AGE

, Volume 35, Issue 5, pp 1651–1662

Regulatory regions of the paraoxonase 1 (PON1) gene are associated with neovascular age-related macular degeneration (AMD)

  • Jadwiga Oczos
  • Christian Grimm
  • Daniel Barthelmes
  • Florian Sutter
  • Moreno Menghini
  • Barbara Kloeckener-Gruissem
  • Wolfgang Berger
Article

DOI: 10.1007/s11357-012-9467-x

Cite this article as:
Oczos, J., Grimm, C., Barthelmes, D. et al. AGE (2013) 35: 1651. doi:10.1007/s11357-012-9467-x

Abstract

Physiological stress response and oxidative damage are factors for aging processes and, as such, are thought to contribute to neovascular age-related macular degeneration (AMD). Paraoxonase 1 (PON1) is an enzyme that plays an important role in oxidative stress and aging. We investigated association of DNA sequence variants (SNP) within the upstream regulatory region of the PON1 gene with neovascular AMD in 305 patients and 288 controls. Four of the seven tested SNPs (rs705379, rs705381, rs854573, and rs757158) were more frequently found in AMD patients compared to controls (P = 0.0099, 0.0295, 0.0121, and 0.0256, respectively), and all but one (SNP rs757158) are in linkage disequilibrium. Furthermore, haplotype TGGCCTC conferred protection (odds ratio (OR) = 0.76, (CI) = 0.60–0.97) as it was more frequently found in control individuals, while haplotype CGATGCT increased the risk (OR = 1.55, CI = 1.09–2.21) for AMD. These results were also reflected when haplotypes for the untranscribed and the 5′untranslated regions (5′UTR) were analyzed separately. To assess haplotype correlation with levels of gene expression, the three SNPs within the 5′UTR were tested in a luciferase reporter assay. In retinal pigment epithelium-derived ARPE19 cells, we were able to measure significant differences in reporter levels, while this was not observed in kidney-derived HEK293 cells. The presence of the risk allele A (SNP rs705381) caused an increase in luciferase activity of approximately twofold. Our data support the view that inflammatory reactions mediated through anti-oxidative activity may be relevant to neovascular age-related macular degeneration.

Keywords

Paraoxonase 1 Gene regulation SNP association Age-related macular degeneration (AMD) 

Supplementary material

11357_2012_9467_MOESM1_ESM.doc (34 kb)
ESM 1(DOC 33 kb)

Copyright information

© American Aging Association 2012

Authors and Affiliations

  • Jadwiga Oczos
    • 1
    • 2
    • 3
  • Christian Grimm
    • 2
    • 3
    • 4
  • Daniel Barthelmes
    • 5
    • 6
  • Florian Sutter
    • 5
  • Moreno Menghini
    • 5
  • Barbara Kloeckener-Gruissem
    • 1
    • 7
  • Wolfgang Berger
    • 1
    • 3
    • 4
  1. 1.Institute of Medical Molecular GeneticsUniversity of ZurichSchwerzenbachSwitzerland
  2. 2.Lab for Retinal Cell Biology, Department of OphthalmologyUniversity of ZurichZurichSwitzerland
  3. 3.Zurich Center for Integrative Human Physiology (ZIHP)University of ZurichZurichSwitzerland
  4. 4.Zurich Center of Neuroscience (ZNZ)ZurichSwitzerland
  5. 5.Department of OphthalmologyUniversity Hospital ZurichZurichSwitzerland
  6. 6.Save Sight InstituteUniversity of SydneySydneyAustralia
  7. 7.Department of BiologyETH ZurichZurichSwitzerland

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