TY - JOUR
T1 - The association between mitochondrial DNA abundance and stroke
T2 - A combination of multivariable-adjusted survival and Mendelian randomization analyses
AU - Martens, Leon G
AU - Luo, Jiao
AU - Wermer, Marieke J H
AU - Willems van Dijk, Ko
AU - Hägg, Sara
AU - Grassmann, Felix
AU - Noordam, Raymond
AU - van Heemst, Diana
N1 - Acknowledgements
The authors are grateful to the UK Biobank for allowing us the use of their data. The analyses done in UK Biobank were done under project number 56340. Furthermore, the authors acknowledge the participants and investigators of the MEGASTROKE consortium and the FinnGen Biobank who contributed to the summary statistics data which are made available for further studies.
Financial support
This work was supported by the VELUX Stiftung [grant number 1156] to DvH and RN, and JL was supported by the China Scholarship Counsel [No.201808500155]. RN was supported by an innovation grant from the Dutch Heart Foundation [grant number 2019T103 to R.N.]. Parts of this work were funded by the Åke Wibergs Foundation (grant number M19-0294 to F.G).
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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 × 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.
AB - 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 × 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.
KW - Cardiovascular diseases
KW - Hemorrhagic stroke
KW - Ischemic stroke
KW - Mendelian randomization
KW - Mitochondrial DNA copy numbers
KW - Mitochondrial function
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85133224453&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2022.06.1012
DO - 10.1016/j.atherosclerosis.2022.06.1012
M3 - Article
C2 - 35793595
VL - 354
SP - 1
EP - 7
JO - Atherosclerosis
JF - Atherosclerosis
SN - 0021-9150
ER -
