title: Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is a major cause of blindness among the elderly in the developed world. Genetic analysis of AMD has identified 34 high-risk loci associated with AMD. The genes at these high risk loci belong to diverse biological pathways, suggesting different mechanisms leading to AMD pathogenesis. Thus, therapies targeting a single pathway for all AMD patients will likely not be universally effective. Recent evidence suggests defects in mitochondria (mt) of the retinal pigment epithelium (RPE) may constitute a key pathogenic event in some AMD patients. The purpose of this study is to determine if individuals with a specific genetic background have a greater propensity for mtDNA damage. We used human eyebank tissues from 76 donors with AMD and 42 age-matched controls to determine the extent of mtDNA damage in the RPE that was harvested from the macula using a long extension polymerase chain reaction assay. Genotype analyses were performed for ten common AMD-associated nuclear risk alleles (ARMS2, TNFRSF10A, CFH, C2, C3, APOE, CETP, LIPC, VEGF and COL10A1) and mtDNA haplogroups. Sufficient samples were available for genotype association with mtDNA damage for TNFRSF10A, CFH, CETP, VEGFA, and COL10A1. Our results show that AMD donors carrying the high risk allele for CFH (C) had significantly more mtDNA damage compared with donors having the wild-type genetic profile. The data from an additional 39 donors (12 controls and 27 AMD) genotyped for CFH alleles further supported these findings. Taken together, these studies provide the rationale for a more personalized approach for treating AMD by uncovering a significant correlation between the CFH high risk allele and accelerated mtDNA damage. Patients harboring this genetic risk factor may benefit from therapies that stabilize and protect the mt in the RPE.
authors: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: ferri013@umn.edu.
authors: Deborah A
authors: DA
authors: Ferrington
authors: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA.
authors: Rebecca J
authors: RJ
authors: Kapphahn
authors: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA.
authors: Michaela M
authors: MM
authors: Leary
authors: Gavin Herbert Eye Institute, University of California, Irvine, CA, 92697, USA.
authors: Shari R
authors: SR
authors: Atilano
authors: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA.
authors: Marcia R
authors: MR
authors: Terluk
authors: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA.
authors: Pabalu
authors: P
authors: Karunadharma
authors: Gavin Herbert Eye Institute, University of California, Irvine, CA, 92697, USA.
authors: George Kuei-Jie
authors: GK
authors: Chen
authors: Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, MD 20892, USA.
authors: Rinki
authors: R
authors: Ratnapriya
authors: Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, MD 20892, USA.
authors: Anand
authors: A
authors: Swaroop
authors: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA.
authors: Sandra R
authors: SR
authors: Montezuma
authors: Gavin Herbert Eye Institute, University of California, Irvine, CA, 92697, USA.
authors: M Cristina
authors: MC
authors: Kenney
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D017242:Complement Factor H / Q000235:genetics*; D004249:DNA Damage / Q000502:physiology*; D004272:DNA, Mitochondrial; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D055213:Retinal Pigment Epithelium
chemical_list: D004272:DNA, Mitochondrial; D017242:Complement Factor H
keywords: Age-related macular degeneration; Complement factor H; Eyebank tissue; Haplogroups; Inflammation; Mitochondria; mtDNA