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J. P. SanGiovanni, D. E. Arking, E. Y. Chew, S. K. Iyengar, A. K. Henning, T. E. Clemons, J. Hoh, M. Elashoff, M. L. Klein, A. Chakravarti; A Mitochondrial DNA Haplogroup Is Associated With Increased Risk of Advanced Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):242.
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To examine the association between inherited variants in the mitochondrial (mt) genome and advanced age-related macular degeneration (AMD).
Our inferences are based on a 2-stage research design in 257 AMD-free people and 786 people with advanced AMD; we applied a mitochondrial genome-sequence scan, evaluation of single marker- and mtDNA haplogroup-AMD associations, and validation with representative SNPs in an independent sample to exaimine the molecular genetics of mitochrondria as they relate to AMD. All data are from elderly self-identified white, non-Hispanic U.S. residents participating in the Age-Related Eye Disease Study (AREDS). We ascertained phenotype annually across a 12-year period from stereoscopic color fundus images using a standardized and validated protocol. The primary outcome is advanced AMD, defined as presence of geographic atrophy and/or neovascular AMD at any time during AREDS. In Stage 1, we examined the complete sequence of the mitochondrial genome, including both coding and noncoding regions; in Stage 2 we genotyped two SNPs characterizing mt haplogroups associated with AMD in Stage 1.
We identified 998 unique variants and analyzed all 315 SNPs that were both called reliably at ≥ 90% of samples and present in at least 1% of cases (n=232) or controls (n=99). A consistent association with AMD in 14 of 17 SNPs characterizing a mtDNA haplotype emerged. Further analysis revealed these associations were driven entirely by a single haplogroup, as defined by two variants in mt Complex I genes. In Stage 2, we replicated this finding in an independent sample of 534 cases and 142 controls. Overall, people carrying the mtDNA haplogroup were 3 times more likely to have advanced AMD than their AMD-free peers (OR=3.4, 95%CI 1.7-6.6,P < 0.005). Our findings persisted (OR=2.69, P ≤ 0.02) after simultaneously modeling presence of the mtDNA haplogroup with occurrence of risk variants for two AMD susceptibility loci (Y402H and LOC387715), age, and smoking history.
These novel findings suggest that loci defining the AMD-associated mtDNA haplogroup and Complex I are reasonable targets for functional analyses and therapeutic research in AMD.
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