APOL1 Genotypes and Kidney Failure Risk: Bessie A. Young, MD, MPH

Carrying 2 high-risk apolipoprotein L1 (APOL1) variants raises the risk of kidney failure, but the gene works together with environmental and social factors rather than on its own, according to Bessie A. Young, MD, MPH, FACP, FASN, professor of medicine at the University of Washington and vice dean of equity, diversity, and inclusion in the Office of Health Care Equity at UW Medicine.

In an interview with The American Journal of Managed Care^®, Young discussed the high-risk APOL1 variants, the ancestry linked to them, and how genetic and environmental risks interact in kidney disease.

What Defines High-Risk APOL1 Status

APOL1 has 2 high-risk variants: G1 and G2. Most people carry the common version, called wild type or G0. However, a person can carry 2 high-risk variants or a combination such as G0 and G1 or G0 and G2.

“You really have to have the 2 high-risk variants to have the higher risk for end-stage kidney disease or going on to kidney failure,” Young said. The 2 high-risk variants are also tied to a higher risk of early kidney disease, such as albuminuria, and the genotype is associated with conditions including focal segmental glomerulosclerosis and hypertension-associated nephropathy.

Whether carrying just 1 high-risk variant increases risk has not been shown. Young said the data may not yet have followed people long enough to detect what is probably a slightly increased risk of kidney failure.

Why Ancestry Is the Link

Young explained that the increased risk is associated with recent West African ancestry. People with the high-risk genotypes have a decreased risk of African sleeping sickness, so the variants protect them from becoming sick or dying from it. In the US, about 13% of the African American or Black population carries 2 high-risk genotypes, which is associated with a greater risk of kidney failure.

Young compared the pattern to sickle cell disease. “It’s a genetic risk where it affects the geography of folks, and so not someone from a specific race, because anyone who has recent African ancestry can be affected by having a high-risk APOL1 genotype,” Young said.

How Genes and Environment Combine

Young described APOL1 as a risk variant that may fit a 2-hit hypothesis. A history of hypertension or certain environmental exposures probably raises the risk of kidney disease in a person who carries the high-risk genotypes. She offered a comparison of 2 people with the same genotypes. One exercises, eats a low-salt diet, and has no diabetes or other well-known risk factors for kidney disease. That person probably has a lower risk of end-stage kidney disease than someone who may not have had access to care, has a history of hypertension, and eats a high-salt diet.

“It’s a combination of the genetic risk and environmental risk factors, and some of our social drivers of adverse health can contribute to that increased risk,” Young said.