Purchase this article with an account.
Aaron M. Newman, Natasha Gallo, Lisa Hancox, Norma Miller, Carolyn Radeke, Don Anderson, Gregory Hageman, Lincoln Johnson, Monte Radeke; Novel Gene Expression Signatures Associated With AMD And Its Risk Factors. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2333.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Both genetic and environmental risk factors for AMD have been identified, however the molecular processes underlying the disease remain poorly characterized. Utilizing global transcriptional analysis of a large collection of human RPE-choroid tissue samples, we sought to identify novel gene expression profiles associated with both AMD and its risk factors.
Human RPE-choroid RNA was purified from the macular and extramacular regions of 31 normal and 35 AMD donor eyes ranging in age from 9-101 years. Eyes were graded by established morphological criteria to determine disease state. Transcriptome profiling was performed using Agilent 4x44K whole genome microarrays and statistical analyses were performed using a novel unsupervised clustering algorithm (AutoSOME), two-class comparisons (permuted p-value t-tests), and gene ontology analysis (DAVID web tool).
Whole-transcriptome cluster analysis revealed expression modules associated with known physiological states, including a large cluster enriched for RPE signature genes and clusters enriched in genes for local and lymphocyte-mediated inflammation. Unexpectedly, none of the clusters correlate with the AMD disease state, possibly reflecting its heterogeneous nature and inherent noise in postmortem tissues. To identify genes associated with specific disease states, we employed an exhaustive class comparison approach. We identified ~1000 genes differentially expressed between the macula and extramacula, hundreds of genes associated with the aging RPE-choroid, and importantly, many genes associated with various AMD disease states and with the CFH genotype. Consistent with a role for inflammation in AMD, nearly all AMD disease states show elevated expression of a unique set of chemokines, revealing an AMD inflammatory signature. Further, expression of angiogenesis-related genes is elevated in CNV and apoptosis-related genes are elevated in GA. Finally, we found novel gene expression modules associated with the CFH Y402H locus that show step-wise increases or decreases in expression levels from YY to YH to HH genotypes.
We completed global transcriptome analysis of the largest set of RPE-choroid tissue samples analyzed to date, and identified novel gene sets with potential relevance to AMD. These data have potentially significant utility for the design of new AMD therapeutics.
This PDF is available to Subscribers Only