A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration

  1. Gregory S. Hagemana,b,c,
  2. Don H. Andersonb,d,
  3. Lincoln V. Johnsonb,d,
  4. Lisa S. Hancoxa,
  5. Andrew J. Taibera,
  6. Lisa I. Hardistya,
  7. Jill L. Hagemana,
  8. Heather A. Stockmana,
  9. James D. Borchardta,
  10. Karen M. Gehrsa,
  11. Richard J. H. Smithe,
  12. Giuliana Silvestrif,
  13. Stephen R. Russella,
  14. Caroline C. W. Klaverg,
  15. Irene Barbazettoh,
  16. Stanley Changh,
  17. Lawrence A. Yannuzzih,
  18. Gaetano R. Barileh,
  19. John C. Merriamh,
  20. R. Theodore Smithh,
  21. Adam K. Olshi,
  22. Julie Bergeronj,
  23. Jana Zernanth,
  24. Joanna E. Merriamh,
  25. Bert Goldi,
  26. Michael Deani, and
  27. Rando Allikmetsh,k,l
  1. aDepartment of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52240; bCenter for the Study of Macular Degeneration and dNeuroscience Research Institute, University of California, Santa Barbara, CA 93106; eInterdepartmental Program in Genetics and Department of Otolaryngology-Head and Neck Surgery and fDivision of Surgery and Perioperative Care, Department of Ophthalmology, Queen's University, Belfast BT7 1NN, United Kingdom; gDepartments of Ophthalmology and Epidemiology and Biostatistics, Erasmus University, and Netherlands Ophthalmic Research Institute, 3000-DR Rotterdam, The Netherlands; iLaboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702; jScience Applications International Corporation, National Cancer Institute, Frederick, MD 21702; and Departments of hOphthalmology and kPathology and Cell Biology, Columbia University, New York, NY 10027

  1. Edited by Jeremy Nathans, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 5, 2005 (received for review February 25, 2005)

Abstract

Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1/CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of ≈900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, χ2 = 26.1 and P = 3.2 × 10-7 and Y402H, χ2 = 54.4 and P = 1.6 × 10-13). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.

Footnotes

  • ↵ c To whom correspondence may be addressed at: Department of Ophthalmology and Visual Sciences, Cell Biology and Functional Genomics Laboratory, University of Iowa, 11190E PFP, 200 Hawkins Drive, Iowa City, IA 52240. E-mail: gregory-hageman{at}uiowa.edu.

  • ↵ l To whom correspondence may be addressed at: Department of Ophthalmology, Eye Institute Research, Columbia University, Room 715, 630 West 168th Street, New York, NY 10032. E-mail: rla22{at}columbia.edu.

  • Author contributions: G.S.H., M.D., and R.A. designed research; G.S.H., D.H.A., L.V.J., L.S.H., A.J.T., L.I.H., J.L.H., H.A.S., J.D.B., R.J.H.S., J.S., C.C.W.K., I.B., A.K.O., J.B., J.Z., J.E.M., B.G., M.D., and R.A. performed research; G.S.H. contributed new reagents/analytic tools; G.S.H., D.H.A., L.V.J., L.S.H., A.J.T., L.I.H., J.L.H., H.A.S., J.D.B., R.J.H.S., C.C.W.K., I.B., A.K.O., J.B., J.Z., J.E.M., B.G., M.D., and R.A. analyzed data; G.S.H., D.H.A., L.V.J., M.D., and R.A. wrote the paper; and G.S.H., J.L.H., H.A.S., K.M.G., G.S., S.R.R., S.C., L.A.Y., G.R.B., J.C.M., and R.T.S. contributed patient DNA samples and clinical history information.

  • This paper was submitted directly (Track II) to the PNAS office.

  • Abbreviations: AMD, age-related macular degeneration; eAMD, early AMD; RPE, retinal pigmented epithelium; MAC, membrane attack complex; BM, Bruch's membrane; MPGN, membranoproliferative glomerulonephritis; SSCP, single-strand conformation polymorphism; GA, geographic atrophy; IR, immunoreactivity; OR, odds ratio; CI, confidence interval.

  • See Commentary on page 7053.

  • Freely available online through the PNAS open access option.

« Previous | Next Article »Table of Contents
From the Cover

This Article

  1. Published online before print May 3, 2005, doi: 10.1073/pnas.0501536102 PNAS May 17, 2005 vol. 102 no. 20 7227-7232
  1. » Abstract
  2. Figures Only
  3. Full Text
  4. Full Text (PDF)
  5. Supporting Information

Classifications

About Our New Site Design >>
Link: Advanced Search

This Week's Issue

  1. July 22, 2008, 105 (29)
  1. Current Issue
  1. Alert me to new issues of PNAS

Most