African-Enriched Genetic Variants Hold the Key to Treating High Cholesterol

Stephane Castel
Variant Bio
Published in
3 min readJan 29, 2020


Image credit: Getty Images

LDL cholesterol (also known as “bad” cholesterol) is one of the most closely monitored biomarkers due to its strong association with coronary artery disease. Measuring cholesterol is part of standard health check ups across the world, and people from India to Idaho can be overheard asking what they can do to lower their cholesterol levels. Sometimes a person’s cholesterol levels don’t seem to match up with their diet and lifestyle, and for this reason, as a marker of cardiovascular health, cholesterol levels can seem senseless. There are people who eat terribly and haven’t exercised a day in their lives, with healthy levels, and those who eat healthy and hit the gym every day, with stubbornly high levels.

It’s now known that genetics plays a role in determining cholesterol levels, and may be partly to blame for these seemingly senseless levels. In fact, genetics has been directly implicated in extreme cases of very high and very low LDL cholesterol. On the high end, genetic studies of French families with extremely high cholesterol, termed hypercholesterolemia, discovered they had an overactive version of the gene PCSK9, which encodes an enzyme involved in cholesterol metabolism¹. Building on this, researchers in Texas looked for other changes in the PCSK9 gene by studying people with very low levels of cholesterol. They found that people with non-functional versions of the PCSK9 gene had very low levels of cholesterol, exactly mirroring the effects seen in people with the overactive versions².

Genes where versions that increase or decrease function have opposite effects on a trait are compelling targets for therapeutic intervention and can inspire entirely new types of drugs (discussed at length in this great blog). Thus, began the journey to develop PCSK9-inhibitors, which would ultimately become one of the most effective ways to treat high cholesterol³. This drug is an antibody against the PCSK9 protein, which inactivates it, mirroring the version of the gene found in those individuals with very low cholesterol.

Still, this story is not without a few bumps in the road. PCSK9 inhibiting drugs don’t reduce heart attack risk as much as experts expected, and sky high prices have made insurance companies hesitant to cover prescriptions⁴. Nonetheless, there are new versions of the drug on the horizon that will lower costs and reduce the frequency that treatment is needed by using small RNA technology as opposed to antibodies⁵.

Perhaps one of the most interesting parts of the PCSK9 story is that the Texas study discovered the protective version of the gene in African Americans. In fact, the protective version of the gene is not all that rare among people of African ancestry⁵, being present at a frequency of over 2%. The same protective version is almost entirely absent from people of European ancestry, with a frequency of less than 0.01%. This is a powerful reminder of how vital it is that genetic studies include people of diverse ancestries. This is not just important to help understand population-specific phenomena, but as this story illustrates, to make discoveries that shed light on new biology and ultimately inspire therapies to people of all ancestries.

1. Abifadel, M., Varret, M., Rabès, J. P., Allard, D., Ouguerram, K., Devillers, M., … Boileau, C. (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics, 34(2), 154–156.

2. Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H. (2006). Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease. New England Journal of Medicine, 354(12), 1264–1272.

3. Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., … Pedersen, T. R. (2017). Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine, 376(18), 1713–1722.


5. Fitzgerald, K., White, S., Borodovsky, A., Bettencourt, B. R., Strahs, A., Clausen, V., … Simon, A. (2017). A highly durable RNAi therapeutic inhibitor of PCSK9. New England Journal of Medicine, 376(1), 41–51.

6. Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., & Hobbs, H. H. (2005). Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genetics, 37(2), 161–165.