title: Relevance of the ACTN4 gene in African-Americans with non-diabetic end-stage renal disease.
abstract: BACKGROUND
  African-Americans (AAs) are predisposed to non-diabetic (non-DM) end-stage renal disease (ESRD), and studies have shown a genetic component to this risk. Rare mutations in ACTN4 (α-actinin-4), an actin-binding protein expressed in podocytes, cause familial focal segmental glomerulosclerosis.
  
  
  METHODS
  We assessed the contribution of coding variants in ACTN4 to non-DM ESRD risk in AAs. Nineteen exons, 2,800 bases of the promoter and 392 bases of the 3' untranslated region of ACTN4 were sequenced in 96 AA non-DM ESRD cases and 96 non-nephropathy controls (384 chromosomes). Sixty-seven single-nucleotide polymorphisms (SNPs) including 51 novel SNPs were identified. The SNPs comprised 33 intronic, 21 promoter, 12 exonic, and one 3' variant. Sixty-two of the SNPs were genotyped in 296 AA non-DM ESRD cases and 358 non-nephropathy controls.
  
  
  RESULTS
  One SNP, rs10404257, was associated with non-DM ESRD (p < 1.0E-4, odds ratio, OR = 0.76; confidence interval, CI = 0.59-0.98; additive model). Forty-seven SNPs had minor allele frequencies <5%. These SNPs were segregated into risk and protective SNPs, and each category was collapsed into a single marker, designated by the presence or absence of any rare allele. The presence of any rare allele at a risk SNP was significantly associated with non-DM ESRD (p = 0.001, dominant model). The SNPs with the strongest evidence for association (n = 20) were genotyped in an independent set of 467 non-DM ESRD cases and 279 controls. Although rs10404257 was not associated in this replication sample, when the samples were combined, rs10404257 was modestly associated (p = 0.032, OR = 0.78, CI = 0.63-0.98; dominant model). SNPs were tested for interaction with markers in the APOL1 gene, previously associated with non-DM ESRD in AAs, and rs10404257 was modestly associated (p = 0.0261, additive model).
  
  
  CONCLUSIONS
  This detailed evaluation of ACTN4 variation revealed limited evidence of association with non-DM ESRD in AAs.
authors.affiliation: David H. Murdoch Research Institute, Kannapolis, NC, USA.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Bostrom
authors.forename: Peter
authors.initials: P
authors.lastname: Perlegas
authors.forename: Lingyi
authors.initials: L
authors.lastname: Lu
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.forename: Greg
authors.initials: G
authors.lastname: Hawkins
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000502:physiology; D000328:Adult; D001741:Black or African American; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005091:Exons; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007676:Kidney Failure, Chronic / Q000208:ethnology* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009393:Nephritis / Q000473:pathology; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide
chemical_list: C111453:ACTN4 protein, human; D005819:Genetic Markers; D000185:Actinin