Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 13, Pages 3445-3455Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu053
Keywords
-
Funding
- National Institute of Health Core [5P30EY019007]
- National Cancer Institute Core [5P30CA013696]
- Research to Prevent Blindness, New York, NY, USA
- Tistou and Charlotte Kerstan Foundation
- National Institute of Health [R01EY018213]
- Research to Prevent Blindness Physician-Scientist Award, Association for Research in Vision and Ophthalmology (ARVO) Foundation, Macular Society, Retina Research Foundation Cox Macular Research Project
- Bernard and Shirlee Brown Family Fund
- Schneeweiss Stem Cell Fund, New York State [N09G-302]
- Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312]
- Joel Hoffman Fund
- Professor Gertrude Rothschild Stem Cell Foundation
- Gebroe Family Foundation
- Research to Prevent Blindness Medical Student Fellowship
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available