title: Gene-gene interactions in APOL1-associated nephropathy.
abstract: BACKGROUND
  Two APOL1 nephropathy variants confer substantial risk for non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs). Since not all genetically high-risk individuals develop ESKD, modifying factors likely contribute. Forty-two potentially interactive single nucleotide polymorphisms (SNPs) from a genome-wide association study in non-diabetic ESKD were tested for interaction with APOL1 to identify genes modifying risk for non-diabetic nephropathy.
  
  
  METHODS
  SNPs were examined in an expanded sample of 1367 AA non-diabetic ESKD cases and 1504 AA non-nephropathy controls, with validation in an independent family-based cohort containing 608 first-degree relatives of index cases with non-diabetic ESKD. Logistic regression and mixed models were fitted to test for interaction effects with APOL1 on ESKD, estimated kidney function and albuminuria.
  
  
  RESULTS
  Among ESKD samples, 14 of 42 SNPs demonstrated suggestive APOL1 interaction with P-values <0.05. After Bonferroni correction, significant interactions with APOL1 were seen with SNPs in podocin (rs16854341; NPHS2, P = 8.0 × 10(-4)), in SDCCAG8 (rs2802723; P = 5.0 × 10(-4)) and near BMP4 (rs8014363; P = 1.0 × 10(-3)); with trends for ENOX1 (rs9533534; P = 2.2 × 10(-3)) and near TRIB1 (rs4457349; P = 5.7 × 10(-3)). The minor allele in NPHS2 markedly changed the APOL1-ESKD association odds ratio (OR) from 7.03 to 1.76 (∼50% reduction in effect per copy of the minor allele), rs2802723 changed the OR from 5.1 to 10.5, and rs8014363 increased the OR from 4.8 to 9.5. NPHS2 (P = 0.05) and SDCCAG8 (P = 0.03) SNPs demonstrated APOL1 interaction with albuminuria in independent family-based samples.
  
  
  CONCLUSIONS
  Variants in NPHS2, SDCCAG8 and near BMP4 appear to interact with APOL1 to modulate the risk for non-diabetic ESKD in AAs.
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Divers
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.forename: Lingyi
authors.initials: L
authors.lastname: Lu
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Michael V
authors.initials: MV
authors.lastname: Rocco
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.forename: Mariana
authors.initials: M
authors.lastname: Murea
authors.forename: Lijun
authors.initials: L
authors.lastname: Ma
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
mesh_terms: D000328:Adult; D001741:Black or African American; D000368:Aged; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D001324:Autoantigens / Q000235:genetics*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005919:Glomerular Filtration Rate; D005921:Glomerulonephritis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000503:physiopathology; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D001324:Autoantigens; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; C407223:NPHS2 protein; D009363:Neoplasm Proteins; C472380:SDCCAG8 protein, human
keywords: APOL1; African American; bone morphogenetic protein 4 (BMP4); kidney disease; podocin (NPHS2); serologically defined colon cancer antigen 8 (SDCCAG8)