Mitochondrial DNA haplogroups associated with age-related macular degeneration.
OBJECTIVE
To examine the mtDNA control regions in normal and age-related macular degeneration (AMD) retinas. To identify the mtDNA variations 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 the patients with AMD and the control subjects, consistent with the decline in mitochondrial function with age. However, the AMD retinas had higher oxidized DNA levels and a higher number 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; odds ratio [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 patients with AMD. These results implicate mitochondrial alterations in the etiology of AMD.
Udar
Nitin
N
Department of Ophthalmology, University of California Irvine, Orange, California 92868, USA.
Atilano
Shari R
SR
Memarzadeh
Masood
M
Boyer
David S
DS
Chwa
Marilyn
M
Lu
Stephanie
S
Maguen
Barak
B
Langberg
Jonathan
J
Coskun
Pinar
P
Wallace
Douglas C
DC
Nesburn
Anthony B
AB
Khatibi
Nikan
N
Hertzog
Dieter
D
Le
Khoi
K
Hwang
Daniel
D
Kenney
M Cristina
MC
D000368:Aged; D000369:Aged, 80 and over; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA
D004272:DNA, Mitochondrial