APOL1 Gene Discovery: New Pathways to Cure Kidney Disease
Barry Freedman, MD
In a major breakthrough, mutations in a 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), and HIV-associated nephropathy.
These gene mutations cause up to 40 percent of kidney disease in African-Americans who receive renal replacement therapy with either 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 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 “hypertension-attributed” ESRD and FSGS in African-Americans. Together, these diseases account for more than $8.2 billion each year 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 working closely with research teams at Beth Israel Deaconess Medical Center and the National Institutes of Health (NIH). An NIH-sponsored trial, the African-American Study of Kidney Disease and Hypertension (AASK), recently evaluated kidney disease progression in hypertensive African-Americans.
In the vast majority of AASK participants, particularly those with low levels of protein in the urine, aggressively lowering blood pressure with ACE-inhibitors did not halt progression of kidney disease, even though the kidney disease was attributed to high blood pressure. This discovery solidified the observation that hypertension-attributed ESRD in African-Americans actually resides in the FSGS kidney disease family.
Freedman’s research team is now focusing on better understanding the mechanics of how these APOL1 gene variants cause kidney disease. These variants may prove useful for genetic screening and 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 AASK study shows that blood pressure lowering and use of ACE inhibitors do not halt the progression of this kidney disease. Many AASK participants progressed to needing dialysis.
The thrust and 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 groundbreaking work over the last two decades in Wake Forest Baptist’s Section on Nephrology. Previous studies by this group suggested the existence of “kidney failure genes” and refuted the belief that hypertension was a leading cause of ESRD in African-Americans.
APOL1 kidney disease risk variants are common in people of African descent. This relates to selection for these gene variants, much like those associated with sickle cell anemia. Inheriting one copy of the sickle cell variant provides protection from malaria, whereas two copies cause sickle cell anemia.
One copy of the APOL1 gene risk variant provides protection from the parasite (Trypanosoma brucei rhodesiense) that causes African sleeping sickness, a disease 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.”