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

J Am Soc Nephrol. 2016 Mar;27(3):814-23. doi: 10.1681/ASN.2014111131. Epub 2015 Jul 6.

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.

Keywords: APOL1; epidemiology and outcomes; genetic renal disease; glomerular disease; nephrotic syndrome; transcriptional profiling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • African Americans / genetics*
  • Alleles
  • Apolipoprotein L1
  • Apolipoproteins / genetics*
  • Atrophy / genetics
  • Biopsy
  • Chemokine CXCL11 / genetics
  • Chemokine CXCL9 / genetics
  • Child
  • Female
  • Fibrosis
  • Gene Expression
  • Genomics / methods*
  • Genotype
  • Glomerular Filtration Rate / genetics
  • Humans
  • Kidney Glomerulus / physiopathology
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology*
  • Kidney Tubules / physiopathology
  • Lipoproteins, HDL / genetics*
  • Male
  • Middle Aged
  • Mucins / genetics
  • Nephrotic Syndrome / genetics*
  • Nephrotic Syndrome / pathology*
  • Nephrotic Syndrome / physiopathology
  • Proteinuria / genetics
  • RNA, Messenger / metabolism
  • Risk Factors
  • Transcriptome
  • Ubiquitins / genetics
  • Young Adult

Substances

  • APOL1 protein, human
  • Apolipoprotein L1
  • Apolipoproteins
  • CXCL9 protein, human
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Lipoproteins, HDL
  • MUC13 protein, human
  • Mucins
  • RNA, Messenger
  • UBD protein, human
  • Ubiquitins