. 2020 Sep 16;18(1):246.

doi: 10.1186/s12916-020-01715-6.

Mitochondrial DNA copy number and incident atrial fibrillation

Di Zhao¹, Traci M Bartz², Nona Sotoodehnia², Wendy S Post^{1

3}, Susan R Heckbert⁴, Alvaro Alonso⁵, Ryan J Longchamps⁶, Christina A Castellani⁶, Yun Soo Hong¹, Jerome I Rotter⁷, Henry J Lin⁷, Brian O'Rourke⁸, Nathan Pankratz⁹, John A Lane⁹, Stephanie Y Yang⁶, Eliseo Guallar¹⁰, Dan E Arking¹¹

Affiliations

¹ Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, 2024 E. Monument Street, Room 2-645, Baltimore, MD, 21205, USA.
² Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
³ Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
⁵ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁶ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Miller Research Building, Room 459, Baltimore, MD, 21205, USA.
⁷ Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁸ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA.
¹⁰ Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, 2024 E. Monument Street, Room 2-645, Baltimore, MD, 21205, USA. eguallar@jhu.edu.
¹¹ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Miller Research Building, Room 459, Baltimore, MD, 21205, USA. arking@jhmi.edu.

PMID: 32933497
PMCID: PMC7493408
DOI: 10.1186/s12916-020-01715-6

Mitochondrial DNA copy number and incident atrial fibrillation

Di Zhao et al. BMC Med. 2020.

. 2020 Sep 16;18(1):246.

doi: 10.1186/s12916-020-01715-6.

Authors

Affiliations

¹ Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, 2024 E. Monument Street, Room 2-645, Baltimore, MD, 21205, USA.
² Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
³ Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
⁵ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁶ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Miller Research Building, Room 459, Baltimore, MD, 21205, USA.
⁷ Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁸ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA.
¹⁰ Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, 2024 E. Monument Street, Room 2-645, Baltimore, MD, 21205, USA. eguallar@jhu.edu.
¹¹ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Miller Research Building, Room 459, Baltimore, MD, 21205, USA. arking@jhmi.edu.

PMID: 32933497
PMCID: PMC7493408
DOI: 10.1186/s12916-020-01715-6

Abstract

Background: Mechanistic studies suggest 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 the 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 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. 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 of atrial fibrillation risk.

Keywords: Atrial fibrillation; Mitochondria DNA copy number; mtDNA.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Flowchart of study participants

**Fig. 2**
Hazard ratios for incident atrial fibrillation by levels of mtDNA copy number. The figure includes hazard ratios for comparing quintiles 1st to 4th with the 5th quintile (reference) of mtDNA copy number, as well as the hazard ratio for comparing the 10th to the 90th percentile of mtDNA copy number. Models were adjusted for age, sex, race/enrollment center, body mass index, height, smoking, alcohol intake, physical activity, total and HDL cholesterol, cholesterol medication, hypertension, diabetes, prevalent CHD, prevalent heart failure, eGFR, and log-transformed NT-proBNP at baseline

**Fig. 3**
Spline regression analysis of incident atrial fibrillation by levels of mtDNA copy number. The curves represent adjusted hazard ratios (solid line) and their 95% confidence intervals (dashed lines) based on restricted cubic splines of mtDNA copy number with knots at the 5th, 35th, 65th, and 95th percentiles of its distribution. The reference value (diamond dot) was set at the 90th percentile of the distribution. Models were adjusted for age, sex, race/enrollment center, body mass index, height, smoking, alcohol intake, physical activity, total and HDL cholesterol, cholesterol medication, hypertension, diabetes, prevalent CHD, prevalent heart failure, eGFR, and log-transformed NT-proBNP at baseline. Histograms represent the frequency distribution of mtDNA copy number at baseline

See this image and copyright information in PMC

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Mitochondrial DNA copy number and incident atrial fibrillation

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Mitochondrial DNA copy number and incident atrial fibrillation

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