Association of Mitochondrial DNA Copy Number With Cardiovascular Disease

Ashar, Foram N.; Zhang, Yiyi; Longchamps, Ryan J.; Lane, John; Moes, Anna; Grove, Megan L.; Mychaleckyj, Josyf C.; Taylor, Kent D.; Coresh, Josef; Rotter, Jerome I.; Boerwinkle, Eric; Pankratz, Nathan; Güallar, Eliseo; Arking, Dan E.

doi:10.1001/jamacardio.2017.3683

Cited by 222 publications

(216 citation statements)

References 26 publications

(44 reference statements)

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“…As an easily measurable and accessible proxy for mitochondrial function, mitochondrial DNA copy number (mtDNA-CN) is increasingly used to assess the role of mitochondria in disease. Several population-based studies have shown higher levels of mtDNA-CN to be associated with decreased incidence for CVD and its component parts: coronary artery disease (CAD) and stroke 2,3 ; neurodegenerative disorders such as Parkinson's and Alzheimer's 4,5 ; as well as several types of cancer including breast, kidney, liver and colorectal [6][7][8] . Furthermore, mtDNA-CN measured from peripheral blood has consistently been shown to be higher in women, decline with age, and correlate negatively with white blood cell (WBC) count [9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of mitochondrial DNA copy number estimation techniques

Longchamps¹,

Castellani²,

Newcomb³

et al. 2019

Preprint

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Mitochondrial DNA copy number (mtDNA-CN), a measure of the number of mitochondrial genomes per cell, is a minimally invasive proxy measure for mitochondrial function and has been associated with several aging-related diseases. Although quantitative real-time PCR (qPCR) is the current gold standard method for measuring mtDNA-CN, mtDNA-CN can also be measured from genotyping microarray probe intensities and DNA sequencing read counts. To conduct a comprehensive examination on the performance of these methods, we use known mtDNA-CN correlates (age, sex, white blood cell count, Duffy locus genotype, incident cardiovascular disease) to evaluate mtDNA-CN calculated from qPCR, two microarray platforms, as well as whole genome (WGS) and whole exome sequence (WES) data across 1,085 participants from the Atherosclerosis Risk in Communities (ARIC) study and 3,489 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We observe mtDNA-CN derived from WGS data is significantly more associated with known correlates compared to all other methods (p < 0.001). Additionally, mtDNA-CN measured from WGS is on average more significantly associated with traits by 5.6 orders of magnitude and has effect size estimates 5.8 times more extreme than the current gold standard of qPCR. We further investigated the role of DNA extraction method on mtDNA-CN estimate reproducibility and found mtDNA-CN estimated from cell lysate is significantly less variable than traditional phenol-chloroform-isoamyl alcohol (p = 5.44x10 -4 ) and silica-based column selection (p = 2.82x10 -7 ). In conclusion, we recommend the field moves towards more accurate methods for mtDNA-CN, as well as re-analyze trait associations as more WGS data becomes available from larger initiatives such as TOPMed.Δ Ct values >3 standard deviations from the mean of the plate. Outlier replicates were identified and excluded for samples with a Δ Ct standard deviation >0.5. The sample was excluded if the Δ Ct standard deviation remained >0.5 after replicate removal. We

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Section: Introductionmentioning

confidence: 99%

Evaluation of mitochondrial DNA copy number estimation techniques

Longchamps¹,

Castellani²,

Newcomb³

et al. 2019

Preprint

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“…In ARIC and MESA, DNA samples were isolated from buffy coat and genotyped using Affymetrix Genome-Wide Human SNP Arrays 6.0 (the Genvisis software package [www.genvisis.org]). [11, 12, 22] Mitochondrial SNPs were collected across all samples and were signaled with high-quality mitochondrial probes. Unadjusted mtDNA-CN was determined as the median of normalized probe intensity differences across all mitochondrial SNPs.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial DNA Copy Number and Incident Atrial Fibrillation

Zhao

Bartz

Sotoodehnia

et al. 2019

Preprint

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Background: Mechanistic studies suggests that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown. Methods:We conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). mtDNA-CN from peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA, and from multiplexed real time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates. Results: The median follow-up time was 21.4 years in ARIC, 12.9 years in MESA and 11.0 years in CHS, during which 4,021 participants developed incident atrial fibrillation (1,761 in ARIC, 790 in MESA, and 1,470 in CHS). The fully-adjusted pooled hazard ratio for incident atrial fibrillation comparing the 1 st to the 5 th quintile of mitochondria DNA copy number was 1. 13 (1.01, 1.27). The fullyadjusted pooled hazard ratio comparing the 10 th vs the 90 th percentile of mitochondria DNA copy number was 1.13 (1.04, 1.24). Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups. Conclusions:Mitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management 5 of atrial fibrillation risk.

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“…Interestingly, the neuroactive ligand receptor interaction pathway has been identified as having the second highest number of atherosclerosis candidate genes of any KEGG pathway, harboring 53 atherosclerosis candidate genes (272 total genes in the pathway) [30]. This is an interesting finding given the association of mtDNA-CN with cardiovascular disease [6][7][8]. Perhaps unsurprisingly, this pathway also belongs to the class of KEGG pathways that are responsible for environmental information processing and signaling molecules/interactions.…”

Section: Dna Methylation As a Link Between Mtdna-cn And Changes In Numentioning

confidence: 99%

“…The Affymetrix Genome-Wide Human SNP 6.0 Array was used to estimate mtDNA-CN for each participant as previously described [35]. Briefly, mtDNA copy number (mtDNA-CN) was hybridization efficiency were captured via surrogate variable analysis (SVA) as previously described [7,36].…”

Section: Estimation Of Mtdna-cn From Affymetrix Human Snp 60 Arraysmentioning

confidence: 99%

“…mtDNA copy number (mtDNA-CN) was determined utilizing a multiplexed real time quantitative polymerase chain reaction (qPCR) assay with ABI TaqMan chemistry (Applied Biosystems) as previously described [7] (see supplemental methods). The final measure of mtDNA-CN is represented as the standardized residuals from a race-stratified mixed linear regression adjusting for age, sex, and sample collection site.…”

Section: Mtdna-cn Estimation Using Quantitative Pcrmentioning

confidence: 99%

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Mitochondrial DNA Copy Number (mtDNA-CN) Can Influence Mortality and Cardiovascular Disease via Methylation of Nuclear DNA CpGs

Castellani

Longchamps

Sumpter

et al. 2019

Preprint

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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 2,507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings we assayed an additional 2,528 participants from the Cardiovascular Health Study (CHS) (N=533) and Framingham Heart Study (FHS) (N=1,995). 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<5x10 -8 ). Meta-analysis across all cohorts identified six mtDNA-CN associated CpGs at genome-wide significance (P<5x10 -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 directly drives 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= 5.24x10 -12 ), as well as the TFAM knockout methylation (P=4.41x10 -4 ) and expression (P=4.30x10 -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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Association of Mitochondrial DNA Copy Number With Cardiovascular Disease

Abstract: Mitochondrial DNA-CN was independently associated with incident CVD in 3 large prospective studies and may have potential clinical utility in improving CVD risk classification.

Cited by 222 publications

References 26 publications

Evaluation of mitochondrial DNA copy number estimation techniques

Evaluation of mitochondrial DNA copy number estimation techniques

Mitochondrial DNA Copy Number and Incident Atrial Fibrillation

Mitochondrial DNA Copy Number (mtDNA-CN) Can Influence Mortality and Cardiovascular Disease via Methylation of Nuclear DNA CpGs

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