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Common Variants Within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage

Anderson, Christopher D. ; Biffi, Alessandro ; Nalls, Michael A. ; Devan, William J. ; Schwab, Kristin ; Ayres, Alison M. ; Valant, Valerie ; Ross, Owen A. ; Rost, Natalia S. and Saxena, Richa , et al. (2013) In Stroke: a journal of cerebral circulation 44(3). p.612-619
Abstract
Background and Purpose-Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods-This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment... (More)
Background and Purpose-Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods-This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. Results-IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). Conclusions-This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. (Stroke. 2013;44:612-619.) (Less)
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published
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keywords
genes, mitochondria, OXPHOS, stroke
in
Stroke: a journal of cerebral circulation
volume
44
issue
3
pages
612 - 619
publisher
American Heart Association
external identifiers
  • wos:000315447400013
  • scopus:84876292195
  • pmid:23362085
ISSN
1524-4628
DOI
10.1161/STROKEAHA.112.672089
language
English
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yes
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77284986-1dc2-41d9-a84c-cd2e486f855f (old id 3657370)
date added to LUP
2016-04-01 14:57:55
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2020-01-12 17:53:38
@article{77284986-1dc2-41d9-a84c-cd2e486f855f,
  abstract     = {Background and Purpose-Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods-This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. Results-IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). Conclusions-This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. (Stroke. 2013;44:612-619.)},
  author       = {Anderson, Christopher D. and Biffi, Alessandro and Nalls, Michael A. and Devan, William J. and Schwab, Kristin and Ayres, Alison M. and Valant, Valerie and Ross, Owen A. and Rost, Natalia S. and Saxena, Richa and Viswanathan, Anand and Worrall, Bradford B. and Brott, Thomas G. and Goldstein, Joshua N. and Brown, Devin and Broderick, Joseph P. and Norrving, Bo and Greenberg, Steven M. and Silliman, Scott L. and Hansen, Björn and Tirschwell, David L. and Lindgren, Arne and Slowik, Agnieszka and Schmidt, Reinhold and Selim, Magdy and Roquer, Jaume and Montaner, Joan and Singleton, Andrew B. and Kidwell, Chelsea S. and Woo, Daniel and Furie, Karen L. and Meschia, James F. and Rosand, Jonathan},
  issn         = {1524-4628},
  language     = {eng},
  number       = {3},
  pages        = {612--619},
  publisher    = {American Heart Association},
  series       = { Stroke: a journal of cerebral circulation},
  title        = {Common Variants Within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage},
  url          = {http://dx.doi.org/10.1161/STROKEAHA.112.672089},
  doi          = {10.1161/STROKEAHA.112.672089},
  volume       = {44},
  year         = {2013},
}