A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration
Abstract
Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong 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, 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 four 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 AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.
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Two reports implicated HTRA1 as a target of AMD susceptibility, whereas recent studies support the original claim of ARMS2 as a stronger candidate.
“Whereas two reports implicated HTRA1 as a target of AMD susceptibility (37, 167), recent studies support the original claim (122) of ARMS2 (previously LOC387715) as a stronger candidate (52, 82).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [167]
Both neovascular age-related macular degeneration and geographic atrophy have similar risk allele distribution.
“Both neovascular age-related macular degeneration and geographic atrophy have similar risk allele distribution.72”
From Age-related macular degeneration (2008) · cites this paper as [72]
HtrA1, a secretory protein and an inhibitor of transforming growth factor β, is also associated with the development of age-related macular degeneration.
“HtrA1, a secretory protein and an inhibitor of transforming growth factor β,144 is also associated with the development of age-related macular degeneration.69,70,72,73”
From Age-related macular degeneration (2008) · cites this paper as [72]
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- Authors
- Yang, Z., Camp, N. J., Sun, H., Tong, Z., Gibbs, D., Cameron, D. J., Chen, H., Zhao, Y., Pearson, E., Li, X., Chien, J., DeWan, A., Harmon, J., Bernstein, P. S., Shridhar, V., Zabriskie, N. A., Hoh, J., Howes, K., & Zhang, K.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Yang, Zhenglin
- Camp, Nicola J.
- Zhang, Kang
- ORCID
- Venue
- Science
- Published
- 2006-11-10
- Volume
- 314
- Issue
- 5801
- Pages
- 992-993
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2106901733
- Cited by
- 796
- References
- 19
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 19 · 2023: 15 · 2022: 20 · 2021: 48 · 2020: 19 · 2019: 31 · 2018: 25 · 2017: 28 · 2016: 28 · 2015: 37 · 2014: 34 · 2013: 57 · 2012: 53
- FWCI
- 61.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Eye Institute (R01EY014448, R01EY014428, R01-EY15771, R01EY14428, R01EY015771, R01EY14448, P30EY014800)
- National Cancer Institute (K07CA098364, CA98364)
- National Center for Research Resources (GCRC M01-RR00064, M01RR000064)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- age-related macular degeneration, HTRA1, promoter polymorphism, genetic susceptibility, chromosome 10q26, serine protease, drusen, retinal pigment epithelium, gene expression, population attributable risk, AMD pathogenesis
- MeSH terms
- High-Temperature Requirement A Serine Peptidase 1, Aged, Aging, Alleles, Chromosomes, Human, Pair 10, Female, Genotype, Homozygote, Humans, Lymphocytes, Macular Degeneration, Male, Middle Aged, Pigment Epithelium of Eye, Promoter Regions, Genetic, RNA, Messenger, Serine Endopeptidases, Cohort Studies, Retinal Drusen, Case-Control Studies, Genetic Predisposition to Disease, Reverse Transcriptase Polymerase Chain Reaction, Polymorphism, Single Nucleotide, White People
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