APOL1 Gene Discovery: New Pathways to Cure Kidney Disease

Barry Freedman, MD
Barry Freedman, MD

In a major breakthrough, two variants in the gene called apolipoprotein L1 (APOL1) were found to be associated with a family of common kidney diseases in African-Americans, including non-diabetic or “hypertension-attributed” end-stage renal disease (ESRD), idiopathic focal segmental glomerulosclerosis (FSGS), lupus nephritis, sickle cell nephropathy and HIV-associated nephropathy. 

These genetic variants cause up to 40 percent of all kidney disease in African Americans receiving renal replacement therapy with dialysis or kidney transplantation. The genetic association is one of the strongest ever reported for a common disease and provides an explanation for the higher rates of non-diabetic kidney disease in African Americans, relative to Caucasians. New pathways for treating and preventing kidney disease in tens of thousands of patients may result from this finding. 

The APOL1 gene discovery represents a major step toward an improved understanding of what causes the kidney disease that had long been ascribed to hypertension in the African American population. It will also lead to the reclassification of idiopathic FSGS in this population.  Together, FSGS and “hypertension-attributed” kidney disease account for more than $8 billion annually in dialysis costs. The APOL1 gene variant is associated with more than a ten-fold increase in risk for FSGS and more than a seven-fold increase in risk for “hypertension-attributed” ESRD. 

“A cure for non-diabetic kidney disease may directly result from this finding. APOL1 is that important,” said Barry I. Freedman, MD, John Felts III Distinguished Professor and chief of the Section on Nephrology at Wake Forest Baptist Health.

The Wake Forest Baptist team is focused on better understanding the mechanisms of how these gene variants cause kidney disease, as well as identifying factors that trigger the variants to produce kidney disease. The variants have proven to be useful for genetic screening in African Americans and in the selection of kidney donors. They will eventually assist in developing preventive measures for those at risk.  “Now that the gene has been found, unlocking how this gene and its protein products damage kidney cells will bring us closer to finding a cure for non-diabetic kidney disease in African-Americans,” Freedman said. 

The focus of our Wake Forest Baptist nephrology genomics research team is figuring out how the APOL1 gene damages kidney cells.” This discovery is the continuation of more than 25 years of groundbreaking work in Wake Forest Baptist’s Section on Nephrology.  Wake Forest Baptist Health now offers CLIA-approved APOL1 genetic testing for clinical use (physicians can order at www.apol1genetest.com).

Freedman

APOL1 kidney disease risk variants are common in people of African descent. In African Americans, 13% possess two APOL1 kidney disease risk variants and are at heightened risk for kidney disease, another 39% possess one APOL1 kidney disease risk variant. One copy of the APOL1 risk variant provides protection from the parasite that causes African sleeping sickness (Trypanosoma brucei rhodesiense), a disease that is transmitted by the tse-tse fly. When individuals inherit two copies of the APOL1 risk variant—one from each parent—their risk of kidney disease increases seven to tenfold. 

“Transmission of this variant relates to natural selection. As more people survived the deadly African sleeping sickness, the percentage of the population with kidney disease risk variants increased,” Freedman said. “Curing this disease will require an improved understanding of the mechanisms involved in these APOL1-associated kidney diseases.” 

Last Updated: 08-12-2016
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