Introduction

Diet and physical activity aren’t the only factors which can lead to high cholesterol and other lipid disorders. The cause of dyslipidaemia, abnormal levels of lipids, including cholesterol, in the blood, can be down to your genetics. Understanding the genetic aspects of dyslipidaemia makes it possible for earlier action to be taken by people, their families, and healthcare providers. This article will shed light on these inherited conditions, including their importance and what you can do to manage them. 

What is dyslipidaemia?

Dyslipidaemia is when the lipids (described below) in the blood are not at the expected levels. This greatly increases your risk of being affected by cardiovascular disease. Dyslipidaemia can be inherited (primary), where mutations in your genes change your body’s ability to break down lipids. It can also be caused by your lifestyle or pre-existing conditions (secondary). In this article, we will focus mainly on primary dyslipidaemia.¹

What are lipids?

Lipids are a natural, fat-like substance in your body. This includes a number of different substances, such as phospholipids, which are required for cells in our body to function; fats, which the body stores for energy; and steroids, like cholesterol. 

There are 2 main types of cholesterol. Low-density lipoprotein (LDL) is commonly described as bad cholesterol and carries most of your cholesterol that can build up and cause problems in your blood vessels. High-density lipoprotein (HDL), described as good cholesterol, helps your body get rid of excess cholesterol.²

Having the right levels of lipids in the body is important for a healthy heart. High LDL and total cholesterol cause an increased risk of cardiovascular disease.² 

How genes influence lipids 

There are various genes which are involved in keeping the amount of lipid in the blood under control. Mutations in one or more of these genes can lead to dyslipidaemia. 

Some dyslipidaemias are a result of a single dominant mutation in a gene. This means that if you have this mutated gene and your child inherits just one copy of this gene, it is enough to cause dyslipidaemia. In other words, there is a 50% chance that your child will inherit dyslipidaemia. Other dyslipidaemias are inherited recessively, where one copy of the mutated gene is required from each parent for the child to inherit the dyslipidaemia, a 25% chance of dyslipidaemia.³ 

Familial hypercholesterolaemia

What is familial hypercholesterolaemia?

Familial hypercholesterolaemia (FH) is one of the most common inherited dyslipidaemias. Put simply, the name means you have high cholesterol levels in your blood which has been passed down through your family. This is because of a gene mutation which makes your liver unable to remove LDL (bad cholesterol) the way it should, causing high amounts of LDL in the blood. This causes LDL to build up in your arteries, which makes it more difficult for blood to flow through. As a result, you will also be at a high risk for developing cardiovascular disease, heart attacks, and stroke, if the condition is not treated appropriately.

The genetics of FH

As it is a dominant condition, a child has a 50% chance of inheriting FH from their parents. Gene mutations cause FH because of their negative effect on LDL receptors, which are required for LDL to be properly removed from the blood by the liver. Mutations can occur in the following genes:

• LDLR gene mutations lead to decreased LDL receptors^3,4
• APOB gene mutations stop LDL from binding to the receptor, so it will not be broken down 
• PCSK9 gene mutations make the receptors break down faster, so less of them are available³ 

Signs and symptoms of FH

Here are some of the signs and symptoms that could mean you have FH:

• Having family members with FH
• Having a heart attack/stroke, particularly when you are young
• High cholesterol levels seen in blood test results
• Family history of early strokes and/or heart disease

There can be physical cholesterol buildup, which you may also see:

• Buildup which shows around the knees, knuckles, or tendons, such as the Achilles
• Lumps of buildup on the skin around the eyes
• A white circle in the coloured area of the eyes (iris)

Diagnosis

Your doctor will look to see whether your blood test shows high cholesterol levels. They will ask you about your family history, including any history of high cholesterol levels or cardiovascular conditions. 

You will then usually be referred for genetic testing and other evaluation if you are found to have high cholesterol and/or other signs, such as the visible cholesterol deposits mentioned previously.⁵ The test will check if you have any of the gene mutations involved in FH, using a DNA sample. This can be taken from your blood or swabbed from inside your mouth. 

It is strongly encouraged that your siblings, parents, and children are tested if you are confirmed to have FH, as they may also have the condition.⁴ Diagnosing FH earlier is important to ensure a better outcome for your health, as you can receive treatment and make any necessary lifestyle changes to reduce cholesterol levels.

Treating and managing FH

Treatment and management of FH is crucial for lowering your chances of being affected by cardiovascular diseases, heart attacks, and other complications. 

Statins are a type of medication which are often prescribed for FH, as they aid in lowering LDL levels.⁶ You may be prescribed a different kind of medicine in place of statins, or along with them. Examples of these are bempedoic acid, ezetimibe, and inclirisan. 

It is also important that lifestyle changes are made to manage cholesterol levels effectively. This includes frequent physical activity, managing your weight, and avoiding smoking and drinking alcohol. 

Making changes to your diet, along with other management methods already mentioned, will provide further help in reducing LDL levels. It is encouraged for those with FH to:

• Consume less saturated fats, for example, by replacing these with unsaturated fats like nuts, avocados, and vegetable oils such as olive oil
• Consume less foods which have high cholesterol content, to a maximum of 300mg of cholesterol a day 
• Eat foods high in fibre to decrease the amount of cholesterol that is kept in the body after digestion

Other inherited dyslipidaemias 

Familial combined hyperlipidaemia (FCH)

Unlike FH, FCH is a result of multiple gene mutations rather than just one. With FCH, you may also have varying levels of different lipids along with, or instead of, high cholesterol. FCH causes excess cholesterol production and fat around the liver. Like other dyslipidaemias, it greatly increases your risk for cardiovascular diseases.^3,7

Familial Hypertriglyceridaemia (FHT)

FHT involves various gene mutations, like FCH. These lead to higher levels of triglycerides (a type of lipid), but cholesterol levels are normal. People with FHT are usually insulin-resistant and are obese.³

Type 1 hyperlipoproteinaemia (T1H)

T1H is known by several names, including familial chylomicronaemia syndrome. T1H is inherited recessively and causes very high levels of a type of lipid called triglycerides. This is commonly as a result of mutations in the gene that makes the enzyme, lipoprotein lipase (LPL). This enzyme is responsible for breaking down triglycerides. 

Some signs of T1H are:

• Very high triglyceride levels that are found after testing
• Cholesterol deposits on the skin
• Enlarged liver & spleen
• Inflammation of the pancreas, which is recurring 

The diagnosis of T1H involves looking at your triglyceride level, if they are very high, and not because of any pre-existing condition, then it is likely that you have T1H. A genetic test can then confirm this by looking for specific gene mutations that occur in T1H. 

Medicines commonly given to lower triglycerides or cholesterol, such as those given in FH, do not work when you have T1H. The main treatment they use is maintaining a diet that is very low in fat.³

Summary

Dyslipidaemias can cause negative effects on the heart, such as causing cardiovascular disease. They present as various distinct conditions affecting levels of different types of lipids, and in primary dyslipidaemias, each caused by different genetic mutations. Because of this variation, different treatments are required for each respective condition. Examples of these are familial hypercholesterolaemia (FH) and type 1 hyperlipoproteinaemia (T1H). 

Understanding primary dyslipidaemias is crucial for earlier diagnosis, allowing these conditions to be managed from a younger age and preventing complications, both in the present and later in life. It also allows earlier diagnosis and treatment to be put in place for affected relatives. With these aspects combined, you can greatly improve the outcome of your health while living with a primary dyslipidaemia.