Association Between Whole Blood–Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk

TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

BACKGROUND: The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. METHODS AND RESULTS: We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P<0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P<0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P=0.11) or in the reverse direction (β=−0.012; P=0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P<0.001), but the reverse direction was not significant (P=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (P=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P<0.001). CONCLUSIONS: Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Original languageEnglish (US)
Article numbere029090
JournalJournal of the American Heart Association
Volume12
Issue number20
DOIs
StatePublished - Oct 17 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors.

Keywords

  • Mendelian randomization
  • cardiometabolic risk factors
  • cardiovascular disease
  • low-density lipoprotein cholesterol
  • mitochondrial DNA copy number
  • vascular atherosclerosis

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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