Professor of Medicine Jeff Miner, PhD, FASN, Division of Nephrology, is co-author of a recent study in Nature Medicine that proves that certain variants of the APOL1 gene cause kidney disease.
For years, it has been known that African Americans have a 3-5-fold increased risk of developing chronic kidney disease (CKD) and end-stage renal disease (ESRD), and this increased risk has been ascribed to the coding-region variants G1 and G2 in the apolipoprotein L1 (APOL1) gene. However, little is known about the functional role of these variants in the development of kidney disease because of the lack of experimental “proof of causality” in animal models.
“The key missing piece has been whether these variants are true disease culprits,” says senior author Katalin Susztak, MD, PhD, Perelman School of Medicine, University of Pennsylvania, in a news release for the article in Penn Medicine News. The study was a collaboration of 13 laboratories.
The research team generated new mouse models with podocyte-specific inducible expression of the APOL1 reference G0 (“normal”) gene or G1/G2 risk alleles. The study showed that mice expressing either of the risk alleles, but not the reference gene, developed functional, structural and molecular changes that recapitulate features of human kidney disease. Expression of the risk-variant alleles interfered with endosomal trafficking and blocked autophagic flux, ultimately leading to inflammatory-mediated podocyte death and glomerular scarring.
The G1 and G2 APOL1 gene variants are found almost exclusively in people of West African descent. More than one third of African Americans carry the G1 and G2 variants. Positive selection is thought to play a part in the prevalence of these two mutations because the variant proteins protect humans against the Trypanosoma brucei rhodesiense parasite, which causes African sleeping sickness. The G1 and G2 variants of the APOL1 protein are taken up by the parasite, and through lysosomal swelling cause a lysis of the parasites.
“I am thrilled to have been able to participate in a study that helps us to better understand the pathogenesis of kidney disease in African-Americans,” says Dr. Miner. “Hopefully this will lead to new treatments to slow or prevent kidney disease in those who carry the risk alleles.”
Read the full article in Nature Medicine here.
Follow Drs. Susztak and Miner on Twitter: @KSustak, @JeffMinerPhD.