# Mitochondrial DNA heteroplasmy and risk for atherosclerotic cardiovascular disease (ASCVD)

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $770,215

## Abstract

Cardiovascular disease (CVD) continues to be a leading cause of mortality and morbidity worldwide. We have
previously demonstrated that mitochondrial DNA copy number (mtDNA-CN), which reflects the high degree of
variation in the number of mitochondrial genomes per cell (10s to 100s), is a novel risk factor for CVD. In a
prospective cohort analysis including 21,870 participants, a 1 standard deviation decrease in mtDNA-CN was
associated with a 1.23 (95%CI 1.19 to 1.26) increased risk of CVD. Moreover, a direct clinical utility was
demonstrated, with the addition of mtDNA-CN to the 2013 ACC/AHA Pooled Cohorts Equations for estimating
10-yr atherosclerotic CVD risk significantly improving both sensitivity and specificity for the recommendations on
initiating statin therapy. While mtDNA-CN captures the quantity of mitochondria, and higher mtDNA-CN levels
are associated with increased mitochondrial function this measurement does not take into account the quality of
the mitochondria. Mitochondrial DNA heteroplasmy, which is universally observed and accumulates with age, is
likely to have negative consequences for mitochondrial function. Thus, we hypothesize that the effect of mtDNA-
CN on CVD risk will be directly impacted by levels of heteroplasmy, and that higher levels of heteroplasmy will
be an independent risk factor for CVD. To test this hypothesis, we will first use the combined ARIC, CHS, FHS,
MESA and RS cohorts (n=23,954; 6,048 incident CVD events), to determine the association of baseline
measures of mtDNA heteroplasmy with incident CVD. Second, changes in mtDNA heteroplasmy may reflect
ongoing disease processes (e.g. inflammation), and thus we will use DNA collected from the initial baseline visit
along with up to 2 follow-up visits in each cohort (n=7,364, 3,430 incident CVD events) to assess how longitudinal
changes in mtDNA heteroplasmy influence future CVD risk. Third, one potential consequence of decreased
mitochondrial function arising from somatic mutation is an upregulation in the production of mitochondria.
Therefore, high mtDNA-CN in the presence of high heteroplasmy may actually be harmful rather than protective.
Thus, we propose to combine these measures and assess their role in improving the ACC/AHA risk score.
Finally, we will functionally characterize the consequences of mtDNA heteroplasmy by introducing and
manipulating the levels of specific mtDNA genetic variants through mitoTALENs. We will further explore a
plausible biological mechanism testing the impact of heteroplasmy on nuclear DNA methylation and gene
expression, both of which are modified by mtDNA-CN. This proposal leverages 5 well-established cohorts, with
~6000 cases of incident CVD in over 20 years of follow-up, together with a comprehensive set of functional
validation experiments, to elucidate the role of mtDNA heteroplasmy in CVD risk. Both heteroplasmy and mtDNA-
CN are readily measured in whole blood, a highly relevant tissue that plays a primary role in th...

## Key facts

- **NIH application ID:** 9989168
- **Project number:** 5R01HL144569-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Dan E Arking
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $770,215
- **Award type:** 5
- **Project period:** 2019-08-05 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989168

## Citation

> US National Institutes of Health, RePORTER application 9989168, Mitochondrial DNA heteroplasmy and risk for atherosclerotic cardiovascular disease (ASCVD) (5R01HL144569-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989168. Licensed CC0.

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