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Originally published in Science Express on 10 March 2005
Science 15 April 2005:
Vol. 308. no. 5720, pp. 385 - 389
DOI: 10.1126/science.1109557
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Research Articles

Complement Factor H Polymorphism in Age-Related Macular Degeneration

Robert J. Klein,1 Caroline Zeiss,2* Emily Y. Chew,3* Jen-Yue Tsai,4* Richard S. Sackler,1 Chad Haynes,1 Alice K. Henning,5 John Paul SanGiovanni,3 Shrikant M. Mane,6 Susan T. Mayne,7 Michael B. Bracken,7 Frederick L. Ferris,3 Jurg Ott,1 Colin Barnstable,2 Josephine Hoh7{dagger}

Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene (CFH) is strongly associated with AMD (nominal P value <10-7). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.

1 Laboratory of Statistical Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
2 Department of Ophthalmology and Visual Science, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA.
3 National Eye Institute, Building 10, CRC, 10 Center Drive, Bethesda, MD 20892-1204, USA.
4 Biological Imaging Core, National Eye Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
5 The EMMES Corporation, 401 North Washington Street, Suite 700, Rockville MD 20850, USA.
6 W. M. Keck Facility, Yale University, 300 George Street, Suite 201, New Haven, CT 06511, USA.
7 Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, CT 06520, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: josephine.hoh{at}yale.edu

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S. Wang, S. Girman, B. Lu, N. Bischoff, T. Holmes, R. Shearer, L. S. Wright, C. N. Svendsen, D. M. Gamm, and R. D. Lund (2008)
Invest. Ophthalmol. Vis. Sci. 49, 3201-3206
   Abstract »    Full Text »    PDF »
Genetic model selection in two-phase analysis for case-control association studies.
G. Zheng and H. K. T. Ng (2008)
Biostat. 9, 391-399
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Genotype-Phenotype Correlations for Exudative Age-Related Macular Degeneration Associated with Homozygous HTRA1 and CFH Genotypes.
N. Leveziel, J. Zerbib, F. Richard, G. Querques, G. Morineau, V. Fremeaux-Bacchi, G. Coscas, G. Soubrane, P. Benlian, and E. H. Souied (2008)
Invest. Ophthalmol. Vis. Sci. 49, 3090-3094
   Abstract »    Full Text »    PDF »
AMD-like Lesions in the Rat Retina: A Latent Consequence of Perinatal Hemorrhage.
D. V. Pow and C. M. Diaz (2008)
Invest. Ophthalmol. Vis. Sci. 49, 2790-2798
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Altered Function of Factor I Caused by Amyloid {beta}: Implication for Pathogenesis of Age-Related Macular Degeneration from Drusen.
J. Wang, K. Ohno-Matsui, T. Yoshida, A. Kojima, N. Shimada, K.-i. Nakahama, O. Safranova, N. Iwata, T. C. Saido, M. Mochizuki, et al. (2008)
J. Immunol. 181, 712-720
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Microarray Technology and Applications in the Arena of Genome-Wide Association.
S. F. A. Grant and H. Hakonarson (2008)
Clin. Chem. 54, 1116-1124
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Age-Related Macular Degeneration.
R. D. Jager, W. F. Mieler, and J. W. Miller (2008)
N. Engl. J. Med. 358, 2606-2617
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Association Analysis of CFH, C2, BF, and HTRA1 Gene Polymorphisms in Chinese Patients with Polypoidal Choroidal Vasculopathy.
K. Y. Lee, E. N. Vithana, R. Mathur, V. H. Yong, I. Y. Yeo, A. Thalamuthu, M.-W. Lee, A. H. Koh, M. C. Lim, A. C. How, et al. (2008)
Invest. Ophthalmol. Vis. Sci. 49, 2613-2619
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Late Outgrowth Endothelial Progenitor Cells in Patients with Age-Related Macular Degeneration.
M. Thill, N. V. Strunnikova, M. J. Berna, N. Gordiyenko, K. Schmid, S. W. Cousins, D. J. S. Thompson, and K. G. Csaky (2008)
Invest. Ophthalmol. Vis. Sci. 49, 2696-2708
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Racial Differences and Other Risk Factors for Incidence and Progression of Age-Related Macular Degeneration: Salisbury Eye Evaluation (SEE) Project.
M. A. Chang, S. B. Bressler, B. Munoz, and S. K. West (2008)
Invest. Ophthalmol. Vis. Sci. 49, 2395-2402
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Ceruloplasmin/Hephaestin Knockout Mice Model Morphologic and Molecular Features of AMD.
M. Hadziahmetovic, T. Dentchev, Y. Song, N. Haddad, X. He, P. Hahn, D. Pratico, R. Wen, Z. L. Harris, J. D. Lambris, et al. (2008)
Invest. Ophthalmol. Vis. Sci. 49, 2728-2736
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Estrogen Receptor Alpha and Matrix Metalloproteinase 2 Polymorphisms and Age-related Maculopathy in Older Women.
R. L. Seitzman, V. B. Mahajan, C. Mangione, J. A. Cauley, K. E. Ensrud, K. L. Stone, S. R. Cummings, M. C. Hochberg, T. A. Hillier, J. S. Sinsheimer, et al. (2008)
Am. J. Epidemiol. 167, 1217-1225
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