The population genetics of chronic kidney disease: insights from the MYH9–APOL1 locus

Abstract

Many rare kidney disorders exhibit a monogenic, Mendelian pattern of inheritance. Population-based genetic studies have identified many genetic variants associated with an increased risk of developing common kidney diseases. Strongly associated variants have potential clinical uses as predictive markers and may advance our understanding of disease pathogenesis. These principles are elegantly illustrated by a region within chromosome 22q12 that has a strong association with common forms of kidney disease. Researchers had identified DNA sequence variants in this locus that were highly associated with an increased prevalence of common chronic kidney diseases in people of African ancestry. Initial research concentrated on MYH9 as the most likely candidate gene; however, population-based whole-genome analysis enabled two independent research teams to discover more strongly associated mutations in the neighboring APOL1 gene. The powerful evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are highly associated with an increased risk of kidney disease. We describe the data sources, process of discovery, and reasons for initial misidentification of the candidate gene, as well as the lessons that can be learned for future population genetics research.

APOL1 Variants Associate with Increased Risk of CKD among African Americans

“…19 Other possible mechanisms include effects of APOL1 variants on lipid metabolism or autophagy. 20 However, lipidrelated mechanisms are not supported by our findings given that we did not observe significant associations with the APOL1 risk alleles and HDL cholesterol and that additional adjustment for HDL cholesterol or HDL cholesterol subparticle concentrations did not materially change our findings. Finally, it may be possible that the association of APOL1 variants with kidney disease is not causal and because of these variants being in linkage disequilibrium with the true causal variants.…”

Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

“…These risk variants (G1, nonsynonymous coding variants S342G:I384M [leading to a change in two amino acids]; G2, del.N388/ Y38 [deleting two amino acids]) were shown to be associated with ORs from 7.3-to 29-fold in ESRD, with this range of ORs in APOL1-associated disease corresponding to the spectrum of leading etiologies of nondiabetic CKD and accounting for up to 40% of the total disease burden in African Americans (7,8,(15)(16)(17)(18)(19)(20)(21). Disease etiologies include focal global glomerulosclerosis (FGGS) historically ascribed to hypertension, nonmonogenic forms of FSGS, HIV-associated nephropathy (HIVAN), sickle cell kidney disease, and severe lupus nephritis (LN) (7,8,(22)(23)(24)(25).…”

Race in Biological and Biomedical Research

“…As this literature matures, however, the role of specific variants appears to be becoming more and more complex. In addition, a relatively uncommon form of chronic renal failure-focal segmental glomerulosclerosis-is strongly associated with a mutation in a gene related to lipid metabolism (ApoL1), and one copy of this version of the gene likewise occurs in almost 90% of West Africans (Rosset et al 2011). Some evidence suggests that positive selection may be operating for the risk alleles for both prostate cancer and kidney disease-again, potentially through their role in immunity-although not all of the pieces of the puzzle fit together.…”