Variations of Mitochondrial DNA: Individualizing the Ischemic Stroke Genome

Genomewide association studies have proved to be effective in the identification of common genetic determinants in disease. Nevertheless, this research doesn't account for influence of the approximately 16.5 kb of closed circular mitochondrial genome (mtDNA). The mitochondrial organelle is composed of both nuclear and mtDNA encoded proteins, and its dysfunction is hypothesized to play a prominent role in age-associated neurologic degeneration.

Thus, our lab is conducting sequence and copy number analysis of the entire 16.5-kb mtDNA genome to complement our existing genomewide association study in ischemic stroke. We're using Affymetrix mtDNA resequencing arrays and lymphocyte-derived DNA from our North American Caucasian concordant sibling pairs with ischemic stroke. Association analysis of mtDNA genetic variability contributing to ischemic stroke is being performed. Identified genetic mtDNA variability is validated in larger series of patients with ischemic stroke and normal control participants.

The scientific aim of our proposal is to identify variation within the mtDNA genome that associates with ischemic stroke. Associated variants may inform the development of functional cellular or animal models, act as preclinical biomarkers, define high-responder populations in clinical trials, and direct future first-in-class pharmacotherapeutic intervention strategies.