Mitochondrial DNA Copy Number as a Marker and Mediator of Stroke Prognosis
Michael Chong, Sukrit Narula, Robert W. Morton, Conor Judge, Loubna Akhabir, Nathan Cawte, Nazia Pathan, Ricky Lali, Pedrum Mohammadi‐Shemirani, Ashkan Shoamanesh, Martin O’Donnell, Salim Yusuf, Peter Langhorne, Guillaume Paré
Abstract
<h3>Background and Objectives</h3> 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. <h3>Methods</h3> 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. <h3>Results</h3> 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; <i>p</i> = 4.7 × 10<sup>−12</sup>). 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; <i>p</i> = 4.4 × 10<sup>−5</sup>), poor functional outcome status (mRS score 3–6 vs 0–2: OR 1.21, 95% CI 1.08–1.34; <i>p</i> = 6.9 × 10<sup>−4</sup>), and mortality (OR 1.35, 95% CI 1.14–1.59; <i>p</i> = 3.9 × 10<sup>−4</sup>). 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; <i>p</i> = 3.6 × 10<sup>−5</sup>) and mortality (NRI score 0.31, 95% CI 0.19–0.43; <i>p</i> = 1.7 × 10<sup>−7</sup>) 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; <i>p</i> = 0.02) and poor functional outcome status (OR 2.68, 95% CI 1.05–6.86; <i>p</i> = 0.04). <h3>Discussion</h3> Buffy coat mtDNA-CN is a novel and robust marker of poststroke prognosis that may also be a causal determinant of poststroke outcomes. <h3>Classification of Evidence</h3> 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.