| Title: | The association between mitochondrial DNA abundance and stroke: A combination of multivariable-adjusted survival and Mendelian randomization analyses |
| Journal: | Atherosclerosis |
| Published: | 19 Jun 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35793595/ |
| DOI: | https://doi.org/10.1016/j.atherosclerosis.2022.06.1012 |
| URL: | http://www.atherosclerosis-journal.com/article/S0021915022012990/pdf |
Publication 14018
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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.</p>
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 (R2 < 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.</p>
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).</p>
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.</p>
14 Keywords
- DNA, Mitochondrial
- Female
- Genome-Wide Association Study
- Humans
- Ischemia
- Ischemic Stroke
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Mitochondria
- Polymorphism, Single Nucleotide
- Prospective Studies
- Risk Factors
- Stroke
8 Authors
- Leon G Martens
- Jiao Luo
- Marieke J H Wermer
- Ko Willems van Dijk
- Sara Hägg
- Felix Grassmann
- Raymond Noordam
- Diana van Heemst
1 Application
| Application ID | Title |
|---|---|
| 56340 | Prevention of myocardial infarction and primary atherogenic cardiovascular disease from a sex-specific life course perspective |
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