercholesterolemia, or unusually high levels of cholesterol in the blood, can be caused by factors such as genetics and environment. There are two main types: familial hypercholesterolemia, caused by a single gene mutation, and polygenic hypercholesterolemia, which results from multiple genetic variations.
For instance, only 40% of people diagnosed with familial hypercholesterolemia actually have a gene mutation. This suggests that the rest could have severe hypercholesterolemia because of polygenic causes. They are typically diagnosed with polygenic hypercholesterolemia, a more common condition.
Both forms of hypercholesterolemia increase the amount of low-density lipoprotein cholesterol (LDL-C) – the ‘bad’ cholesterol – in the person’s blood. This puts them at a higher risk of developing atherosclerotic cardiovascular diseases (ASCVDs), or heart diseases caused by the hardening and narrowing of arteries, at an early age.
Though it can be tough to tell the difference between polygenic and familial hypercholesterolemia, it’s very important to diagnose and treat people with polygenic hypercholesterolemia because they have a higher risk of developing heart disease. Doing so can help reduce the risk of complications from the disease.
What Causes Polygenic Hypercholesterolemia?
Polygenic hypercholesterolemia is a condition where high cholesterol levels in the body are caused by a mix of inherited genes and environmental factors. Instead of being caused by a single major gene mutation, it’s linked to multiple small-effect changes in genes, known as single-nucleotide polymorphisms (SNPs). Researchers have discovered over 50 regions in our DNA that are linked with high levels of bad cholesterol (LDL-C).
Each of these gene changes, or SNPs, only slightly influences cholesterol synthesis (how it’s made), metabolism (how it’s used), and clearance (how it’s gotten rid of), but together they can lead to increased LDL cholesterol levels.
In addition to these genetic factors, lifestyle choices like poor diet, lack of exercise, obesity, and unhealthy habits also likely contribute to high cholesterol levels and play a role in the development of polygenic hypercholesterolemia.
Risk Factors and Frequency for Polygenic Hypercholesterolemia
Over half of the people living in the United States, more than 100 million people, have high levels of LDL-C (bad cholesterol). However, only half of these individuals are receiving treatment, and less than 35% manage to control their cholesterol levels properly. This lack of control increases their risk for ASCVD (atherosclerotic cardiovascular disease). Certain groups, including Asian Indians, Filipinos, Japanese, and Vietnamese, are more likely to have elevated LDL-C levels compared to White individuals.
Recent studies indicate that a condition called heterozygous familial hypercholesterolemia, which involves high cholesterol levels, may affect about 1 in 250 people. This translates to about 30 million people worldwide. Unfortunately, it’s estimated fewer than 10% of familial hypercholesterolemia cases are accurately identified. Of the people diagnosed with this condition, roughly 20% to 30% are actually believed to have a different high cholesterol condition called polygenic hypercholesterolemia.
Signs and Symptoms of Polygenic Hypercholesterolemia
Polygenic hypercholesterolemia usually doesn’t show any symptoms and is usually found during routine check-ups. When doctors are taking a patient’s medical history, they should ask if any family members have had heart-related issues or diseases at a young age. An early diagnosis of heart disease is typically made in men 55 or younger and women 65 or younger. In addition, it’s important to check if any immediate family members with high cholesterol and early heart disease are present. Healthcare providers should also check lifestyle habits such as tobacco use, diet, and exercise levels, all of which can contribute to high cholesterol levels and an elevated risk of heart disease.
During a physical exam, doctors should look for a whitish ring around the cornea, known as corneal arcus. This is particularly indicative in younger patients. Another sign to look out for is lumpy deposits (xanthomas), especially in finger extension tendons or the Achilles tendon. The use of ultrasound on the Achilles tendon can help detect these deposits.
Testing for Polygenic Hypercholesterolemia
Screening adults for high cholesterol levels, also known as dyslipidemias, is a topic with differing opinions among health experts. That being said, identifying high cholesterol levels in young adults is crucial as it allows doctors to intervene early and reduce the person’s risk of developing heart disease over their lifetime. Some guidelines do not recommend universal screening for individuals under 40 who do not have risk factors for heart disease. However, others like the US National Cholesterol Education Program Adult Treatment Panel III suggest that all adults should start getting checked for cholesterol levels at the age of 20 and repeat the test every 5 years.
The most effective initial screening would involve a standard fasting or non-fasting lipid profile, a blood test that measures different types of fats in your blood, including triglycerides, LDL-C (bad cholesterol), total cholesterol, HDL-C (good cholesterol) and non-HDL-C.
There isn’t a consensus on which genes and gene sites should be included in genetic risk assessments for high cholesterol. In addition, it’s still unclear whether the effects of each gene should be weighed differently. Genes that increase LDL-C levels in a condition called polygenic hypercholesterolemia, tend to run in families, which makes screening family members essential.
Before diagnosing familial hypercholesterolemia or polygenic hypercholesterolemia, which are inherited forms of high cholesterol, doctors need to rule out other potential causes of high cholesterol. These may include kidney conditions like nephrotic syndrome, an underactive thyroid (hypothyroidism), or liver disease.
Treatment Options for Polygenic Hypercholesterolemia
People with genetic conditions that lead to high cholesterol levels are at a greater risk of developing heart disease, so it’s really important to manage these conditions. The usual treatment includes a combination of changes to diet and lifestyle, medication and sometimes more involved procedures like apheresis, which is a treatment that filters the blood to remove excess cholesterol. All of these treatment strategies have been proven to reduce heart-related problems and minimize visible signs of heart disease on imaging scans. Handling these genetic cholesterol conditions entails continuous management and regular check-ups, as sadly, as present, there’s no outright cure.
