Genome-wide association studies suggest that APOL1-environment interactions more likely trigger kidney disease in African Americans with nondiabetic nephropathy than strong APOL1–second gene interactions

Abstract

African Americans carrying two apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)-ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1 G1/G2 renal-risk variants were completed and stratified by APOL1 risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1 risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1 interactions with other single nucleotide polymorphisms.

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

“…Preliminary studies have identified polymorphisms in NPHS2, BMP4, SDCCAG4, and UBD that modify APOL1-mediated CDK risk (7,25,64). However, a recent meta-analysis of genome-wide association data concluded there are likely few genetic factors that contribute a strong modifying second hit to APOL1-associated CKD risk and concludes the critical second-hit stressors for disease induction are more likely to be environmental (29).…”

ProfilingAPOL1Nephropathy Risk Variants in Genome-Edited Kidney Organoids with Single-Cell Transcriptomics

“…With these cell-type specific differences in G1 organoid gene expression, we next evaluated whether introducing an additional stressor alters G1 cell phenotypes. Because APOL1-mediated kidney disease is incompletely penetrant, others have proposed a "second-hit hypothesis" that individuals carrying two APOL1 risk alleles develop disease after exposure to environmental or genetic modifiers 28,29 . We tested whether ER stress could provide a stimulus to alter stress response and cellular phenotypes in the high-risk genotype.…”

Profiling APOL1 Nephropathy Risk Variants in Genome-Edited Kidney Organoids with Single-Cell Transcriptomics

“…Having identified these cell type-specific differences in G1 organoid gene expression, we next evaluated whether introducing an additional stressor alters G1 cell phenotypes. Because APOL1-mediated kidney disease is incompletely penetrant, others have proposed a "second-hit" hypothesis that individuals carrying two APOL1 risk alleles develop disease after exposure to environmental or genetic modifiers (34,35). We tested whether ER stress could provide a stimulus to alter stress response and cellular phenotypes in the highrisk genotype.…”