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Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease)
  1. M A Abrera-Abeleda1,2,
  2. C Nishimura1,
  3. J L H Smith1,
  4. S Sethi3,
  5. J L McRae4,
  6. B F Murphy4,
  7. G Silvestri5,
  8. C Skerka6,
  9. M Józsi6,
  10. P F Zipfel6,
  11. G S Hageman7,
  12. R J H Smith1,2,8
  1. 1Department of Otolaryngology, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
  2. 2Interdepartmental PhD Program in Genetics, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
  3. 3Department of Laboratory Medicine and Pathology, The Mayo Clinic, Rochester, MN, USA
  4. 4Immunology Research Centre, St Vincent’s Hospital, Melbourne, Australia
  5. 5Division of Surgery and Perioperative Care, Department of Ophthalmology, Queen’s University, Belfast, UK
  6. 6Department of Infection Biology, Leibniz-Institute for Natural Products Research and Infection Biology - Hans Knoell Institute, Beutenbergstrasse 11a, D-07745 Jena, Germany
  7. 7Department of Ophthalmology and Visual Sciences, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
  8. 8Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
  1. Correspondence to:
 Professor R J H Smith
 Sterba Hearing Research Professor of Otolaryngology and Director, Molecular Otolaryngology Research Laboratories, 200 Hawkins Drive, The University of Iowa, Iowa City, IA 52242, USA; richard-smith{at}uiowa.edu

Abstract

Introduction: Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology.

Subjects: Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded.

Results: Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls.

Conclusion: We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.

  • AMD, age related macular degeneration
  • C3NeF, C3 nephritic factor
  • C4BP, C4 binding protein
  • CFH, complement factor H
  • CFHL1, complement factor H-like protein 1
  • CFI, complement factor I
  • CR1, complement receptor 1
  • DAF, decay accelerating factor
  • DDD, dense deposit disease
  • DHPLC, denaturing high performance liquid chromatography
  • ESRD, end stage renal disease
  • GBM, glomerular basement membrane
  • LD, linkage disequilibrium
  • MCP, membrane co-factor protein
  • MPGN I/II/III, membranoproliferative glomerulonephritis types I/II/III
  • SNP, single nucleotide polymorphism
  • membranoproliferative glomerulonephritis type II
  • dense deposit disease
  • complement factor H
  • complement factor H-related 5
  • end-stage renal failure

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Footnotes

  • Published Online First 18 November 2005

  • Competing interests: there are no competing interests

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