Let's talk about Familial Hypercholesterolemia & Genetics
Learn more about how a person’s genetics, age, and other factors all may influence the risk of developing high cholesterol.
Concerned about how your genetics and lifestyle might be contributing to your risk? Talk to your doctor. Want to learn a little more about a common genetic cause for high cholesterol called Familial Hypercholesterolemia? Read on.
What is Familial Hypercholesterolemia and how common is it?
Familial hypercholesterolemia (FH) is a genetic condition associated with very high levels of cholesterol in the blood, specifically low-density lipoprotein (LDL), or “bad” cholesterol. High cholesterol due to FH increases the risk for early cardiovascular disease, which can lead to a heart attack.
FH in medical terms can be broken down into two words. “Familial” refers to a condition that can run in a family due to shared genetics. “Hypercholesterolemia” breaks down into “hyper”, meaning high or elevated, and “cholesterolemia”, meaning the presence of cholesterol in the blood.
In the general population, LDL cholesterol levels tend to start increasing in middle age and are often influenced by diet and other lifestyle choices. (You can learn more about complex factors involved in cholesterol levels on the LDL cholesterol page.) But for people who have FH, LDL levels can be elevated from birth. In both people with and without FH, high LDL cholesterol increases the risk for heart disease, but in people with FH the risk is higher because their cumulative exposure to elevated LDL is longer.
FH is serious, yet many people don’t know they have it. It’s estimated that one in 250 people around the world have FH, and according to the Family Heart Foundation, as many as 70% of people with FH have not been properly diagnosed. It affects all sexes, and the prevalence of FH in men is the same as the prevalence of FH in women.
Symptoms of FH can be overlooked or confused with other conditions. These include high levels of total cholesterol and LDL, chest pain, coronary artery disease, fatty deposits around the eyes and around the body, and other heart disease symptoms. A heart attack is often the first sign. It is also common to find LDL cholesterol levels over 190 mg/dL in adults with FH and over 160 mg/dL in children. High LDL cholesterol increases the risk for heart disease, and in people with FH the risk is higher because their exposure to elevated LDL starts younger.
A family history of high cholesterol isn’t considered a symptom of FH, but it can be a red flag and a reason to look more closely and ask more questions. Finding out your mom or dad has familial hypercholesterolemia, or a sibling or other relative is affected, can be a reason to take action and see if you also have it.
Other terms for the condition have been used in the past. Familial hypercholesterolemia is the preferred term over familial hyperlipidemia.
Is FH more common in men or women?
FH is caused by a genetic variant that is inherited in the same way by men and women. Men and women are at the same risk (50%) of inheriting a genetic variant for FH if a parent has it. But, the growing body of research on FH is revealing that the presentation of the condition and how well it is managed may be different between males and females. This shows the complexity involved in genetic and non-genetic factors even for conditions that are caused by a single gene. For example, if left untreated, men with FH have a 50% risk of having a heart attack by age 50, and women have a 30% risk of having a heart attack by age 60. You can learn more about complex factors involved in cholesterol levels in our article about LDL cholesterol.
Is FH more common in certain ancestry groups?
Studies on the frequency of FH variants have shown that the condition is present worldwide, but some FH variants are more common in certain ancestral populations than others. The 24 variants included in the 23andMe Familial Hypercholesterolemia Genetic Health Risk report* are most commonly found in people of European and Lebanese descent, as well as in the Old Order Amish. There are over 1,000 variants known to cause FH.
Racial and ethnic disparities in access to health care for genetic conditions have been well-documented, and FH is no exception. Research on FH shows that Asian and Black individuals with FH are less likely to have recommended LDL levels, which may be due to social determinants of health like insurance status. More research in the under-diagnosis and under-treatment of FH is needed to reduce these disparities. 23andMe is leading efforts to increase diagnosis and reduce health disparities for under-represented groups.
What causes familial hypercholesterolemia?
