From Risk to Resilience: Tracking a Genetic Variant's Impact on Kidney Diseases

African Americans are five times more likely to develop chronic kidney disease (CKD) than European Americans. One of the most common forms of CKD is focal segmental glomerulosclerosis (FSGS), which causes scar tissue to develop in the small parts of the kidney that filter waste from the blood. It can lead to kidney failure, which can only be treated with dialysis or transplant.  

Researchers have discovered that a genetic variant in the APOL1 gene may provide protection against developing CKD in some Black Americans.  

Two African ancestry-associated genetic variants in the APOL1 gene, G1 and G2, likely helped combat two forms of African sleeping sickness. However, people with two copies of these variants, such as G1/G1, G1/G2, or G2/G2, are at higher risk for developing FSGS and other kidney diseases.  

“The effect is so strong that kidney diseases associated with these variants are referred to as APOL1 mediated kidney disease,” said Rasheed Gbadegesin, MD, MBBS, Wilburt C. Davison Distinguished Professor of Pediatrics and Nephrology. 

However, less than 20 percent of people with these high-risk genotypes go on to develop CKD. “This tells us that this is actually a complex inheritance,” Gbadegesin said. “There are possible genetic and environmental modifiers that may predispose or prevent development of kidney disease despite the high-risk genotype.”  

Gbadegesin is part of a large collaboration spearheaded by Simone Sanna-Cherchi, MD, from Columbia University that worked to determine why some people with the G1/G2 and G2/G2 variants are more likely to develop kidney diseases than others. Their results were published in Nature Communications

The team analyzed data from patient cohorts who have the high-risk genotypes with or without FSGS. They found that if G2/G2 or G1/G2 is co-inherited with another genetic variant called N264K, the individuals are protected from developing FSGS.  

This has big – and immediate - implications. 

First, a person with both the G2/G2 or G1/G2 and N264K variants no longer needs to be classified as having a high risk of kidney disease. “If these individuals present with kidney diseases,” Gbadegesin said, "there is a need to meticulously search for other causes of kidney diseases.”  

Additionally, people with both G2/G2 or G1/G2 variants and N264K variant should now be eligible to donate a kidney, which could increase the donor pool and save more lives. Recognizing the effect of this variant will also help in selecting patients for clinical trials and potentially identifying new treatment for patients with APOL1 mediated kidney disease.  

Gbadegesin notes that the N264K variants is present in only about 2.6% of individuals of African ancestry and will not explain why majority of patients with the high-risk genotype do not develop disease. He and other researchers suspect that other hidden modifiers probably exist that can either reduce or increase the risk of developing kidney disease in individuals with the high-risk genotype G1/G1, G2/G2, or G1/G2.  

In addition to Gbadegesin, study authors from Duke include Brandon Lane PhD, Kinsie Huggins BS, and Megan Stangl MS.