title: Complement factor H gene associations with end-stage kidney disease in African Americans.
abstract: BACKGROUND
  Mutations in the complement factor H gene (CFH) region associate with renal-limited mesangial proliferative forms of glomerulonephritis including IgA nephropathy (IgAN), dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Lack of kidney biopsies could lead to under diagnosis of CFH-associated end-stage kidney disease (ESKD) in African Americans (AAs), with incorrect attribution to other causes. A prior genome-wide association study in AAs with non-diabetic ESKD implicated an intronic CFH single nucleotide polymorphism (SNP).
  
  
  METHODS
  Thirteen CFH SNPs (8 exonic, 2 synonymous, 2 3'UTR, and the previously associated intronic variant rs379489) were tested for association with common forms of non-diabetic and type 2 diabetes-associated (T2D) ESKD in 3770 AAs (1705 with non-diabetic ESKD, 1305 with T2D-ESKD, 760 controls). Most cases lacked kidney biopsies; those with known IgAN, DDD or C3GN were excluded.
  
  
  RESULTS
  Adjusting for age, gender, ancestry and apolipoprotein L1 gene risk variants, single SNP analyses detected 6 CFH SNPs (5 exonic and the intronic variant) as significantly associated with non-diabetic ESKD (P = 0.002-0.01), three of these SNPs were also associated with T2D-ESKD. Weighted CFH locus-wide Sequence Kernel Association Testing (SKAT) in non-diabetic ESKD (P = 0.00053) and T2D-ESKD (P = 0.047) confirmed significant evidence of association.
  
  
  CONCLUSIONS
  CFH was associated with commonly reported etiologies of ESKD in the AA population. These results suggest that a subset of cases with ESKD clinically ascribed to the effects of hypertension or glomerulosclerosis actually have CFH-related forms of mesangial proliferative glomerulonephritis. Genetic testing may prove useful to identify the causes of renal-limited kidney disease in patients with ESKD who lack renal biopsies.
authors.affiliation: Department of Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, NC, USA Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bonomo
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.affiliation: Division of Renal Medicine, Department of Medicine, Emory School of Medicine, Atlanta, GA, USA.
authors.forename: Janice P
authors.initials: JP
authors.lastname: Lea
authors.affiliation: Division of Nephrology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
mesh_terms: D001741:Black or African American / Q000235:genetics*; D016022:Case-Control Studies; D017242:Complement Factor H / Q000235:genetics; D004247:DNA / Q000032:analysis / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis
chemical_list: C493495:CFH protein, human; D017242:Complement Factor H; D004247:DNA
keywords: African Americans; CFH; end-stage kidney disease; genetics; kidney disease