Abstract
Purpose: :
To examine the association between inherited variants in the mitochondrial (mt) genome and advanced age-related macular degeneration (AMD).
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Clinical Trial: :
www.clinicaltrials.gov NCT00000145
Keywords: age-related macular degeneration • mitochondria • genetics