Polygenic hypercholesterolaemia

Polygenic hypercholesterolaemia is a term used to describe raised cholesterol caused by variations in a number of different genes, as opposed to just one.

When there is only one gene involved, this is known as a ‘monogenic’ condition, such as familial hypercholesterolaemia (FH).

What is polygenic hypercholesterolaemia?

Hypercholesterolaemia means too much cholesterol in the blood. And polygenic means there are many different genes involved.

If you have polygenic hypercholesterolaemia, this means your cholesterol is raised because of the small effects of many different genes added together. It's quite common, around 1 in 20 to 1 in 100 people have it.

Polygenic hypercholesterolaemia is a term that can be used to describe slightly or moderately raised cholesterol. If cholesterol is raised to very high levels, our specialists refer to this as severe polygenic hypercholesterolaemia. This can look like FH but the cause is different, as many genes are involved.

How does polygenic hypercholesterolaemia raise your cholesterol?

Cholesterol is built up and broken down in your body and used for different jobs to keep you healthy. Certain genes are involved in these processes and a problem with any of them can mean that cholesterol isn’t taken out of your blood or broken down as it should be. This means there will be too much cholesterol in your blood.

What causes polygenic hypercholesterolaemia?

Polygenic hypercholesterolaemia is a genetic condition where you inherit a number of genes which add up to raise your cholesterol.

Researchers have found 12 different small gene changes that they think are important in polygenic hypercholesterolaemia. Each of these small gene changes can raise your LDL cholesterol a little. If you inherit several of these, they may have an additive effect which can lead to much higher cholesterol.  

Your parents might not have high cholesterol

It’s possible to have this condition even if your parents don’t have high cholesterol themselves – they might have only a small number of genetic variants each – but if you inherit the genetic variants from both your parents, you will then have a larger number.

What are the symptoms of polygenic hypercholesterolaemia?

High cholesterol doesn’t usually have any symptoms itself. It's the effect that high cholesterol has on your body that can lead to health problems affecting the heart and blood vessels, and symptoms such as angina (chest pain) might not develop until the problem is quite serious. This is why it's a good idea for everyone to get a cholesterol test – even if you’re young and feel perfectly healthy.

How is polygenic hypercholesterolaemia diagnosed?

Most people with polygenic hypercholesterolaemia have slightly or moderately raised cholesterol. If a cholesterol test shows your cholesterol is slightly or moderately raised, your healthcare professional should assess your risk of heart disease.

If a cholesterol test shows that your cholesterol is very high, your doctor will want to find out why, so that they can give you the right treatment. They might refer you to a lipid clinic for an assessment, including a genetic test.

Genetic testing

This is where specialists look at your genes in detail to look for any changes which could be raising your cholesterol.

Specialist lipid clinics can look for the main genes involved in FH (a monogenic condition, which means it involves just one gene). There are four genes associated with FH – LDLR, APOB, PCSK9 and APOE. If an alteration can’t be found in at least one of these genes, the specialists can offer to look for the 12 common gene variants that together may raise LDL cholesterol into the FH range, causing severe polygenic hypercholesterolaemia.

Finding out your risk of heart disease

If you have raised cholesterol, in the long term this can lead to heart disease, so your doctor will try to get an idea of your risk and your overall health. For example, they might:

• ask whether you smoke
• ask how much alcohol you drink
• ask how active you are
• measure your blood pressure
• test your blood sugar to see if you have diabetes.

Your healthcare professional can also assess your risk using a risk assessment tool such as QRISK3, which looks at your risk of disease over the next 10 years. These tools can sometimes underestimate the risk if you have very high cholesterol so your healthcare professional should always use their clinical judgement, as well as the assessment tools, to decide if you need treatment.

There is also QRISK3 lifetime risk which measures risk over a longer time period which is useful in younger people and recommended in current national guidelines.

How is polygenic hypercholesterolaemia treated?

