Are APOL1 Genetic Variants the Missing Link Between African Ancestry and Kidney Disease?

If you are of African ancestry, your risk of chronic kidney disease (CKD) is much higher than that of people of European ancestry. One reason is genetic. About 15% of African Americans carry two copies of specific APOL1 gene variants, called G1 and G2. These variants originally evolved in Sub-Saharan Africa because they protect against deadly parasites that cause African sleeping sickness. But there is a trade-off. When inherited from both parents, G1 and G2 increase the risk of kidney damage by up to tenfold.

What is the APOL1 Gene?

The APOL1 gene makes a protein called apolipoprotein L1. It helps your body fight infections, including HIV, and also interacts with HDL cholesterol in ways that affect lipid transport. But when present in high-activity genetic forms, the APOL1 protein can damage kidney podocytes, the specialized cells that filter blood. This injury leads to protein in the urine, swelling, high blood pressure, and eventually, kidney failure. Studies show that APOL1-related disease explains up to one-third of non-diabetic kidney disease in African Americans.

Not Everyone With the Gene Gets Sick

Not everyone with two APOL1 risk variants develops kidney disease. Only about 20–25% do. Researchers call this the “two-hit hypothesis.” Carrying the gene variants “loads the gun,” but something else has to “pull the trigger.” Chronic inflammation, viral infections (such as HIV or COVID-19), autoimmune disorders, high blood pressure, and diabetes are all examples of second hits that can accelerate disease.

What Can Be Done?

For now, strategies focus on reducing kidney stress and lowering inflammation. This means controlling blood pressure with ACE inhibitors or ARBs, using SGLT2 inhibitors when appropriate, limiting salt intake, and keeping weight and blood sugar in check. Preventing and treating infections is especially important for people with APOL1 variants. Clinical trials are now underway to test targeted treatments, including small molecules that block APOL1 channels, antisense therapies that lower APOL1 expression, and drugs that reduce inflammation through interferon and JAK/STAT pathways.

Understand Your Risk

Because APOL1 testing isn’t routine yet, some advanced genetic panels now include it to help people understand their risk earlier.