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

Leon G Martens; Jiao Luo; Marieke J H Wermer; Ko Willems van Dijk; Sara Hägg; Felix Grassmann; Raymond Noordam; Diana van Heemst

doi:10.1016/j.atherosclerosis.2022.06.1012

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

Leon G Martens^* (Corresponding Author), Jiao Luo, Marieke J H Wermer, Ko Willems van Dijk, Sara Hägg, Felix Grassmann, Raymond Noordam, Diana van Heemst

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

2 Downloads (Pure)

Abstract

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.

Original language	English
Pages (from-to)	1-7
Number of pages	7
Journal	Atherosclerosis
Volume	354
Early online date	3 Jul 2022
DOIs	https://doi.org/10.1016/j.atherosclerosis.2022.06.1012
Publication status	Published - 1 Aug 2022

Bibliographical note

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).

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.atherosclerosis.2022.06.1012Licence: CC BY

Martens_etal_A_The_Association_Between_VoR
© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license https://creativecommons.org/licenses/by/4.0/
Final published version, 1.38 MBLicence: CC BY

Cite this

@article{1c1736c3f9d549be9f108cbbd4949e76,

title = "The association between mitochondrial DNA abundance and stroke: A combination of multivariable-adjusted survival and Mendelian randomization analyses",

abstract = "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.",

keywords = "Cardiovascular diseases, Hemorrhagic stroke, Ischemic stroke, Mendelian randomization, Mitochondrial DNA copy numbers, Mitochondrial function, Reactive oxygen species",

author = "Martens, {Leon G} and Jiao Luo and Wermer, {Marieke J H} and {Willems van Dijk}, Ko and Sara H{\"a}gg and Felix Grassmann and Raymond Noordam and {van Heemst}, Diana",

note = "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 {\AA}ke Wibergs Foundation (grant number M19-0294 to F.G).",

year = "2022",

month = aug,

day = "1",

doi = "10.1016/j.atherosclerosis.2022.06.1012",

language = "English",

volume = "354",

pages = "1--7",

journal = "Atherosclerosis",

issn = "0021-9150",

publisher = "Elsevier Ireland Ltd",

}

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

SN - 0021-9150

VL - 354

SP - 1

EP - 7

JO - Atherosclerosis

JF - Atherosclerosis

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this