Association between mitochondrial DNA copy number and cardiovascular disease: Current evidence based on a systematic review and meta-analysis

Abstract Background Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. Methods To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. Results Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10− 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10− 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the “neuroactive ligand receptor interaction” KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10− 12), as well as the TFAM knockout methylation (P = 4.41 × 10− 4) and expression (P = 4.30 × 10− 4) studies. Conclusions These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

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Mitochondrial DNA copy number and trimethylamine levels in the blood: New insights on cardiovascular disease biomarkers

The FASEB Journal ◽

10.1096/fj.202100056r ◽

2021 ◽

Vol 35 (7) ◽

Author(s):

Laura Bordoni ◽

Irene Petracci ◽

Iwona Pelikant‐Malecka ◽

Adriana Radulska ◽

Marco Piangerelli ◽

...

Keyword(s):

Cardiovascular Disease ◽

Mitochondrial Dna ◽

Copy Number ◽

Dna Copy Number ◽

Disease Biomarkers ◽

Mitochondrial Dna Copy Number

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Mitochondrial DNA copy number and trimethylamine levels in the blood: new insights on cardiovascular disease biomarkers

10.1101/2020.12.29.20248667 ◽

2021 ◽

Author(s):

Laura Bordoni ◽

Irene Petracci ◽

Iwona Pelikant-Malecka ◽

Adriana Radulska ◽

Marco Piangerelli ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Mitochondrial Dna ◽

Copy Number ◽

Cardiovascular Health ◽

Predictive Biomarker ◽

List Type ◽

Dna Copy Number ◽

Mitochondrial Dna Copy Number ◽

Artery Disease

ABSTRACTAmong cardiovascular disease (CVD) biomarkers, the mitochondrial DNA copy number (mtDNAcn) is a promising candidate. A growing attention has been also dedicated to trimethylamine-N-oxide (TMAO), an oxidative derivative of the gut metabolite trimethylamine (TMA). With the aim to identify biomarkers predictive of CVD, we investigated TMA, TMAO and mtDNAcn in a population of 389 coronary artery disease (CAD) patients and 151 healthy controls, in association with established risk factors for CVD (gender, age, hypertension, smoking, diabetes, glomerular filtration rate (GFR)). MtDNAcn was significantly lower in CAD patients and in hypertensive subjects; it correlates with GFR and TMA, but not with TMAO. A biomarker including mtDNAcn, gender, and hypertension (but neither TMA nor TMAO) emerged as a good predictor of CAD. Our findings support the usage of mtDNAcn as a plastic biomarker to monitor the exposure to risk factors and the efficacy of preventive interventions for a personalized CAD risk reduction.Highlights-mtDNAcn measured in whole blood is associated to the cardiovascular health status in humans;-mtDNAcn is reduced in CAD and hypertension, and inversely correlates with GFR;-mtDNA, gender and hypertension together represent a good predictive biomarker for CAD;-TMA metabolism is different in healthy and CAD subjects;-TMA and TMAO are not good predictors of CAD.

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Elevated Mitochondrial DNA Copy Number in Peripheral Blood and Tissue Predict the Opposite Outcome of Cancer: A Meta-Analysis

Scientific Reports ◽

10.1038/srep37404 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 13

Author(s):

Nan Chen ◽

Shu Wen ◽

Xiaoru Sun ◽

Qian Fang ◽

Lin Huang ◽

...

Keyword(s):

Mitochondrial Dna ◽

Peripheral Blood ◽

Copy Number ◽

Meta Analysis ◽

Dna Copy Number ◽

Mitochondrial Dna Copy Number

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A genome-wide association study of mitochondrial DNA copy number in two population-based cohorts

10.1101/372177 ◽

2018 ◽

Author(s):

Anna L. Guyatt ◽

Rebecca R. Brennan ◽

Kimberley Burrows ◽

Philip A. I. Guthrie ◽

Raimondo Ascione ◽

...

Keyword(s):

Mitochondrial Dna ◽

Copy Number ◽

Meta Analysis ◽

Genome Wide Association ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Dna Copy Number ◽

Mitochondrial Dna Copy Number ◽

Genome Wide ◽

A Genome

AbstractMitochondrial DNA copy number (mtDNA CN) exhibits interindividual and intercellular variation, but few genome-wide association studies (GWAS) of directly assayed mtDNA CN exist.We undertook a GWAS of qPCR-assayed mtDNA CN in the Avon Longitudinal Study of Parents and Children (ALSPAC), and the UK Blood Service (UKBS) cohort. After validating and harmonising data, 5461 ALSPAC mothers (16-43 years at mtDNA CN assay), and 1338 UKBS females (17-69 years) were included in a meta-analysis. Sensitivity analyses restricted to females with white cell-extracted DNA, and adjusted for estimated or assayed cell proportions. Associations were also explored in ALSPAC children, and UKBS males.A neutrophil-associated locus approached genome-wide significance (rs709591 [MED24], β[SE] −0.084 [0.016], p=1.54e-07) in the main meta-analysis of adult females. This association was concordant in magnitude and direction in UKBS males and ALSPAC neonates. SNPs in and around ABHD8 were associated with mtDNA CN in ALSPAC neonates (rs10424198, β[SE] 0.262 [0.034], p=1.40e-14), but not other study groups. In a meta-analysis of unrelated individuals (N=11253), we replicated a published association in TFAM β[SE] 0.046 [0.017], p=0.006), with an effect size much smaller than that observed in the replication analysis of a previous in silico GWAS.In a hypothesis-generating GWAS, we confirm an association between TFAM and mtDNA CN, and present putative loci requiring replication in much larger samples. We discuss the limitations of our work, in terms of measurement error and cellular heterogeneity, and highlight the need for larger studies to better understand nuclear genomic control of mtDNA copy number.

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