Tomorrow is February 1st, which marks the first day of American Heart Month—a good opportunity to make sure we’re doing all the right things to keep our hearts healthy. It’s also a good time to talk about a gene known as PCSK9. Research into this gene, and its different variants, has taught us a lot about how the body handles cholesterol (which impacts heart health) and may lead to new therapeutic treatments for a genetic condition known as Familial Hypercholesterolemia (FH).
Here’s a staggering statistic: Scientists suspect that 1 in every 250-500 people have FH, which increases the likelihood of a person having chronically high levels of blood cholesterol and can lead to serious heart problems1-3. At its root, FH is a condition where variants in the DNA decrease the body’s ability to clear LDL cholesterol (also known as “bad cholesterol”) from the bloodstream. These variants all occur in genes that play a critical role in cholesterol metabolism, including PCSK92-4.
Your heart pumps oxygen, sugar, and cholesterol (among many other things) throughout the body via an extensive network of blood vessels. In doing so, your body is able to distribute important nutrients to different parts of the body for storage or use. You may not typically think of cholesterol as an important nutrient, but it actually plays a vital role in human physiology: It’s a precursor to many hormones, helps our body’s metabolism, and can help build cellular membranes. In excess, however, cholesterol is problematic5.
Because of this, the human body tries to regulate the distribution of cholesterol by transporting it from various organs to the liver where it can be metabolized. To do this, cholesterol, proteins, and various fats are all packed up into structures known as lipoproteins which serve as vehicles that are capable of traveling through the bloodstream and depositing their contents in specific locations. There are different kinds of lipoproteins with different functions. Low Density Lipoproteins (LDLs) take cholesterol to many places in the body, and are generally considered “bad” because they contribute to cholesterol buildup in blood vessels where it can restrict blood flow. High levels of LDLs in the blood are correlated with cardiovascular disease.
LDLs are transferred from the blood into cells when they bind to proteins on the surface of a cell. Those proteins (known as LDL receptors) recognize the LDLs, escort them into the cell, and help them unload their contents. Once this happens, the LDL receptors are sent back to the surface of the cell to start the process over again. In an effort to limit the amount of cholesterol being brought into the cell, your body uses the PCSK9 protein, which stands for proprotein convertase subtilisin/kexin type 9. PCSK9 is released by cells and helps regulate cholesterol intake by mediating the destruction of LDL receptor proteins—effectively preventing a cell from taking in LDLs6. While helpful, too much of this action can lead to the buildup of LDLs in the bloodstream and increase a person’s risk of heart disease7,8. Some people inherit variants in their DNA which can cause PCSK9 to become overactive, leading to the chronically high levels of LDLs in the bloodstream, and development of FH7.
Research and treatment In 2003, it was first reported that variants in the PCSK9 gene can cause FH7. Since that time, scientists have found that these variants cause PCSK9 to become overactive and reduce the body’s ability to clear LDLs from the bloodstream6-8. From these studies, researchers figured out that they could target the PCSK9 protein with therapeutics to suppress its effects8.
This has led to several new drugs, called PCSK9 inhibitors, that can be used on their own or combined with other therapies to decrease the risk of heart disease by nearly 50% in people with FH—not just those with variants in PCSK9!
Here’s another remarkable statistic: As many as 90% of individuals with FH aren’t aware that they have it. Often, people with FH are only diagnosed after they’ve already had a serious complication. This doesn’t need to be the case, though, because genetic testing can help you find FH earlier. DNA tests can identify FH by analyzing multiple genes linked with this disease. In many cases, inheriting just one copy of an FH causing variant from either parent can lead to high cholesterol. It’s also important for people who have been diagnosed with this disease to share the diagnosis with family members, because there is a significant chance that they have also inherited one of these variants and can take steps to avoid serious health complications.
The bottom line? Having FH doesn’t have to be scary, but knowing whether you’re affected by it is the first step. Thanks to modern science and medicine, there are many resources available to help people manage their disease and prevent serious health complications before they happen.
1Varghese, Mithun J. “Familial Hypercholesterolemia: A Review.” Annals of Pediatric Cardiology 7.2 (2014): 107–117. PMC. Web. 31 Jan. 2018.
2Bouhairie, Victoria Enchia, and Anne Carol Goldberg. “Familial Hypercholesterolemia.” Cardiology clinics 33.2 (2015): 169–179. PMC. Web. 31 Jan. 2018.
3Youngblom E, et al. Familial Hypercholesterolemia. 2014 Jan 2 [Updated 2016 Dec 8]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK174884/
4Varret, M, et al. “Genetic heterogeneity of autosomal dominant hypercholesterolemia.” Clinical Genetics, vol. 73, no. 1, 2007, pp. 1–13., doi:10.1111/j.1399-0004.2007.00915.x.
5Tabas, Ira. “Cholesterol in Health and Disease.” The Journal of Clinical Investigation 110.5 (2002): 583–590. PMC. Web. 31 Jan. 2018.
6Yadav, K., et al. “Proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors: Present perspectives and future horizons.” Nutrition, Metabolism and Cardiovascular Diseases, vol. 26, no. 10, 2016, pp. 853–862., doi:10.1016/j.numecd.2016.05.006.
7Abifadel, Marianne, et al. “Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.” Nature Genetics, vol. 34, no. 2, May 2003, pp. 154–156., doi:10.1038/ng1161.
8Ogura, Masatsune. “PCSK9 inhibition in the management of familial hypercholesterolemia.” Journal of Cardiology, vol. 71, no. 1, 2018, pp. 1–7., doi:10.1016/j.jjcc.2017.07.002.