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M. A. Morrison, H. Xu, M. G. Kotoula, E. E. Tsironi, A. N. Tsiloulis, D. A. Schaumberg, I. K. Kim, J. W. Miller, J. Ott, M. M. DeAngelis; The Retinoic Acid Receptor-Related Orphan Receptor Gene (RORA), A Potential Anti-Angiogenic Therapeutic Target for Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2328.
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To examine the candidate gene RORA, chosen for its expression pattern, genomic location, and its function as an anti-angiogenic factor, as a possible contributor to the pathophysiology of neovascular age-related macular degeneration (AMD).
We ascertained 150 unrelated patients with AMD who had one sibling with normal maculae and was 65 years of age or older, i.e., 300 subjects comprising 150 extremely discordant sibpairs. SNPs spaced approximately every 3000 - 5000 bp across and surrounding RORA were genotyped by employing the Sequenom iPLEX technology. Single SNP analysis was conducted using conditional logistic regression (CLR). Haplotype blocks were constructed by Haploview (Gabriel) and individual haplotypes were inferred and tested for associationusing the family based association test (FBAT) and CLR. CLR was used to determine the best fit for each genotypic model tested (Additive, Dominant or Recessive).
Under a recessive genetic model, we have identified a protective haplotype that is significantly associated with neovascular AMD (OR, 0.488; CI, 0.285-0.836; p = 10-3). Haplotype analysis supported our single SNP analyses, demonstrating that the most significant haplotype contained the most significant SNP (p = 10-3), which was also protective under a recessive model. This finding is complemented by our gene expression microarray studies that show that RORA mRNA is statistically significantly upregulated in unaffected patients when compared to their matched affected sibling.
This protective haplotype has potential functional consequences as evidenced by software that predicts changes in binding properties of RORA due to genetic alterations (www.genomatix.de). Additionally, RORA is believed to function as an anti-angiogenic factor by regulating oxidative stress, immunity/inflammation and lipid transport, processes that have been implicated in the pathophysiology of neovascular AMD. Direct sequencing in our discovery cohort to identify the precise disease associated variant(s) is ongoing. Subsequent replication and validation is being performed on a population from Central Greece as well as nested case-controls.
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