May 2008
Volume 49, Issue 13
ARVO Annual Meeting Abstract  |   May 2008
A Mitochondrial DNA Haplogroup Is Associated With Increased Risk of Advanced Age-Related Macular Degeneration
Author Affiliations & Notes
  • J. P. SanGiovanni
    Clinical Trials Branch - DECR, National Eye Institute/NIH, Bethesda, Maryland
  • D. E. Arking
    Johns Hopkins University School of Medicine, Baltimore, Maryland
  • E. Y. Chew
    Clinical Trials Branch - DECR, National Eye Institute/NIH, Bethesda, Maryland
  • S. K. Iyengar
    Case Western Reserve Univ, Cleveland, Ohio
  • A. K. Henning
    EMMES Corp., Rockville, Maryland
  • T. E. Clemons
    EMMES Corp., Rockville, Maryland
  • J. Hoh
    Yale University, New Haven, Connecticut
  • M. Elashoff
    EMMES Corp., Rockville, Maryland
  • M. L. Klein
    Oregon Health Sci. Univ., Portland, Oregon
  • A. Chakravarti
    Johns Hopkins University School of Medicine, Baltimore, Maryland
  • Footnotes
    Commercial Relationships  J.P. SanGiovanni, None; D.E. Arking, None; E.Y. Chew, None; S.K. Iyengar, None; A.K. Henning, None; T.E. Clemons, None; J. Hoh, None; M. Elashoff, None; M.L. Klein, None; A. Chakravarti, Affimextrix, C.
  • Footnotes
    Support  N01-EY-0-2127, EY015810, EY015771, Lincy Fdn., Verto, MVRF, EMF, AHAF
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 242. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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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: : NCT00000145

Keywords: age-related macular degeneration • mitochondria • genetics 

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