Understanding health disparities in kidney disease

2010

Challenge

African Americans experience higher rates of kidney disease than do European-Americans, yet the increased prevalence of chronic kidney and end-stage kidney diseases in populations of African ancestry remains largely unexplained.

Advance

IRP researchers Jeffrey Kopp, M.D., and Cheryl Winkler, Ph.D., led a team that identified a genetic region on chromosome 22 within a specific gene—MYH9, a key component of the  actin cytoskeleon—that genetically predisposes individuals to chronic kidney disease. Genetic variation in this region substantially explains the major health disparity between African Americans and those of non-African descent.

Impact

The finding inspired subsequent work on this locus, led by Dr. Martin Pollak, that identified the main contributor as genetic variants in APOL1, encoding apolipoprotein L1. APOL1 is a component of the innate immune system, and work defining how the variants disrupt cell function may offer new pharmacologic approaches to treating kidney disease.

Publications

Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T,  McKenzie LM, Ahuja TS. Berns JS, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Kajiyama H, Winkler CA. (2008). MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nature Genet. 40(10), 1175-84.

Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langfeld CD, Olesyk TK, Knob AU, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CW, Kopp JB, Pays E, Pollak MR. (2010). Association of trypanolytic ApoL1 variants with kidney disease in African-Americans. Science. 329(5993), 841-5.

Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet A, Mokrzycki M, Kimmel PL, Limou S, Ahuja TS, Berns JS, Simon E, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winker CA. (2011). APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 22(11), 2129-37.

Parsa A, Kao WHL, Xie D, Asator BC, Li M, Hsu C0y, Feldman HI, Parekh RS, Kusek JW, Greene TH, Find JC, Anderson AH, Choi MJ, WrightJT, Lash JP, Freedman BI, Ojo A,Winkler CA, Rasj DS, Kopp JB, He J, Jensvold NG, Tao K, Lipkowitz JS, Appel, LS. (2013). APOL1 risk variants, race and progression of chronic kidney disease. for the African-American Study of Kidney Disease and Hypertension (AASK) and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. New Eng J Med. 369(23), 2183-96.