TY - JOUR
T1 - Low leukocyte mitochondrial DNA abundance drives atherosclerotic cardiovascular diseases
T2 - cohort and Mendelian randomization study
AU - Luo, Jiao
AU - Noordam, Raymond
AU - Jukema, J Wouter
AU - Willems van Dijk, Ko
AU - Hägg, Sara
AU - Grassmann, Felix
AU - le Cessie, Saskia
AU - van Heemst, Diana
N1 - Funding
This work was supported by the VELUX Stiftung (grant number 1156) (to D.H. and R.N.). J.L. was supported by the China Scholarship Council (No. 201808500155). R.N. was supported by an innovation grant from the Dutch Heart Foundation (grant number 2019T103). S.H. is supported by the Karolinska Institutet Strategic Research Area in Epidemiology and the Swedish Research Council (2019-01272).
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PY - 2022/12/20
Y1 - 2022/12/20
N2 - AIM: Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations of leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial copy numbers and function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies.METHODS AND RESULTS: Multivariable-adjusted Cox regression analyses were conducted in 273,619 unrelated participants of European ancestry from UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analyzed using fixed-effects models. During a median follow-up of 11.8 years, cox regression restricted cubic spline analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively.CONCLUSION: Our findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF.
AB - AIM: Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations of leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial copy numbers and function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies.METHODS AND RESULTS: Multivariable-adjusted Cox regression analyses were conducted in 273,619 unrelated participants of European ancestry from UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analyzed using fixed-effects models. During a median follow-up of 11.8 years, cox regression restricted cubic spline analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively.CONCLUSION: Our findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF.
U2 - 10.1093/cvr/cvac182
DO - 10.1093/cvr/cvac182
M3 - Article
C2 - 36536985
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
M1 - cvac182
ER -
