New Insight into Aggressive Age-related Macular Degeneration
October 2006
Researchers at Yale University have discovered a genetic variant that increases by 10-fold the risk of developing a particularly aggressive form of age-related macular degeneration (AMD). The discovery may lead to better diagnoses of aggressive or "wet" AMD and new targets for developing treatments.
Wet AMD accounts for just 10 percent of AMD cases, but usually results in blindness. In patients with wet AMD, new blood vessels form and break beneath the retina, ultimately causing permanent damage to the retina and destroying central vision. The factors leading to development of wet AMD rather than the more common and less aggressive dry AMD are poorly understood, leaving treatment options limited.
In the October 19, 2006, issue of Science, Josephine Hoh and her colleagues at Yale reported using Affymetrix 100K Mapping Arrays in combination with DNA sequencing to discover an SNP responsible for wet AMD. Hoh's group compared a cohort of 96 Southeast Asian patients in Hong Kong who had been diagnosed with wet AMD, to 130 age-matched, AMD-free controls. They pinpointed a single variant, rs11200638, in the promoter region of HTRA1, a gene on chromosome 10q26 that encodes a heat shock serine protease activated upon cellular stress.
The team's whole-genome association study revealed that only one SNP of the 97,824 informative SNPs was significantly associated with wet AMD. That SNP, rs10490924, is between the PLEKHA1 and HTRA1 genes on chromosome 10q26. The SNP had previously been associated with AMD and was thought to cause a protein coding change in a hypothetical locus (LOC387715). Evidence was based only on a single cDNA sequence found in placental tissue and LOC387715 was later removed from the GenBank database. Hoh's team hypothesized that rs10490924 is a surrogate marker in linkage disequilibrium with an AMD disease-causing variant. They sequenced the entire genomic region around both PLEKHA1 and HTRA1 for 50 patients homozygous for the risk allele and 38 controls homozygous for the wild type allele. They found just one SNP, rs11200638, that exhibited complete linkage disequilibrium with rs10490924 (D' > 0.99). Using HeLaS3 cells transiently transfected with a luciferase reporter plasmid driven by the HTRA1 promoter, the team determined that rs11200638 enhances transcription of HTRA1 in patients homozygous for the risk allele, showing for the first time that overproduction of a protease is key to the type of AMD a patient develops.
Using Affymetrix 100K Mapping Arrays, Hoh and her colleagues were able to rapidly scan 100,000 known SNPs in the human genome for those associated with AMD. This technology allowed them to look at the entire genome at once, including SNPs with no known association with AMD. Previously, locating an associated SNP would have required knowledge of its likely position and painstaking sequencing of large portions of the genome. Using microarray technology in combination with genomic sequencing allowed Hoh's team to uncover a previously unknown variant, providing a defining genetic variant for wet AMD and a potential target for future therapies.
Uncovering the rs11200638 variant and determining its effect on HTRA1 expression is a critical first step in accurately diagnosing and treating wet AMD. Knowing that a patient has a more aggressive form of AMD may lead clinicians to prescribe more aggressive treatments and ultimately one day prevent the blindness so often caused by this devastating form of the disease.
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