Gene-gene interactions in APOL1-associated nephropathy

Nephrol Dial Transplant. 2014 Mar;29(3):587-94. doi: 10.1093/ndt/gft423. Epub 2013 Oct 24.

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.

Keywords: APOL1; African American; bone morphogenetic protein 4 (BMP4); kidney disease; podocin (NPHS2); serologically defined colon cancer antigen 8 (SDCCAG8).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • African Americans
  • Aged
  • Apolipoprotein L1
  • Apolipoproteins / genetics*
  • Autoantigens / genetics*
  • Bone Morphogenetic Protein 4 / genetics
  • Case-Control Studies
  • Epistasis, Genetic
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Glomerular Filtration Rate
  • Glomerulonephritis / genetics*
  • Glomerulonephritis / physiopathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Kidney Failure, Chronic / genetics*
  • Kidney Failure, Chronic / physiopathology
  • Lipoproteins, HDL / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Risk

Substances

  • APOL1 protein, human
  • Apolipoprotein L1
  • Apolipoproteins
  • Autoantigens
  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Intracellular Signaling Peptides and Proteins
  • Lipoproteins, HDL
  • Membrane Proteins
  • NPHS2 protein
  • Neoplasm Proteins
  • SDCCAG8 protein, human