April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
The Roundabout, Axon Guidance Receptor, Homolog 1 (ROBO1), a Potential Modifier and Therapeutic Target for Early and Intermediate Dry Age-Related Macular Degeneration
Author Affiliations & Notes
  • B. Jian Seyedahmadi
    Retina Service and Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
  • Y. Yonekawa
    Retina Service and Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
  • M. A. Morrison
    Retina Service and Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
  • I. K. Kim
    Retina Service and Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
  • J. W. Miller
    Retina Service and Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
  • N. B. Haider
    Genetics, Cell Biology, Anatomy, Univ of Nebraska Medical Ctr, Omaha, Nebraska
  • G. S. Hageman
    Ophthalmology & Visual Sciences, University of Iowa Hospitals & Clinics, Coralville, Iowa
  • L. A. Farrer
    Departments of Medicine, Neurology, Genetics and Genomics, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • G. Jun
    Departments of Medicine, Neurology, Genetics and Genomics, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • M. M. DeAngelis
    Retina Service and Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  B. Jian Seyedahmadi, None; Y. Yonekawa, None; M.A. Morrison, None; I.K. Kim, None; J.W. Miller, None; N.B. Haider, None; G.S. Hageman, None; L.A. Farrer, None; G. Jun, None; M.M. DeAngelis, None.
  • Footnotes
    Support  The Lincy Foundation, the Knight AMD Fund, the Mass. Lions, Friends of the MEEI, Genetics of AMD Fund, Research to Prevent Blindness, NIH grants EY014458 & EY14104
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 1661. doi:https://doi.org/
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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)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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).

Conclusions: : 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.

Keywords: age-related macular degeneration • gene screening • clinical (human) or epidemiologic studies: risk factor assessment 
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