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Senior Citizen Health & Medicine
Gene Linked to Aggressive 'Wet' Age-Related Macular
Degeneration
Patients with HTRA1 SNP 10 times more
likely to have wet AMD
 November 22, 2006 - A gene variant that increases
the risk of developing the aggressive "wet" form of age-related macular
degeneration (AMD), the most common cause of blindness in people over
age 50, is reported in two recent articles in Science by researchers at
Yale School of Medicine.
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AMD causes light-sensitive cells in the retina to
break down, resulting in progressive loss of central vision. Of the two
forms of AMD, the "dry" is more common than the "wet" form. Wet macular
degeneration can rapidly lead to blindness, while the dry AMD progresses
more slowly.
Last year, Josephine Hoh, associate professor in
the Departments of Epidemiology & Public Health and Ophthalmology at
Yale and senior author on one of the two new studies, identified a gene
for dry AMD and found that both wet and dry AMD are associated with a
variant in the complement factor H (CFH) gene on chromosome 1.
Hoh now reports they have found a single nucleotide
polymorphism (SNP)a one-base change in the sequenceof the regulatory
part of the HTRA1 gene on chromosome 10 that leads to greatly increased
risk of developing the wet form of AMD.
According to Hoh, buildup of abnormal blood vessels
in Caucasian patients is compounded by development of large waste
deposits called drusen.
Chinese patients, she said, develop little to no
drusen and progress directly to wet AMD.
This study demonstrates that these two major genes,
CFH and HTRA1, in two different biological pathways, each affect the
risk for a distinct component of the AMD phenotype: CFH influences the
drusen of dry AMD, whereas HTRA1 influences blood vessel development,
the hallmark of the wet disease type.
When the two processes are combined, it leads to
the composite characteristics that are seen in some cases of AMD.
Hoh, her collaborators in Hong Kong, and her
colleagues at Yale including Michael Snyder and Colin Barnstable in the
Departments of Molecular, Cellular and Developmental Biology and
Molecular Biophysics and Biochemistry, and Ophthalmology, did
trans-racial gene mapping by comparing genomes between precisely defined
populations to find the incidence of SNP in a Chinese population96 with
AMD and 130 with normal vision.
"We found that patients with the HTRA1 SNP were 10
times more likely to have wet AMD than those without this gene variant,"
said Hoh.
"While this is only preliminary work, it points to
possible directions for future treatment of wet AMD."
Hoh also worked on a replication study led by Kang
Zhang at the University of Utah School of Medicine that found a link
between the same SNP and AMD. Zhang and his team studied 581 Caucasian
patients with AMD and 309 with normal vision. These patients had wet AMD
as well as a large amount of drusen.
To confirm the association, the Utah team also
examined several donor eyes and measured the expression of the gene and
the encoded protein. They found that the expressions were elevated in
the eyes of patients who carry HTRA1.
"The marker we have identified is very much
associated with AMD, but no one has ever pinpointed the clinical
features of the gene. We need to conduct further analysis in order to
understand the biological mechanisms," said Hoh.
Editor's Notes:
In addition to Hoh, Snyder and Barnstable, authors
on the first study included first author Andrew DeWan, Mugen Liu,
Stephen Hartman, Samuel Shao-Min Zhang, David T.L. Liu, Connie Zhao,
Pancy O.S. Tam, Wai Man Chan, Dennis S.C. Lam and Chi Pui Pang.
In addition to Zhang and Hoh, authors on the second
study included Zhenglin Yang, Nicola J. Camp, Hui Sun, Zongzhong Tong,
Daniel Gibbs, D. Joshua Cameron, Haoyu Chen, Yu Zhao, Erik Pearson, Xi
Li, Jeremy Chien, Andrew DeWan, Jennifer Harmon, Paul S. Bernstein, Viji
Shridhar, Norman A. Zabriskie and Kimberly Howes.
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