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

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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.

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Acknowledgments

We would like to thank Marijana Samardzija for help with Excel macros to ease data entry in PHASE. We appreciate the genomic DNA preparations by Esther Glaus. Financial support by a cooperative project grant by the Zurich Center for Integrative Human Physiology (ZIHP) of the University of Zurich, Zurich, Switzerland, is greatly acknowledged. DB was supported by a grant from the Swiss National Foundation (SNF/SSMBS), a grant from the Holcim Foundation, and the Walter and Gertrud Siegenthaler Foundation Zürich, Switzerland.

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Authors and Affiliations

  1. Institute of Medical Molecular Genetics, University of Zurich, Schwerzenbach, Switzerland

    Jadwiga Oczos, Barbara Kloeckener-Gruissem & Wolfgang Berger

  2. Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Zurich, Switzerland

    Jadwiga Oczos & Christian Grimm

  3. Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

    Jadwiga Oczos, Christian Grimm & Wolfgang Berger

  4. Zurich Center of Neuroscience (ZNZ), Zurich, Switzerland

    Christian Grimm & Wolfgang Berger

  5. Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland

    Daniel Barthelmes, Florian Sutter & Moreno Menghini

  6. Save Sight Institute, University of Sydney, Sydney, Australia

    Daniel Barthelmes

  7. Department of Biology, ETH Zurich, Zurich, Switzerland

    Barbara Kloeckener-Gruissem

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  1. Jadwiga Oczos
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  2. Christian Grimm
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Correspondence to Barbara Kloeckener-Gruissem or Wolfgang Berger.

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Barbara Kloeckener-Gruissem and Wolfgang Berger contributed equally to this work.

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Oczos, J., Grimm, C., Barthelmes, D. et al. Regulatory regions of the paraoxonase 1 (PON1) gene are associated with neovascular age-related macular degeneration (AMD). AGE 35, 1651–1662 (2013). https://doi.org/10.1007/s11357-012-9467-x

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