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Hum Mol Genet. 2014 Jul 1;23(13):3445-55. doi: 10.1093/hmg/ddu053. Epub 2014 Feb 4.

Validation of genome-wide association study (GWAS)-identified disease risk alleles with patient-specific stem cell lines.

Author information

  • 1Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, Department of Ophthalmology, Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA, Edward S. Harkness Eye Institute, Columbia University, New York, NY 10032, USA, Tianjin Medical University Eye Hospital, Tianjin 300384, China.
  • 2Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, Department of Ophthalmology, Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA, Edward S. Harkness Eye Institute, Columbia University, New York, NY 10032, USA.
  • 3Tianjin Medical University Eye Hospital, Tianjin 300384, China.
  • 4Quantitative Proteomics Center, Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • 5The New York Stem Cell Foundation Laboratory, New York, NY 10032, USA and.
  • 6Edward S. Harkness Eye Institute, Columbia University, New York, NY 10032, USA.
  • 7Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, Department of Ophthalmology, Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA, Edward S. Harkness Eye Institute, Columbia University, New York, NY 10032, USA, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY 10032, USA sht2@columbia.edu.

Abstract

While the past decade has seen great progress in mapping loci for common diseases, studying how these risk alleles lead to pathology remains a challenge. Age-related macular degeneration (AMD) affects 9 million older Americans, and is characterized by the loss of the retinal pigment epithelium (RPE). Although the closely linked genome-wide association studies ARMS2/HTRA1 genes, located at the chromosome 10q26 locus, are strongly associated with the risk of AMD, their downstream targets are unknown. Low population frequencies of risk alleles in tissue banks make it impractical to study their function in cells derived from autopsied tissue. Moreover, autopsy eyes from end-stage AMD patients, where age-related RPE atrophy and fibrosis are already present, cannot be used to determine how abnormal ARMS2/HTRA1 expression can initiate RPE pathology. Instead, induced pluripotent stem (iPS) cell-derived RPE from patients provides us with earlier stage AMD patient-specific cells and allows us to analyze the underlying mechanisms at this critical time point. An unbiased proteome screen of A2E-aged patient-specific iPS-derived RPE cell lines identified superoxide dismutase 2 (SOD2)-mediated antioxidative defense in the genetic allele's susceptibility of AMD. The AMD-associated risk haplotype (T-in/del-A) impairs the ability of the RPE to defend against aging-related oxidative stress. SOD2 defense is impaired in RPE homozygous for the risk haplotype (T-in/del-A; T-in/del-A), while the effect was less pronounced in RPE homozygous for the protective haplotype (G-Wt-G; G-Wt-G). ARMS2/HTRA1 risk alleles decrease SOD2 defense, making RPE more susceptible to oxidative damage and thereby contributing to AMD pathogenesis.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PMID:
24497574
[PubMed - indexed for MEDLINE]
PMCID:
PMC4049304
Free PMC Article
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