Lifestyle advice for all patients includes quitting smoking, getting regular exercise, and managing body weight. It’s also important to control any underlying health conditions that can worsen cholesterol levels, such as diabetes or high blood pressure. Following a diet low in saturated fats can reduce the levels of LDL (bad cholesterol) by 8% to 10%, while limiting daily cholesterol intake to less than 200 mg can lead to a reduction of LDL levels by 3% to 5%. However, it’s noted that lifestyle changes alone often aren’t enough to lower LDL cholesterol levels, and patients tend to need medication as well.
Medication plays a significant role in controlling cholesterol levels, particularly when LDL cholesterol levels exceed 190 mg/dL. The treatment commonly begins with achieving a minimum 50% reduction through the use of statins, which are drugs usually given as the first step. If the cholesterol level doesn’t reduce enough with statins alone, other drugs may be introduced.
High-intensity statins such as atorvastatin or rosuvastatin are usually the initial treatment of choice. These drugs inhibit an enzyme called HMG-CoA reductase and have been known to lower the risks associated with heart diseases.
If cholesterol levels remain high with statins alone, a drug called ezetimibe, which blocks cholesterol absorption in the gut, might be added to the treatment plan. When taken with statins, ezetimibe has been shown to provide further reduction in LDL cholesterol levels in the blood.
If cholesterol levels are still not under control, drugs called PCSK9 inhibitors may be introduced. These drugs are given via an injection under the skin and can considerably decrease levels of LDL cholesterol and lipoprotein (a), another fatty substance linked to heart disease.
Additional treatment options include a drug called bempedoic acid which works by inhibiting a key enzyme required in cholesterol production. When added to ongoing statin therapy, the daily addition of bempedoic acid can decrease LDL cholesterol levels further. Another drug, inclisiran, interferes with PCSK9 production and can achieve a significant reduction in LDL cholesterol levels when given as a subcutaneous injection every six months.
For patients at a high risk of heart disease who are unable to achieve desired cholesterol levels with medication, a procedure known as lipoprotein apheresis could be considered. This treatment, which is provided every 1 to 2 weeks, can reduce LDL cholesterol levels by 50% to 75%.
What else can Polygenic Hypercholesterolemia be?
There are many factors considered when looking at what causes high levels of LDL-C, or “bad cholesterol”. Before we label it as polygenic hypercholesterolemia, it’s vital to rule out other potential causes of high cholesterol. These may include:
- Diabetes
- Drinking too much alcohol
- Hypothyroidism (an underactive thyroid)
- Nephrotic syndrome (a kidney disorder)
- Chronic kidney disease
- Anorexia
- Metabolic syndrome
- Obesity
Some medicines, like glucocorticoids, diuretics, and cyclosporine, might also raise LDL-C levels. When it comes to genetic causes, there are several that warrant significant consideration like familial hypercholesterolemia, familial combined hyperlipidemia, and dysbetalipoproteinemia.
What to expect with Polygenic Hypercholesterolemia
Patients with higher levels of LDL-C, often called “bad cholesterol,” tend to have a larger buildup of plaque in their arteries. This condition, known as atherosclerosis, is more common in people with a genetic condition known as “monogenic hypercholesterolemia” compared to those with “polygenic hypercholesterolemia.”
To simplify, individuals with monogenic hypercholesterolemia received gene for this condition from one parent while those with polygenic hypercholesterolemia received genes from both parents. Patients with polygenic hypercholesterolemia are usually managed by their regular doctor, whereas those with monogenic hypercholesterolemia may need to see a cholesterol expert. People with polygenic hypercholesterolemia usually have half the number of relatives affected by this condition compared to those with a monogenic cause, so they do not require an extended family check for the condition.
Several treatments can be used individually or together to lower LDL-C levels. Use of cholesterol-lowering drugs called statins has cut heart disease deaths by more than a third in patients with a hereditary form of high cholesterol known as familial hypercholesterolemia. Those with familial hypercholesterolemia who’ve been treated show similar heart disease rates to the general public who don’t carry the condition. Research indicates that over the last 20 years, men have seen a greater drop in heart disease rates than women, possibly due to differences in the courseness of statin treatment.
Possible Complications When Diagnosed with Polygenic Hypercholesterolemia
People with high cholesterol levels, a condition known as hyperlipidemia, are twice as likely to develop heart diseases, also known as Cardiovascular Disease (CVD), compared to those with normal cholesterol levels. For individuals with high cholesterol due to genetic factors, clinically known as hypercholesterolemia, the probability of developing Coronary Heart Disease (CHD) at an early age is even higher compared to the general population. These people are more susceptible to health conditions such as heart attack (myocardial infarction), poor blood circulation in their limbs (peripheral limb ischemia), or potentially experiencing a stroke.
Risks of High Cholesterol:
- Twice the risk of developing heart disease
- Increased likelihood of developing coronary heart disease at a young age (for those with genetic high cholesterol)
- Increased chances of conditions such as heart attack
- Poor blood circulation in limbs
- Higher risk of stroke
Preventing Polygenic Hypercholesterolemia
Polygenic hypercholesterolemia is a condition in which someone has high cholesterol levels due to both genetic issues and environmental factors. Some of these factors can include unhealthy eating habits, being overweight, and leading a lifestyle with little to no physical activity. It’s really important to control these high cholesterol levels because they can put you at a greater risk of heart disease and stroke.
Your healthcare provider can check for this condition by taking a thorough look at your medical history and doing a blood test. There are several ways to treat this condition, which include changes in your lifestyle, like improving your diet and exercising more, and medications your doctor may prescribe to help lower your cholesterol levels.
What makes polygenic hypercholesterolemia sneaky is that you might not have any symptoms, further emphasizing why it’s so important to regularly check in with your family doctor.
