Association between mitochondrial DNA copy number and sudden cardiac death: findings from the Atherosclerosis Risk in Communities study (ARIC)

ABSTRACTBackgroundThe association between mitochondrial DNA-copy number (mtDNA-CN) and incident heart failure (HF) in the general population is unclear.MethodsWe examined the association between mtDNA-CN and the risk of incident HF among 10,802 participants free of HF at baseline from the Atherosclerosis Risk in Communities (ARIC) study, a large bi-racial population-based cohort. mtDNA-CN was estimated using probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms Array 6.0. Incident HF events were identified through hospital discharge codes from 1987 until 2005 and through adjudication by the ARIC HF Classification Committee since 2005.ResultsDuring a median follow-up of 23.1 years, there were 2,227 incident HF events (incidence rate 10.3 per 1000 person-years). In fully adjusted models, the hazard ratios (95% confidence intervals) for HF comparing the 2nd through 5th quintiles of mtDNA-CN to the 1st quintile were 0.91 (0.80–1.04), 0.82 (0.72–0.93), 0.81 (0.71–0.92), and 0.74 (0.65–0.85), respectively (P for trend < 0.001). In stratified analyses, the associations between mtDNA-CN and HF were similar across examined subgroups. The inverse association between mtDNA-CN and incident HF was stronger in HF with reduced ejection fraction (HFrEF) than in HF with preserved ejection fraction (HFpEF).ConclusionsIn this prospective cohort, mtDNA-CN was inversely associated with the risk of incident HF suggesting that reduced levels of mtDNA-CN, a biomarker of mitochondrial dysfunction, could reflect early susceptibility to HF.

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Mitochondrial DNA copy number and diabetes: the Atherosclerosis Risk in Communities (ARIC) study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001204 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001204

Author(s):

Bailey DeBarmore ◽

Ryan J Longchamps ◽

Yiyi Zhang ◽

Rita R Kalyani ◽

Eliseo Guallar ◽

...

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Copy Number ◽

Buffy Coat ◽

Incident Diabetes ◽

Atherosclerosis Risk In Communities ◽

Mitochondrial Dna Copy Number ◽

Atherosclerosis Risk ◽

Aric Study

IntroductionMitochondrial DNA copy number (mtDNA-CN) is a measure of mitochondrial dysfunction and is associated with diabetes in experimental models. To explore the temporality of mitochondrial dysfunction and diabetes, we estimated the prevalent and incident association of mtDNA-CN and diabetes.Research design and methodsWe assessed the associations of mtDNA-CN measured from buffy coat with prevalent and incident diabetes, stratified by race, in 8954 white and 2444 black participants in the Atherosclerosis Risk in Communities (ARIC) study, an observational cohort study. Follow-up for incident analyses was complete through visit 6, 2016.ResultsMean age at mtDNA-CN measurement was 57 years and 59% were female. Prevalence of diabetes at time of mtDNA-CN measurement was higher in blacks (563/2444, 23%) than whites (855/8954, 10%). The fully adjusted odds of prevalent diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.05 (95% CI 0.74 to 1.49) among black and 1.49 (95% CI 1.20 to 1.85) among white participants. Over a median follow-up time of 19 years (Q1, Q3: 11, 24 years), we observed 617 incident diabetes cases among 1744 black and 2121 cases among 7713 white participants free of diabetes at baseline. The fully adjusted hazard of incident diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.07 (95% CI 0.84 to 1.38) among black and 0.97 (95% CI 0.86 to 1.10) among white participants.ConclusionsLower mtDNA-CN in buffy coat was associated with prevalent diabetes in white but not black ARIC participants. Lower mtDNA-CN was not associated with incident diabetes over 20 years of follow-up in whites or blacks.

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Association between Mitochondrial DNA Copy Number and Sudden Cardiac Death: Findings from the Atherosclerosis Risk in Communities Study (ARIC)

10.1101/113878 ◽

2017 ◽

Author(s):

Yiyi Zhang ◽

Eliseo Guallar ◽

Foram N. Ashar ◽

Ryan J. Longchamps ◽

Christina A. Castellani ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Copy Number ◽

Cardiac Death ◽

Ventricular Tachyarrhythmia ◽

Snp Array ◽

Surrogate Marker ◽

Expert Committee ◽

Atherosclerosis Risk In Communities ◽

Wide Range ◽

Atherosclerosis Risk

ABSTRACTAimsSudden cardiac death (SCD) is a major public health burden. Mitochondrial dysfunction has been implicated in a wide range of cardiovascular diseases including cardiomyopathy, heart failure, and arrhythmias, but it is unknown if it also contributes to SCD risk. We sought to examine the prospective association between mtDNA copy number (mtDNA-CN), a surrogate marker of mitochondrial function, and SCD risk.Methods and ResultsWe measured baseline mtDNA-CN in 11,093 participants from the Atherosclerosis Risk in Communities (ARIC) study. mtDNA-CN was calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) on the Affymetrix Genome-Wide Human SNP Array 6.0. SCD was defined as a sudden pulseless condition presumed due to a ventricular tachyarrhythmia in a previously stable individual without evidence of a non-cardiac cause of cardiac arrest. SCD cases were reviewed and adjudicated by an expert committee. During a median follow-up of 20.4 years, we observed 361 SCD cases. After adjusting for age, race, sex, and center, the hazard ratio (HR) for SCD comparing the 1st to the 5th quintiles of mtDNA-CN was 2.24 (95% CI 1.58 to 3.19; p-trend <0.001). When further adjusting for traditional CVD risk factors, prevalent CHD, heart rate, and QT interval duration, the association remained statistically significant. Spline regression models showed that the association was approximately linear over the range of mtDNA-CN values. No apparent interaction by race or by sex was detected.ConclusionIn this community-based prospective study, mtDNA-CN in peripheral blood was inversely associated with the risk of SCD.

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Evaluation of mitochondrial DNA copy number estimation techniques

10.1101/610238 ◽

2019 ◽

Cited By ~ 4

Author(s):

RJ Longchamps ◽

CA Castellani ◽

SY Yang ◽

CE Newcomb ◽

JA Sumpter ◽

...

Keyword(s):

Mitochondrial Dna ◽

Gold Standard ◽

Copy Number ◽

Isoamyl Alcohol ◽

Dna Copy Number ◽

Microarray Probe ◽

Gold Standard Method ◽

Atherosclerosis Risk In Communities ◽

Current Gold Standard ◽

Mitochondrial Dna Copy Number

AbstractMitochondrial 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 = 5.44×10-4) and silica-based column selection (p = 2.82×10-7). 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.

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