The association between mitochondrial DNA abundance and stroke: a combination of multivariable-adjusted survival and Mendelian randomization analyses

Martens, L.G.; Luo, J.; Wermer, M.J.H.; Dijk, K.W. van; Hagg, S.; Grassmann, F.; ... ; Heemst, D. van (2022)

Article / Letter to editor

Background and aims: Mitochondrial dysfunction is associated with increased reactive oxygen species (ROS) that are thought to drive disease risk, including stroke. We investigated the association between mtDNA abundance, as a proxy measure of 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 mtDNA abundance, and incident ischemic and hemorrhagic stroke over a maximum of 14-year follow-up in European -ancestry participants from UK Biobank. MR was conducted using independent (R-2 < 0.001) lead variants for mtDNA abundance (p < 5 x 10(-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 (2404/368,771) and FinnGen (10,551/202,223). MR was performed per study, and results were subsequently meta-analyzed. Results: In total, 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 low versus high mtDNA abundance and ischemic (HR: 1.06 [95% CI: 0.95, 1.18]) or hemorrhagic (HR: 0.97 [95% CI: 0.82, 1.15]) stroke. However, in the MR analyses after removal of platelet count-associated SNPs, we found evidence for an association between genetically-influenced mtDNA abundance and ischemic stroke (odds ratio, 1.17; confidence interval, 1.03, 1.32). Conclusions: Although the results from both multivariable-adjusted prospective and basis MR analyses did not show an association between low mtDNA and increased risk of ischemic stroke, in-depth MR sensitivity analyses may suggest evidence for a causal relationship.

• Ischemic stroke
• Hemorrhagic stroke
• Mitochondrial DNA copy numbers
• Reactive oxygen species
• Mitochondrial function
• Cardiovascular diseases
• Mendelian randomization

• All authors: Martens, L.G.; Luo, J.; Wermer, M.J.H.; Dijk, K.W. van; Hagg, S.; Grassmann, F.; Noordam, R.; Heemst, D. van
• Date: 2022-08-01
• Journal: Atherosclerosis
• Volume: 354
• Pages: 1 - 7
• DOI: doi:10.1016/j.atherosclerosis.2022.06.1012
• Link: https://www.sciencedirect.com/science/article/pii/S0021915022012990?via%...