The amount of cholesterol we have in our blood stream results from a combination of genetics, environment, and age. LDL (low-density lipoprotein) helps carry cholesterol from from your liver to other cells in your body. The body needs cholesterol to build cells, make hormones, and carry out other tasks. But if there’s too much LDL cholesterol in the blood, it can build up on the walls of blood vessels. This can make it harder for the blood to flow to the heart, brain, and other parts of the body. For this reason, LDL cholesterol is sometimes called “bad” cholesterol.
LDL cholesterol levels tend to start increasing in middle age and are often influenced by diet and lifestyle. However, people with FH have very high levels of low-density lipoprotein (LDL), often from birth, because of an altered gene that runs in the family. Certain genetic variants associated with the condition decrease the liver’s ability to remove excess LDL cholesterol from the blood. The result is higher levels of LDL in the bloodstream, which in turn can lead to cardiovascular disease and a higher risk for heart attack.
23andMe research shows that nearly 80% of people in their 20s who have a variant linked to FH have high LDL cholesterol levels, which is significantly higher than people who don’t have one of these variants. No matter their age, the research suggests adults with a variant linked to FH are significantly more likely to develop high LDL cholesterol compared to those without an FH variant.
There are several genes linked to FH. The APOB gene provides instructions for making a protein called apolipoprotein B. This protein helps LDL cholesterol bind to LDL receptors on the surface of cells, particularly in the liver. Certain variants in this gene reduce the ability of LDL cholesterol to bind to its receptor, causing fewer LDL cholesterol particles to be removed from the blood.
The LDLR gene provides instructions for making a protein called low-density lipoprotein (LDL) receptor. This protein helps move LDL cholesterol from the blood into the liver, where it is broken down for recycling or removal. Certain variants in this gene either reduce the number of LDL receptors made, or disrupt LDL receptor function, resulting in higher levels of LDL cholesterol in the blood.
Although less common, the PCSK9 and LDLRAP1 genes have also been linked to FH, and there are likely others yet to be discovered.
Does familial hypercholesterolemia run in families?
If one person has familial hypercholesterolemia, it is much more likely that others in the family do as well. For example if your mother or father has FH, you are more likely to have it because FH is caused by variants that are inherited from your parents.
One important step you can take if you learn about an FH variant is to talk about it!
Because FH is hereditary and genetic variants can be passed down from generation to generation, you may want to alert family members about a potential health risk they might have. Parents, siblings, and children–and even more distant family like aunts, uncles, and cousins–might carry an FH variant, too. And FH isn’t the only type of high cholesterol that can run in families. Other types, like high lp(a) and LDL cholesterol, can run in families, too.
Talk with family members about health history to see if there are any red flags that may suggest FH runs in the family, like young death from a heart attack in a family member or heart issues for multiple generations. It’s important to connect with a healthcare provider to find out what to do next, especially if you or someone else in the family has high cholesterol.
Not quite sure how to talk about it? Genetic counselors have special training that makes them a great partner in communicating with family about genetic risk.
Is familial hypercholesterolemia genetic?
Yes. FH is one of the most common genetic conditions. FH is linked to variants in multiple genes. Two of these genes are called APOB and LDLR. There are over 1,000 genetic variants known to be associated with FH.
Variants in these genes are passed from parent to child in an autosomal dominant pattern of inheritance. People with genetic variants causing FH are likely to have elevated LDL cholesterol levels, which is associated with an increased risk for heart disease.
The 23andMe Familial Hypercholesterolemia Genetic Health Risk report* looks for 24 specific variants linked to two of these genes, APOB and LDLR.
If you’ve been told there is an APOB or LDLR variant in your family or have a close family member with a variant in one of these genes, you could be at higher risk of genetic high cholesterol, specifically Familial Hypercholesterolemia. If your parent carries one or more variants in genes associated with Familial Hypercholesterolemia, these variants can be passed onto you, and you can pass them to your children.
There are some genetic causes of FH that are not included in the 23andMe Familial Hypercholesterolemia Genetic Health Risk report*, including variants in the PCSK9 gene. 23andMe does not test for variants in this gene, meaning that you could carry a risk for FH but the 23andMe test would not detect it. There are likely to be other genes and variants identified in the future that cause FH.
