Observed genes

Polygenic score

Influential genes: LPA,LDLR, APOB

The LPA gene provides instructions for making a protein, which combines with LDL to form Lp(a). High levels of Lp(a) are associated with an increased risk of cardiovascular disease.

Mutations in LDLR can lead to reduced uptake of LDL cholesterol by cells, leading to higher levels of cholesterol in the blood.

If the APOB gene is altered due to mutations, it can interfere with the process of LDL cholesterol recognition by the LDL receptor, which can cause a higher concentration of LDL cholesterol in the blood.

‍

Overview

High cholesterol is a condition characterized by high levels of cholesterol in the blood. Cholesterol is a fatty substance that is synthesized by the human body and is a part of every human cell. It's an important structure needed for hormone synthesis (for example vitamin D), utilization of other fats, and forming cell membranes. Cholesterol is both synthesized by the human body and absorbed from food intake. Once the amount of cholesterol exceeds the physiological values, cholesterol reacts with other substances and can form plaques that build up on the walls of arteries, a state also known as atherosclerosis. Atherosclerosis can result in a narrowing of the vessels, restricted blood flow and, therefore, limited oxygen supply to the tissue behind the affected vessel. Without treatment, patients are at a high risk of developing heart failure, strokes, or heart attacks. 

‍

Cholesterol is carried through the blood bound to lipoproteins. Based on those lipoproteins, it's possible to point out different types of cholesterol. Each type of cholesterol has a different effect, with some being protective and some increasing the risk of complications.

• LDL (low-density lipoprotein) - referred to as “bad cholesterol”, makes up most of the body's cholesterol. High levels of LDL increase the risk of developing heart disease and stroke. 
• HDL (high-density lipoprotein) - the so-called “good cholesterol” helps to return LDL from arteries to the liver and therefore lowers the risk of atherosclerosis and other complications. 

‍

The most common cause of high cholesterol is an unhealthy lifestyle. Unhealthy eating habits, lack of physical activity and smoking increase the blood levels of LDL and decrease HDL values. 

‍

Prevalence & Risk factors

High cholesterol is a very common condition representing a serious and increasing threat, especially in developed countries, due to unhealthy lifestyle habits. The global prevalence among adults is estimated to be approximately 39%.^[1]  Western European countries, such as Greenland, Iceland, Andora, and Germany have the highest cholesterol levels in the world. The lowest cholesterol levels have been reported in African countries. Raised cholesterol levels majorly increase the risk of heart disease (almost one-third of ischemic heart disease worldwide is attributed to high cholesterol levels) and stroke.

‍

Risk factors are closely associated with an unhealthy lifestyle:

• Unhealthy diet - intake of “bad” fats can increase LDL levels. 

• Saturated fats - in baked goods, fried and processed foods. 
• Trans fats - present in fried and processed foods or margarine, that is often used instead of butter. 

• Lack of physical activity - insufficient physical activity leads to lowering of the good cholesterol (HDL). 
• Smoking - has an effect on both HDL and LDL cholesterol, especially in women. It also damages blood vessels, facilitating plaque attachment.
• Alcohol abuse

‍

Other risk factors include:

• Obesity (BMI > 30)
• Age (Men 45 or older and women 55 or older have a higher risk of high cholesterol and heart disease)
• Race 
• Sex (more prevalent in women - LDL levels increase after menopause)
• Type 2 diabetes
• High blood pressure
• Positive family history

‍

Genetics

There has been no exact gene discovered that would be responsible for high cholesterol as we know it in most of the population. But genetics definitely play a role, mainly in conditions causing the increase of cholesterol levels, such as obesity, overeating, or diabetes. Patients with a positive family history are at a higher risk if combined with an unhealthy lifestyle. This type of inheritance is called multifactorial. 

‍

In the smaller percentage of cases, high cholesterol can actually be a result of a disease with a clear genetic pattern. Familial hypercholesterolemia is the world’s most common autosomal dominant genetic disease leading to an extreme increase in LDL values, causing the development of heart disease at a very young age. It is caused by mutations in the LDL receptor gene (LDLR), which encodes a protein that removes LDL cholesterol from the bloodstream. Furthermore, mutations in other genes, such as PCSK9, can also cause high cholesterol.^[5] 

‍

In Macromo, we use polygenic risk scores and causative evidence-based genetic variants for evaluation. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.

