title: 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.
authors.affiliation: Division of Nephrology, Department of Pediatrics and Communicable Diseases, mgsamps@med.umich.edu.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Sampson
authors.affiliation: Division of Nephrology, Department of Pediatrics and Communicable Diseases.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Robertson
authors.affiliation: Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Martini
authors.affiliation: Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, and.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Mariani
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Los Angeles, University of Southern California School of Medicine, Los Angeles, California;
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Lemley
authors.affiliation: Division of Nephrology, Department of Pediatrics and Communicable Diseases.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Gillies
authors.affiliation: Division of Nephrology, Department of Pediatrics and Communicable Diseases.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.affiliation: Kidney Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, and.
authors.forename: Anne
authors.initials: A
authors.lastname: Randolph
authors.affiliation: Division of Nephrology, Department of Pediatrics and Communicable Diseases.
authors.forename: Virginia
authors.initials: V
authors.lastname: Vega-Warner
authors.affiliation: Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, and.
authors.forename: Felix
authors.initials: F
authors.lastname: Eichinger
authors.affiliation: Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, and.
authors.forename: Viji
authors.initials: V
authors.lastname: Nair
authors.affiliation: Division of Nephrology, Department of Pediatrics and Communicable Diseases.
authors.forename: Debbie S
authors.initials: DS
authors.lastname: Gipson
authors.affiliation: Department of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Cattran
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Johnstone
authors.affiliation: Division of Nephrology, Department of Internal Medicine and.
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland;
authors.forename: Serena M
authors.initials: SM
authors.lastname: Bagnasco
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan; and.
authors.forename: Peter X
authors.initials: PX
authors.lastname: Song
authors.affiliation: Department of Pathology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Laura
authors.initials: L
authors.lastname: Barisoni
authors.affiliation: Division of Nephrology, Department of Pediatrics and Communicable Diseases.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Troost
authors.affiliation: 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;
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: 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;
authors.forename: John R
authors.initials: JR
authors.lastname: Sedor
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D001284:Atrophy / Q000235:genetics; D001706:Biopsy; D054371:Chemokine CXCL11 / Q000235:genetics; D054370:Chemokine CXCL9 / Q000235:genetics; D002648:Child; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D023281:Genomics / Q000379:methods*; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000235:genetics; D006801:Humans; D007678:Kidney Glomerulus / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009077:Mucins / Q000235:genetics; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D011507:Proteinuria / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D059467:Transcriptome; D014452:Ubiquitins / Q000235:genetics; D055815:Young Adult
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; C080810:CXCL9 protein, human; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D008075:Lipoproteins, HDL; C429552:MUC13 protein, human; D009077:Mucins; D012333:RNA, Messenger; C109184:UBD protein, human; D014452:Ubiquitins
keywords: APOL1; epidemiology and outcomes; genetic renal disease; glomerular disease; nephrotic syndrome; transcriptional profiling