Heterozygous familial hypercholesterolemia vs. homozygous familial hypercholesterolemia
Under the umbrella of familial hypercholesterolemia are two subtypes. One is called heterozygous familial hypercholesterolemia and the other form is called homozygous familial hypercholesterolemia. The main difference is the way the condition is inherited in a family and how early in life symptoms begin.
Most people with FH have the heterozygous type, meaning they inherited a variant in an FH-associated gene from only one parent. This is seen in 1 in 250 people and considered common.
People with homozygous familial hypercholesterolemia have inherited a genetic variant from both parents. It is considered rare for this to happen (1 in 300,000, according to the FH Foundation). People with this form of FH are at highest risk of symptoms, and earlier in life. Someone with homozygous familial hypercholesterolemia might have a heart attack in their teens and 20s rather than 40s or 50s.
Although early detection is important for all people with FH, it’s especially important for those with homozygous FH.
Are there other risk factors for FH?
Although FH itself is genetic, the risk for developing heart disease related to FH is also impacted by lifestyle and other factors.
In general, the risk for heart disease increases as a person gets older. With age, blood vessels become less flexible, which can impede blood flow to the heart. Also, deposits called plaques can build up over time along blood vessels and restrict blood flow to the heart. Men who are 45 or older and women who are 55 or older have a greater risk of developing heart disease.
Smoking increases the risk for heart disease. The chemicals found in tobacco smoke can damage the inner lining of blood vessel walls, increase heart rate, and cause irregularities in the timing of heartbeats, making a person more susceptible to having heart disease. Smoking also interacts with other risk factors for heart disease, including high blood pressure, high cholesterol, and obesity, to increase the risk for heart disease even more. Exposure to secondhand smoke, including smoke from a burning cigarette and smoke exhaled by smokers, also increases the risk for heart disease since it contains many of the same harmful substances found in the smoke inhaled by smokers.
Men are generally at higher risk than women for developing heart disease earlier in life, but women’s risk increases after menopause. Certain risk factors around the time of menopause, including weight gain and high blood pressure, increase a woman’s risk for heart disease.
High blood pressure
Chronic high blood pressure increases the risk for heart disease. High blood pressure puts excess strain and increased workload on the heart and blood vessels, which can damage them over time. Damaged blood vessels are more vulnerable to plaque deposits, which can limit blood flow to the heart. This can lead to chest pain or heart attack.
A diet high in saturated fat, trans fat, dietary cholesterol, and added sugars is associated with increased heart disease risk. In contrast, studies have found foods rich in soluble fiber such as fruits, vegetables, and legumes are associated with reduced heart disease risk.
In general, being physically active can help reduce the risk for heart disease by lowering a person’s LDL cholesterol levels and blood pressure. Current U.S. guidelines recommend that adults should get at least 150 minutes a week of moderate-intensity activity or 75 minutes a week of vigorous-intensity activity for a healthier life.
Being overweight increases a person’s risk of developing heart disease. In addition, excess weight typically worsens other risk factors for heart disease, including high blood pressure and diabetes.
Other genetic factors
Studies have identified more than 1,000 variants linked to FH and associated with an increased risk for heart disease. These variants are in the LDLR and APOB genes, as well as other genes including PCSK9. This report includes one variant in the APOB gene and 23 variants in the LDLR gene. In addition, there are other genetic variants that may impact LDL cholesterol levels. However, most of these variants are either rare or have only a small effect on risk.
Having diabetes, especially type 2 diabetes, increases a person’s risk for heart disease. People with diabetes have a two to four times greater risk of dying from heart disease than people without diabetes. The risk is greater in women than in men. High blood sugar can damage blood vessels, so it is important to control blood sugar levels and manage other modifiable risk factors, such as obesity and physical activity, to minimize risk for heart disease.
High lipoprotein(a) levels
Lipoprotein(a), also called Lp(a), is a lipoprotein similar to LDL. High Lp(a) in the blood is associated with an increased risk for heart disease. Lp(a) may deposit in blood vessels and contribute to plaque buildup, which may reduce blood supply to the heart. Lp(a) levels are primarily determined by inherited genetic factors.