‍

Signs & Symptoms

High cholesterol doesn't have any symptoms and it's only diagnosed based on blood levels. People are often unaware that their cholesterol is high. The absence of symptoms may increase the risk of suffering a stroke or heart attack; however, regular check-ups may help control cholesterol levels and prevent complications

‍

Diagnosis

A blood test, also known as a lipid panel, is the only way to assess cholesterol levels. The lipid profile/panel test evaluates LDL, HDL, Triglycerides, and total cholesterol levels. Everyone older than 20 should undergo a blood test at least once in five years to prevent possible complications early enough. 

‍

Fasting ranges are the following:

• LDL

• Normal values: 1,2 - 3,0 mmol/l
• Values above 3 mmol/l increase the risk of atherosclerosis and connected diseases.
• Desired value for patients with coronary heart disease is < 1,8 mmol/l

• HDL

• Normal values for men: 1,0–2,1 mmol/l.
• Normal values for women: 1,2–2,7 mmol/l.
• Values under 1 mmol/l increase the risk of heart disease.

• Triglycerides (TAG) should be < 1,7 mmol/l
• Total cholesterol

• Normal values: 2,9–5,0 mmol/l. 
• Recommended values for sick people with higher cardiovascular risk: <4,5 mmol/l.
• Patients at the highest risk (already developed cardiovascular disease) should hold their total cholesterol under < 4 mmol/l

‍

Therapy

If your cholesterol is found to be high, medical specialists will recommend various treatment options, starting with lifestyle changes.

• General diet changes 

• The Mediterranean diet can be recommended due to its low content of saturated fats and high amounts of desired mono- and polyunsaturated fats. 
• Avoiding alcohol consumption

• Regular exercise
• Weight management

‍

If those changes aren't sufficient alone, medications, most commonly statins, may be prescribed. But it's important to realize that medications are insufficient without permanent lifestyle changes. 

• Statins - blocking an enzyme needed in cholesterol synthesis. 

• Atorvastatin, fluvastatin, lovastatin

• Cholesterol absorption inhibitors

• Ezetimibe

• Bempedoic acid - same principle as statins with lower side effects. 
• Bile-acid-binding resins - lowering cholesterol indirectly by increasing bile synthesis. 

• Cholestyramine, colesevelam, colestipol

• PCSK9 inhibitors - increasing the LDL absorption in the liver. 

• Alirocumab, evolocumab

‍

Prevention

Good news is that high cholesterol is often preventable and treatable. Combining a healthy diet and regular exercise, as well as avoiding smoking and alcohol, could all be really efficient ways  to prevent the development of high cholesterol. 

• Healthy diet

• Avoid saturated and trans fats - fried and processed foods, coconut oil, cakes, biscuits, sausages, bacon, or cheese. 
• Lower sugar intake, especially processed sugars in soft drinks, syrups, or candy.
• The daily intake of cholesterol in diet shouldn't exceed 300 mg per day (e.g.. 1,5 egg).^[2]

• Regular exercise - at least 30 minutes of moderate exercise per day. 
• Avoid smoking
• Limit your alcohol consumption to a maximum of 1 drink per day for women and 2 drinks per day for men.^[3]

‍

And most importantly - don't postpone regular check-ups and blood tests to prevent any complications on time. 

‍

Prognosis

If the patient adheres to lifestyle changes and treatment recommendations and therefore stabilizes cholesterol levels, the prognosis is very positive and the patient's risk of complications is not significantly increased. A 10% decrease in total blood cholesterol levels can reduce the incidence of heart disease by as much as 30%.^[4]

Recommendations

• Adhere to regular checkups and blood tests, high cholesterol doesn't usually cause any symptoms until it's too late. 
• Make sure that your daily intake of cholesterol in diet shouldn't exceed 300 mg per day (e.g. 1,5 egg) 

‍