April 2009
Volume 50, Issue 13
ARVO Annual Meeting Abstract  |   April 2009
A Single Nucleotide Polymorphism in 5-UTR of ERCC6 Confers Protection Against Age-Related Macular Degeneration
Author Affiliations & Notes
  • J. Tuo
    Laboratory of Immunology,
    National Eye Institute/NIH, Bethesda, Maryland
  • Y. Cho
    Laboratory of Immunology,
    National Eye Institute/NIH, Bethesda, Maryland
  • E. Y. Chew
    Division of Epidemiology and Clinical Research,
    National Eye Institute/NIH, Bethesda, Maryland
  • C.-C. Chan
    Laboratory of Immunology,
    National Eye Institute/NIH, Bethesda, Maryland
  • Footnotes
    Commercial Relationships  J. Tuo, None; Y. Cho, None; E.Y. Chew, None; C.-C. Chan, None.
  • Footnotes
    Support  NEI intramural research program
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 1594. doi:
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      J. Tuo, Y. Cho, E. Y. Chew, C.-C. Chan; A Single Nucleotide Polymorphism in 5-UTR of ERCC6 Confers Protection Against Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1594.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Age-related macular degeneration (AMD) is the leading cause of visual loss in aged people in the world and has genetic components in its pathogenesis. ERCC6 functions in DNA repair and mutations in the ERCC6 gene cause Cockayne syndrome, a disorder featuring accelerated aging and progressive multi-organ degeneration including retina. Previously we reported that a single nucleotide polymorphism (SNP) in ERCC6 regulatory region (rs3793784) was moderately associated with AMD risk. This study is to investigate the association of a set of additional SNPs in ERCC6 with AMD.

Methods: : The study was in case-control design. We selected 12 common SNPs across ERCC6 and evaluated their distribution in 162 advanced AMD cases and 189 normal controls from Washington DC area. Both cases and control are unrelated self-identified White with European descent. The genotyping was performed by Taqman allele discrimination, restriction fragment length polymorphism assay and SNPshot multiplex assay. The data was analyzed by Examplar 4.0 and SAS for the linkage disequilibrium between the SNPs and the comparison of genotypes/alleles between the cases and controls. The comparison was corrected for false discovery by permutation. Bioinformative estimation for transcription factors binding was performed by Alibaba software.

Results: : We identified that a C/A SNP in near 5’-UTR of ERCC6 is highly associated with protection against AMD (odds ratio=0.33, p<0.01 after permutation correction). The SNP is close to the transcriptional starting site, suggesting a function of gene regulation. The SNP is in linkage disequilibrium with rs3793784 but has 2-folds higher impact odds ratio. Interestingly, the control subjects with AA alleles of the SNP (homozygous protective) have a higher average age than the controls with CC or CA. The genotypes and alleles are distributed evenly in both geographic atrophy and neovascular AMD. The incorporation of the A allele of the SNP could cause putatively the loss of Sp1 binding site and the generation of a C/EBPalpha binding site.

Conclusions: : Our data suggest that the A allele(s) carrier of a SNP in the regulatory region of ERCC6 gene has a lower risk of developing AMD. The underlying mechanism might be that the SNP alters DNA repair function via a transcription factor binding.

Keywords: age-related macular degeneration • mutations • protective mechanisms 

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