Consult with a healthcare professional before making any major lifestyle changes. Keep in mind that healthy lifestyle modifications can help lower LDL cholesterol levels and reduce heart attack risk, however, effective treatment for FH typically requires cholesterol-lowering medication in addition to any lifestyle changes.
Can genetic testing for familial hypercholesterolemia tell me if I am at risk for high LDL cholesterol?
Yes. Genetic testing can be one way to find out about your risk for FH and is sometimes the first way people with FH find out they should speak with a healthcare provider and have their blood cholesterol levels checked.
A genetic test can be a first step in finding out about a risk for high cholesterol. Knowing earlier means treatments like medication to lower cholesterol levels can begin earlier in life.
It’s important to know there are different types of genetic tests, and some test for more FH variants than others. 23andMe’s Familial Hypercholesterolemia Genetic Health Risk report* looks for 24 genetic variants linked to FH – one variant in the APOB gene and 23 variants in the LDLR gene. You can get the Familial Hypercholesterolemia Genetic Health Risk report* with the 23andMe Health + Ancestry Service.
Other genetic testing options can offer a more thorough picture of your risk for FH, so it’s important you and your healthcare provider look at all of the information from family health history, blood cholesterol levels, and test results to determine the right action for you.
What can I do if I learn that I have a variant for familial hypercholesterolemia?
If you learn that you have a genetic variant for FH, the biggest step to take next is talking with a healthcare provider who understands the condition. They can help in the process and guide you to the right care that works for you.
The great news for people who find out they have FH is that there are treatment options for FH. Early treatment of FH can substantially reduce the risk for heart disease. Familial hypercholesterolemia treatment options typically include changes to diet and taking a statin medication.
Other treatments are being explored in clinical trials, and some are used to treat patients who meet certain criteria. One treatment, called lipoprotein apheresis, is used to treat those whose LDL levels can’t be controlled by medication and lifestyle alone. It removes harmful cholesterol from the blood through a process similar to dialysis.
As the world of genetic research and therapeutics grows, we can expect to see a better path to diagnosis and treatments for Familial Hypercholesterolemia and other genetic conditions like it.
Consult with your health care provider about your report before making any major lifestyle changes and find out the steps you can take to prevent the impacts of familial high cholesterol.
You can learn more about FH and how to manage it, as well as connect to educational and community resources through the Family Heart Foundation.
*23andMe health predisposition reports include both reports that meet FDA requirements for genetic health risks and reports which are based on 23andMe research and have not been reviewed by the FDA. The test uses qualitative genotyping to detect select clinically relevant variants in the genomic DNA of adults from saliva for the purpose of reporting and interpreting genetic health risks. It is not intended to diagnose any disease. Your ethnicity may affect the relevance of each report and how your genetic health risk results are interpreted. Each genetic health risk report describes if a person has variants associated with a higher risk of developing a disease, but does not describe a person’s overall risk of developing the disease. The test is not intended to tell you anything about your current state of health, or to be used to make medical decisions, including whether or not you should take a medication, how much of a medication you should take, or determine any treatment. The Familial Hypercholesterolemia genetic health risk report is indicated for reporting of one variant in the APOB gene and 23 variants in the LDLR gene and describes if a person has variants associated with an increased risk of developing very high LDL cholesterol, which can lead to heart disease. The majority of the variants included in this report have been most studied in people of European and Lebanese descent, as well as in the Old Order Amish. For important information and limitations regarding each genetic health risk report, visit 23andme.com/test-info/.
Familial hypercholesterolemia – Diagnosis and treatment – Mayo Clinic Retrieved April 4, 2023 from https://www.mayoclinic.org/diseases-conditions/familial-hypercholesterolemia/diagnosis-treatment/drc-20353757
5 Lifestyle Tips for People with FH Retrieved April 5, 2023 from https://familyheart.org/5-lifestyle-tips-people-fh#gsc.tab=0
Rarer Genetic Cholesterol Conditions | HEART UK Retrieved April 5, 2023 from https://www.heartuk.org.uk/genetic-conditions/rarer-genetic-conditions
Health disparities from adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH™ patient registry. Retrieved May 22, 2023 from https://pubmed.ncbi.nlm.nih.gov/29080546/.