Mitochondrial DNA Haplogroups Associated with Age-Related Macular Degeneration

¹ Ophthalmology, UCI, Orange, California, United States
² Retina-Vitreous Associates Medical Group, Beverly Hills, California, United States
³ Ophthalmology, UCI, Irvine, California, United States
⁴ Ophthalmology, UCI, Orange, United States; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, United States
⁵ Center for Molecular and Mitochondrial Medicine and Genetics, Departments of Biological Chemistry, Ecology and Evolutionary Biol, UCI, Irvine, California, United States
⁶ Ophthalmology, UCI, Orange, United States; Cedars Sinai Medical Center, Los Angeles, United States
⁷ Dept of Ophthamology, UCI, 23871 Petrel Court, laguna niguel, California, 92677, United States; Kansas City Medical School, Kansa City, United States
⁸ Loma Linda Medical School, Loma Linda, California, United States
⁹ Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, United States
¹⁰ Ophthalmology, UCI, 101 The City Drive, Orange, California, 92868, United States

^* To whom correspondence should be addressed. E-mail: mkenney{at}uci.edu.

	Abstract

Purpose: To examine the mtDNA control regions in normal and Age-related Macular Degeneration (AMD) retinas. To identify mtDNA variation associated with AMD. Methods: Retinas from 10 normal and 11 AMD globes were isolated and analyzed for mtDNA rearrangements by Long Extension-Polymerase Chain Reaction (LX-PCR) and for the nature and frequency of single nucleotide polymorphisms (SNPs) in the mtDNA control region by direct sequencing. Blood DNA was extracted from 99 AMD and 92 age-matched control subjects. The sequence variations that define haplogroups H,I,J,K,T,V,X and U were characterized by PCR, restriction enzyme digestion and/or sequencing. Results: LX-PCR of retinal mtDNAs revealed high levels of rearrangements in both AMD patients and controls, consistent with the decline in mitochondrial function with age. However, the AMD retinas had higher oxidized DNA levels and higher numbers of SNPs than controls (p=0.02). The control region SNPs T16126C and A73G, commonly found in haplogroups J and T, were more frequent in the AMD retinas than in normal retinas. The associations between AMD and haplogroups J and T were confirmed and extended by analysis of blood DNA. SNPs at position a T16126C (J; OR=3.66), T16126C+G13368A (JT; OR=10.27), A4917G+A73G (T4; OR=5) and T3197C+A12308G (U5; OR=infinity), were all strongly associated with AMD. Conclusions: AMD retinas exhibited increased mtDNA control region SNPs compared to normal retinas. This correlated with an increased frequency of mtDNA SNPs associated with haplogroups J, T and U in AMD patients. These results implicate mitochondrial alterations in the etiology of AMD.

Key Words: age-related macular degeneration, mitochondrial DNA, control region, haplogroups

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