APOL1 Gene Discovery: New Pathways to Cure Kidney Disease
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).
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.”