The treatment you need will depend on your cholesterol level and your risk of cardiovascular disease (such as heart disease and stroke). Your doctor will talk to you about bringing your cholesterol levels down to prevent serious illnesses. For example, with:

• Lifestyle changes – for example, stopping smoking, drinking alcohol only within the recommended limits, being physically active and eating a heart-healthy diet .
• Medications – these include statins, ezetimibe and other medicines that lower cholesterol. 

What are the differences between polygenic hypercholesterolaemia and FH?

Although the severe type of polygenic hypercholesterolaemia can sometimes look like FH, they are separate conditions with some key differences.

With polygenic hypercholesterolaemia, cholesterol may not be raised from birth as it is with FH, but it can be affected by diet and lifestyle, increasing age, by the menopause in women, and by other factors related to your health and environment. The condition can still raise your risk of cardiovascular disease (such as heart disease and stroke) so you should be offered an assessment of your risk of heart disease, and offered treatment and lifestyle advice.

Testing for the condition in your family

With other genetic conditions caused by a single gene (such as FH) whole families can have a genetic test to look for the altered gene in each family member. With polygenic hypercholesterolaemia, this is not yet recommended because the many different genes involved will not all be inherited together.

Instead, relatives can be offered a cholesterol test. If they have raised cholesterol, they can get advice about their cholesterol and other risk factors for heart disease, such as family history.

It is thought that an altered gene can be found in 40-60% of people who are suspected of having FH. For those where no FH-causing gene can be found, some may have FH but we don’t have the technology to find the gene responsible yet – this is known as a ‘novel gene' alteration.

When an altered gene can’t be found, most people are thought to have polygenic hypercholesterolaemia. 

Having polygenic hypercholesterolaemia and FH at the same time 

It’s possible to have polygenic hypercholesterolaemia and FH at the same time. Around one in 250 people in the UK have FH caused by a major change in one of the four genes linked to FH. Some of these will also have one or more of the 12 small gene changes which may have an additive effect to raise their cholesterol a little higher.

This is why there can be a difference in cholesterol levels between people with FH, particularly in members of the same family – they can inherit the FH-causing gene and each inherit a different number of the other small gene changes.

In one example, two sisters were tested for FH. Both had very high cholesterol which met the criteria for diagnosing FH, but only one needed further cascade testing of her family (where genetic testing is used to search for the same gene in other family members).

• The first sister had a total cholesterol level of 15 mmol/L and was found to have a gene known to be involved in FH, plus a ‘polygenic background’, where other genes are involved.
• The second sister had a lower total cholesterol level of 8.5mmol/L. She did not have the ‘altered’ gene involved in FH, but did have the polygenic background.
  

Further investigation

For those who are found to have a small number of genes (where it does not look like there are lots of different genes involved) this may indicate the presence of a single FH-causing gene which has not yet been found by scientists studying genetics and FH.

Specialists recognise that at least 10% of people diagnosed with definite FH (for example, because they have symptoms such as swollen tendons caused by fatty deposits, known as ‘tendon xanthoma’) do not have a known FH-causing gene and probably have one that hasn’t been identified yet.

People with a low SNP score may be eligible for whole genome sequencing to find a novel (new) cause of FH.

Some people with FH and a low SNP score were recruited for the 100,000 Genome Project – an initiative in the UK to study the role of genes in health and disease. Recruitment was completed in 2018 but research and analysis for this project is ongoing.

Testing Lpa

When investigating high cholesterol levels, lipid specialists can also check for other lipoproteins which raise the risk of developing CVD, such as Lipoprotein (a), or Lp(a).

Lp(a) is a large lipoprotein made by the liver which is similar to an LDL particle but it has a sticky protein attached, known as Apo (a). When Lp(a) blood levels are high it is thought to increase the risk of and speed up narrowing in the arteries, and may increase blood clotting.

Specialists can now do a blood test to measure Lp(a), particularly if there is a family history of early heart disease or stroke. 

Learn more about high Lp(a)