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B. Jian Seyedahmadi, Y. Yonekawa, M. A. Morrison, I. K. Kim, J. W. Miller, N. B. Haider, G. S. Hageman, L. A. Farrer, G. Jun, M. M. DeAngelis; The Roundabout, Axon Guidance Receptor, Homolog 1 (ROBO1), a Potential Modifier and Therapeutic Target for Early and Intermediate Dry Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1661. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To examine the ROBO1 gene - -identified using a systems biology based approach that included data from gene expression data, its hypothetical anti-angiogenic network function and its genomic location -- as a candidate for, and possible contributor to the pathophysiology of AMD.
We ascertained 254 families comprised of 585 siblings that included individuals with normal maculas, and all subtypes of AMD (AREDS category 2, 3 and neovascular AMD). Fifteen tagging SNPs were genotyped by employing the Sequenom iPLEX technology. Using AMD categories as a quantitative trait, single SNP analysis was conducted using FBAT after adjusting for age and smoking status under an additive model. Haplotypes were constructed in a moving window approach using SNPs with p ≤ 0.1 in FBAT under an additive model. Gene-gene interaction between variation in ROBO1 and CFH and s ARMS2/HTRA1 was tested in Unphased 3.1.
Under an additive genetic model we identified SNPs and haplotypes in ROBO1 that were associated with risk of dry AMD (AREDS category 2 and 3) when compared to normal siblings. The most significant haplotype was comprised of the minor alleles from the two most significantly associated AMD risk SNPs (rs7640053 and rs7626242), p = 2.5 x 10 -3 after permutation testing correction. Significant interactions between variants in ROBO1 and variation in ARMS2/HTRA1 were identified (p value ranged from 2.5 x 10 -5 to 8.0 x 10 -3). This finding is complemented by our gene expression microarray studies and linkage analysis that show that ROBO1 mRNA is statistically significantly down-regulated in AMD patients and located in a region that harbors AMD susceptibility genes (3p12).
A significant haplotype of ROBO1, a previously unreported dry AMD-associated susceptibility gene coupled with significant interaction with ARMS2/HTRA1 has given us a refined region to identify causal variants by direct sequencing in our family based cohorts as well as subsequent replication and validation in larger unrelated case control populations.
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