Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects

Abstract

APOL1 variants have been associated with renal phenotypes in blacks. To refine clinical outcomes and discover mechanisms of APOL1-associated kidney injury, we analyzed clinical and genomic datasets derived from 90 black subjects in the Nephrotic Syndrome Study Network (NEPTUNE), stratified by APOL1 risk genotype. Ninety subjects with proteinuria $0.5 g/d were enrolled at first biopsy for primary nephrotic syndrome and followed. Clinical outcomes were determined, and renal histomorphometry and sequencing of Mendelian nephrotic syndrome genes were performed. APOL1 variants were genotyped, and glomerular and tubulointerstitial transcriptomes from protocol renal biopsy cores were analyzed for differential and correlative gene expression. Analyses were performed under the recessive model (high-risk genotype defined by two risk alleles). APOL1 high-risk genotype was significantly associated with a 17 ml/min per 1.73 m 2 lower eGFR and a 69% reduction in the probability of complete remission at any time, independent of histologic diagnosis. Neither APOL1 risk group was enriched for Mendelian mutations. On renal biopsy, high-risk genotype was associated with increased fractional interstitial area, interstitial fibrosis, and tubular atrophy. Risk genotype was not associated with intrarenal APOL1 mRNA expression levels. Differential expression analysis demonstrated an increased steady-state level of five genes associated with the high-risk genotype (CXCL9, CXCL11, and UBD in glomerulus; SNOR14B and MUC13 in tubulointerstitium). APOL1 tubulointerstitial coexpression analysis showed coexpression of APOL1 mRNA levels with a group of intrarenal transcripts that together were associated with increased interstitial fibrosis and tubular atrophy. These data indicate the high-risk APOL1 genotype confers renal risk across histopathologic diagnoses.

The Cell Biology of APOL1

“…Another study compared APOL1 transcript levels in glomerular and tubulointerstitial compartments microdissected from human kidney biopsy samples of nephrotic syndrome subjects. Concordant with the immunohistology, APOL1 mRNA in both compartments was similar between nephrotic syndrome subjects with and without APOL1 risk genotypes 34 . These data suggest that APOL1 -associated kidney diseases do not result from differential abundance of variant APOL1 compared to APOL1-G0.…”

“…As previously mentioned, APOL1 transcript levels were similar in glomerular or tubulointerstitial compartments of kidney biopsies from proteinuric African Americans with high and low risk APOL1 risk genotypes 34 . In addition, differential expression analysis, comparing transcriptomes from kidney biopsies of subjects with APOL1 high risk and low risk genotypes, identified only five differentially expressed genes (CXCL9, CXCL11, and UBD in glomerulus; SNOR14B and MUC13 in tubulointerstitium).…”

Plasma Levels of Risk-Variant APOL1 Do Not Associate with Renal Disease in a Population-Based Cohort

“…UBD is a ubiquitin-like protein involved in the targeted degradation of cellular proteins, and UBD transcripts were recently shown to be upregulated in patients with APOL1-associated glomerular disease in the NEPTUNE cohort. 36 The strengths of this study are the high-quality analytical methods used, which enabled the testing of a number of hypotheses regarding APOL1 levels and APOL1-HDL-associated proteins and renal disease, including the association of specific variant proteins with CKD. This study was well powered and was done in a cohort with pre-established association between APOL1 genotype and risk of CKD.…”

Complete Remission in the Nephrotic Syndrome Study Network

“…In epidemiologic studies, Apolipoprotein L1 (APOL1) high-risk genotypes have been associated with poor renal outcomes in individuals of African ancestry (15,16). Because a published subset analysis of 90 NEPTUNE patients of African ancestry found APOL1 to be associated with complete remission and eGFR loss (17), future NEPTUNE studies will benefit from incorporation of complete APOL1 genotyping. IST was not a significant predictor of CRever among patients with MCD.…”