Background and objectives: Low buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and poststroke mortality; however, its prognostic utility has not been extensively explored. Our goal was to investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of poststroke outcomes using epidemiologic and genetic studies.Methods: First, we performed association testing between baseline buffy coat mtDNA-CN measurements and 1-month poststroke outcomes in 3,498 cases of acute, first stroke from 25 countries from the international, multicenter case-control study Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World (INTERSTROKE). Then, we performed 2-sample mendelian randomization analyses to evaluate potential causative effects of low mtDNA-CN on 3-month modified Rankin Scale (mRS) score. Genetic variants associated with mtDNA-CN levels were derived from the UK Biobank study (N = 383,476), and corresponding effects on 3-month mRS score were ascertained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME; N = 6,021) study.Results: A 1-SD lower mtDNA-CN at baseline was associated with stroke severity (baseline mRS score: odds ratio [OR] 1.27, 95% confidence interval [CI] 1.19-1.36; p = 4.7 × 10-12). Independently of baseline stroke severity, lower mtDNA-CN was associated with increased odds of greater 1-month disability (ordinal mRS score: OR 1.16, 95% CI 1.08-1.24; p = 4.4 × 10-5), poor functional outcome status (mRS score 3-6 vs 0-2: OR 1.21, 95% CI 1.08-1.34; p = 6.9 × 10-4), and mortality (OR 1.35, 95% CI 1.14-1.59; p = 3.9 × 10-4). Subgroup analyses demonstrated consistent effects across stroke type, sex, age, country income level, and education level. In addition, mtDNA-CN significantly improved reclassification of poor functional outcome status (net reclassification index [NRI] score 0.16, 95% CI 0.08-0.23; p = 3.6 × 10-5) and mortality (NRI score 0.31, 95% CI 0.19-0.43; p = 1.7 × 10-7) beyond known prognosticators. With the use of independent datasets, mendelian randomization revealed that a 1-SD decrease in genetically determined mtDNA-CN was associated with increased odds of greater 3-month disability quantified by ordinal mRS score (OR 2.35, 95% CI 1.13-4.90; p = 0.02) and poor functional outcome status (OR 2.68, 95% CI 1.05-6.86; p = 0.04).Discussion: Buffy coat mtDNA-CN is a novel and robust marker of poststroke prognosis that may also be a causal determinant of poststroke outcomes.Classification of evidence: This study provides Class II evidence that low buffy coat mtDNA-CN (>1 SD) was associated with worse baseline severity and 1-month outcomes in patients with ischemic or hemorrhagic stroke.
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