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Published Online October 19, 2006
Science DOI: 10.1126/science.1133811

Reports

Submitted on August 14, 2006
Accepted on October 6, 2006

A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration

Zhenglin Yang 1, Nicola J. Camp 2, Hui Sun 3, Zongzhong Tong 4, Daniel Gibbs 4, D. Joshua Cameron 4, Haoyu Chen 4, Yu Zhao 4, Erik Pearson 4, Xi Li 4, Jeremy Chien 5, Andrew DeWan 6, Jennifer Harmon 4, Paul S. Bernstein 7, Viji Shridhar 8, Norman A. Zabriskie 7, Josephine Hoh 6, Kimberly Howes 7, Kang Zhang 4*

1 Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132; Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84132; Sichuan Medical Science Academy and Sichuan Provincial People's Hospital, Sichuan 610071, China.
2 Division of Genetic Epidemiology, Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108 USA.
3 Department of Physiology and Jules Stein Eye Institute, School of Medicine at UCLA, Los Angles, CA 90095 USA.
4 Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132 USA; Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84132 USA.
5 Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
6 Department of Epidemiology and Public Health, Yale University, New Haven, CT 06520 USA.
7 Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132 USA.
8 Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905 USA.

* To whom correspondence should be addressed.
Kang Zhang , E-mail: kzhang{at}hmbg.utah.edu

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a significant genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single nucleotide polymorphism (SNP) rs11200638 in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from three AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of three AMD patients were strongly immunolabeled with HTRA1 antibody.


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