Background and Purpose: Mitochondrial dysfunction is associated with increased Reactive Oxygen Species that are thought to drive risk of disease, including stroke. We investigated the association between mtDNA abundance, as a proxy for mitochondrial function, and incident stroke using multivariable-adjusted survival and Mendelian Randomization (MR) analyses. Methods: Cox-proportional hazard model analyses were conducted to assess the association between lymphocyte mtDNA abundance, and incident ischemic and hemorrhagic stroke over a maximum of 14-years follow-up in unrelated European-ancestry participants from UK Biobank. MR was conducted using independent (R2<0.001) lead variants for lymphocyte mtDNA abundance (p < 5x10-8) as instrumental variables. Single-Nucleotide Polymorphism (SNP)-ischemic stroke associations were derived from three published open source European-ancestry results databases (cases/controls): MEGASTROKE (60,341/454,450), UK Biobank (2,404/368,771) and FinnGen (10,551/202,223). MR was performed per study, and results were subsequently meta-analyzed. Results: A total of 288,572 unrelated participants (46% men) with mean (SD) age of 57 (8) years were included in the cox-proportional hazard analyses. After correction for considered confounders (BMI, hypertension, cholesterol, T2D), no association was found between mtDNA abundance and ischemic or hemorrhagic stroke (lowest 20% versus highest 20%: ischemic stroke, hazard ratio, 1.06 [95% confidence interval 0.95, 1.18]; hemorrhagic stroke, hazard ratio 0.97 [95% confidence interval, 0.82, 1.15]). In line, in the MR analyses, we found no evidence for an association between genetically-influenced mtDNA abundance and ischemic stroke (odds ratio, 1.04; confidence interval, 0.95, 1.15).

中文翻译：

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淋巴细胞线粒体 DNA 丰度与中风之间的关联：多变量调整生存期和孟德尔随机化分析的结合

背景和目的：线粒体功能障碍与活性氧种类增加有关，这些种类被认为是导致疾病（包括中风）风险的因素。我们使用多变量调整生存率和孟德尔随机化 (MR) 分析研究了 mtDNA 丰度（作为线粒体功能的代表）与卒中事件之间的关联。方法：对来自英国生物银行的无关欧洲血统的参与者进行了 Cox 比例风险模型分析，以评估淋巴细胞 mtDNA 丰度与最多 14 年随访中的缺血性和出血性卒中事件之间的关联。使用淋巴细胞 mtDNA 丰度 (p < 5x10-8) 的独立 (R2<0.001) 先导变异作为工具变量进行 MR。单核苷酸多态性 (SNP)-缺血性卒中关联来自三个已发布的开源欧洲血统结果数据库（病例/对照）：MEGASTROKE (60,341/454,450)、UK Biobank (2,404/368,771) 和 FinnGen (10,55223/20) . 每项研究均进行 MR，随后对结果进行荟萃分析。结果：共有 288,572 名平均 (SD) 年龄为 57 (8) 岁的无关参与者（46% 为男性）被纳入 cox 比例风险分析。校正考虑的混杂因素（BMI、高血压、胆固醇、T2D）后，未发现 mtDNA 丰度与缺血性或出血性中风之间存在关联（最低 20% 与最高 20%：缺血性中风，风险比，1.06 [95% 置信区间 0.95， 1.18]；出血性中风，风险比 0.97 [95% 置信区间，0.82, 1.15]）。在线，在 MR 分析中，