Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration

John Paul SanGiovanni, Dan E. Arking, Sudha K. Iyengar, Michael Elashoff, Traci E. Clemons, George F. Reed, Alice K. Henning, Theru A. Sivakumaran, Xuming Xu, Andrew DeWan, Elvira Agrón, Elena Rochtchina, Carolyn M. Sue, Jie Jin Wang, Paul Mitchell, Josephine Hoh, Peter J. Francis, Michael Klein, Emily Y. Chew, Aravinda Chakravarti

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Abstract

Background: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts. Methodology/Prinicipal Findings: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36-4.80, P≤0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95%CI 1.19-22.69, P≤0.029). Conclusion: Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD.

Original languageEnglish (US)
Article numbere5508
JournalPLoS One
Volume4
Issue number5
DOIs
StatePublished - May 12 2009

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Electron Transport Complex I
Macular Degeneration
Mitochondrial DNA
Mitochondria
mitochondrial DNA
Genes
Metabolites
odds ratio
mitochondria
Odds Ratio
Therapeutic Human Experimentation
eye diseases
macular degeneration
retinal diseases
Retinal Diseases
vascular diseases
Mitochondrial Genome
Eye Diseases
blindness
neurodegenerative diseases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. / SanGiovanni, John Paul; Arking, Dan E.; Iyengar, Sudha K.; Elashoff, Michael; Clemons, Traci E.; Reed, George F.; Henning, Alice K.; Sivakumaran, Theru A.; Xu, Xuming; DeWan, Andrew; Agrón, Elvira; Rochtchina, Elena; Sue, Carolyn M.; Wang, Jie Jin; Mitchell, Paul; Hoh, Josephine; Francis, Peter J.; Klein, Michael; Chew, Emily Y.; Chakravarti, Aravinda.

In: PLoS One, Vol. 4, No. 5, e5508, 12.05.2009.

Research output: Contribution to journalArticle

SanGiovanni, JP, Arking, DE, Iyengar, SK, Elashoff, M, Clemons, TE, Reed, GF, Henning, AK, Sivakumaran, TA, Xu, X, DeWan, A, Agrón, E, Rochtchina, E, Sue, CM, Wang, JJ, Mitchell, P, Hoh, J, Francis, PJ, Klein, M, Chew, EY & Chakravarti, A 2009, 'Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration', PLoS One, vol. 4, no. 5, e5508. https://doi.org/10.1371/journal.pone.0005508
SanGiovanni, John Paul ; Arking, Dan E. ; Iyengar, Sudha K. ; Elashoff, Michael ; Clemons, Traci E. ; Reed, George F. ; Henning, Alice K. ; Sivakumaran, Theru A. ; Xu, Xuming ; DeWan, Andrew ; Agrón, Elvira ; Rochtchina, Elena ; Sue, Carolyn M. ; Wang, Jie Jin ; Mitchell, Paul ; Hoh, Josephine ; Francis, Peter J. ; Klein, Michael ; Chew, Emily Y. ; Chakravarti, Aravinda. / Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. In: PLoS One. 2009 ; Vol. 4, No. 5.
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abstract = "Background: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts. Methodology/Prinicipal Findings: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95{\%}CI 1.36-4.80, P≤0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95{\%}CI 1.19-22.69, P≤0.029). Conclusion: Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD.",
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T1 - Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration

AU - SanGiovanni, John Paul

AU - Arking, Dan E.

AU - Iyengar, Sudha K.

AU - Elashoff, Michael

AU - Clemons, Traci E.

AU - Reed, George F.

AU - Henning, Alice K.

AU - Sivakumaran, Theru A.

AU - Xu, Xuming

AU - DeWan, Andrew

AU - Agrón, Elvira

AU - Rochtchina, Elena

AU - Sue, Carolyn M.

AU - Wang, Jie Jin

AU - Mitchell, Paul

AU - Hoh, Josephine

AU - Francis, Peter J.

AU - Klein, Michael

AU - Chew, Emily Y.

AU - Chakravarti, Aravinda

PY - 2009/5/12

Y1 - 2009/5/12

N2 - Background: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts. Methodology/Prinicipal Findings: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36-4.80, P≤0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95%CI 1.19-22.69, P≤0.029). Conclusion: Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD.

AB - Background: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts. Methodology/Prinicipal Findings: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36-4.80, P≤0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95%CI 1.19-22.69, P≤0.029). Conclusion: Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD.

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