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<p>Aberrant mitochondrial DNA (mtDNA) methylation has been implicated in stroke-related mechanisms such as oxidative stress and inflammation, but its association with risk of stroke remains unclear. This nested case-control study aimed to prospectively investigate the impact of mtDNA methylation on risk of stroke. A total of 343 stroke patients and 343 sex- and age-matched controls were included. Targeted bisulfite sequencing assessed methylation at 45 CpG sites in the <i>COX1</i>, <i>COX2</i>, <i>COX3</i>, and <i>ATP6</i> regions. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between mtDNA methylation and risk of stroke. Wilcoxon rank-sum test was conducted to initially explore the possible factor influencing mtDNA methylation levels in the controls. After Bonferroni correction, methylation levels at 17 CpG sites within the <i>COX1</i>, <i>COX2</i>, <i>COX3</i>, and <i>ATP6</i> regions were shown to be significantly higher in stroke patients than in controls, with ORs ranging approximately from 1.05 to 2.31. Higher average methylation levels in the <i>COX1</i>, <i>COX2</i>, <i>COX3</i>, and <i>ATP6</i> regions were significantly associated with increased risk of stroke, with corresponding ORs (95% CIs) of 1.27 (1.04–1.55), 1.75 (1.18–2.59), 1.64 (1.34–2.00), and 1.22 (1.04–1.43). Sex-stratified analyses revealed that these associations were predominantly present in women, with sex acting as a significant effect modifier of the relationship between mtDNA methylation and stroke risk across multiple CpG sites (<i>P</i> <sub>interaction</sub> &lt; 0.05). In addition, higher methylation levels were observed in men, individuals aged ≥ 65, smokers, non-hypertensive cases, and those with low physical activity. Overall, our findings suggest that higher methylation levels in <i>COX1</i>, <i>COX2</i>, <i>COX3</i>, and <i>ATP6</i> were associated with an increased risk of stroke, particularly among women, suggesting that mtDNA methylation may serve as the potential biomarker for stroke risk stratification and prevention.</p>

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Higher mitochondrial DNA methylation is associated with increased risk of stroke: a nested case-control study

  • 期刊论文

  • 发表日期：

    2026年2月28日

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  • Xueru Fu,
  • Yuewan Fang,
  • Yujie Zhao,
  • Bin Yang,
  • Yaqin Su,
  • Li Yang,
  • Weifeng Huo,
  • Liuding Wen,
  • Yuying Wu,
  • Yang Zhao,
  • Fulan Hu,
  • Ming Zhang,
  • Hongwei Wen,
  • Lei Yin,
  • Dongsheng Hu,
  • Chuande Chen

摘要

Aberrant mitochondrial DNA (mtDNA) methylation has been implicated in stroke-related mechanisms such as oxidative stress and inflammation, but its association with risk of stroke remains unclear. This nested case-control study aimed to prospectively investigate the impact of mtDNA methylation on risk of stroke. A total of 343 stroke patients and 343 sex- and age-matched controls were included. Targeted bisulfite sequencing assessed methylation at 45 CpG sites in the COX1, COX2, COX3, and ATP6 regions. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between mtDNA methylation and risk of stroke. Wilcoxon rank-sum test was conducted to initially explore the possible factor influencing mtDNA methylation levels in the controls. After Bonferroni correction, methylation levels at 17 CpG sites within the COX1, COX2, COX3, and ATP6 regions were shown to be significantly higher in stroke patients than in controls, with ORs ranging approximately from 1.05 to 2.31. Higher average methylation levels in the COX1, COX2, COX3, and ATP6 regions were significantly associated with increased risk of stroke, with corresponding ORs (95% CIs) of 1.27 (1.04–1.55), 1.75 (1.18–2.59), 1.64 (1.34–2.00), and 1.22 (1.04–1.43). Sex-stratified analyses revealed that these associations were predominantly present in women, with sex acting as a significant effect modifier of the relationship between mtDNA methylation and stroke risk across multiple CpG sites (P interaction < 0.05). In addition, higher methylation levels were observed in men, individuals aged ≥ 65, smokers, non-hypertensive cases, and those with low physical activity. Overall, our findings suggest that higher methylation levels in COX1, COX2, COX3, and ATP6 were associated with an increased risk of stroke, particularly among women, suggesting that mtDNA methylation may serve as the potential biomarker for stroke risk stratification and prevention.