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

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

Author information

1
Division of Nephrology, Department of Pediatrics and Communicable Diseases, mgsamps@med.umich.edu.
2
Division of Nephrology, Department of Pediatrics and Communicable Diseases.
3
Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, and.
4
Division of Nephrology, Department of Pediatrics, Children's Hospital of Los Angeles, University of Southern California School of Medicine, Los Angeles, California;
5
Kidney Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
6
Department of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada;
7
Division of Nephrology, Department of Internal Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania;
8
Division of Nephrology, Department of Internal Medicine and.
9
Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland;
10
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan; and.
11
Department of Pathology, University of Miami, Miller School of Medicine, Miami, Florida.
12
Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, and Department of Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, Michigan;
13
Division of Nephrology, Department of Internal Medicine and Department of Physiology and Biophysics, Case Western Reserve University and Rammelkamp Center for Education and Research, MetroHealth System, Cleveland, Ohio;

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

PMID:
26150607
PMCID:
PMC4769193
[Available on 2017-03-01]
DOI:
10.1681/ASN.2014111131
[Indexed for MEDLINE]
Free PMC Article

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