Complement Factor H Polymorphism in Age-Related Macular Degeneration

American Association for the Advancement of Science (AAAS) - Tập 308 Số 5720 - Trang 385-389 - 2005
Robert J. Klein1,2,3,4,5, Caroline J. Zeiss1,2,3,4,5, Emily Y. Chew1,2,3,4,5, Jen-Yue Tsai1,2,3,4,5, Richard S. Sackler1,2,3,4,5, Chad Haynes1,2,3,4,5, Alice K. Henning1,2,3,4,5, John Paul SanGiovanni1,2,3,4,5, Shrikant Mane1,2,3,4,5, Susan T. Mayne1,2,3,4,5, Michael B. Bracken1,2,3,4,5, Frederick L. Ferris1,2,3,4,5, Jürg Ott1,2,3,4,5, Colin J. Barnstable1,2,3,4,5, Josephine Hoh1,2,3,4,5
1Biological Imaging Core, National Eye Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
2Department of Ophthalmology and Visual Science, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA
3Laboratory of Statistical Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
4National Eye Institute, Building 10, CRC, 10 Center Drive, Bethesda, MD 20892-1204, USA.
5The Emmes Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850, USA

Tóm tắt

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.

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The Raymond and Beverly Sackler Fund for Arts and Sciences' generous support made this project possible. We thank Raymond Sackler J. Sackler and E. Vosburg for their input and encouragement. We also thank AREDS participants and investigators; G. Gensler T. Clemons and A. Lindblad for work on the AREDS Genetic Repository; S. Westman and A. Evan for assistance with the microarrays; R. Fariss for the human retinal sections and advice on confocal microscopy; E. Johnson for assistance with immunostaining; and J. Majewski for constructive comments on the manuscript. Partially funded by NIH-K25HG000060 and NIH-R01EY015771 (J.H.) Macula Vision Research Foundation and the David Woods Kemper Memorial Foundation (C.B.) NIH-R01MH44292 (J.O.) and NIH-K01RR16090 and Yale Pepper Center for Study of Diseases in Aging (C.Z.). This work also benefited from the International HapMap Consortium making their data available prior to publication.

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American Association for the Advancement of Science (AAAS)

Tập 308 Số 5720

385-389

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