Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy

Am J Kidney Dis. 2012 Feb;59(2):210-21. doi: 10.1053/j.ajkd.2011.09.020. Epub 2011 Nov 25.

Abstract

Background: African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans.

Study design: Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses.

Setting & participants: Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls.

Predictors: Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes.

Outcomes: APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1.

Results: The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10(-24)) and rs136148 (OR, 0.54; additive; P = 1.1 × 10(-7)) with replication in FIND (P = 5.0 × 10(-21) and 1.9 × 10(-05), respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10(-4)). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001).

Limitations: Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy.

Conclusions: This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • African Americans / genetics*
  • Aged
  • Apolipoprotein L1
  • Apolipoproteins / genetics
  • Case-Control Studies
  • Epistasis, Genetic / genetics*
  • Female
  • Follow-Up Studies
  • Genetic Association Studies*
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Humans
  • Incidence
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kidney Diseases / ethnology*
  • Kidney Diseases / genetics*
  • Kidney Diseases / therapy
  • Lipoproteins, HDL / genetics
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Renal Dialysis*

Substances

  • APOL1 protein, human
  • Apolipoprotein L1
  • Apolipoproteins
  • Intracellular Signaling Peptides and Proteins
  • Lipoproteins, HDL
  • Membrane Proteins
  • NPHS2 protein

Grant support