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Heteroplasmic mitochondrial DNA variants in cardiovascular diseases

Lookup NU author(s): Dr Angela Pyle, Dr Helen GriffinORCiD, Dr Jonathan Coxhead, Raf Hussain, Professor Gavin Hudson, Professor Patrick Chinnery



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 Calabrese et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Mitochondria are implicated in the pathogenesis of cardiovascular diseases (CVDs) but the reasons for this are not well understood. Maternally-inherited population variants of mitochondrial DNA (mtDNA) which affect all mtDNA molecules (homoplasmic) are associated with cardiometabolic traits and the risk of developing cardiovascular disease. However, it is not known whether mtDNA mutations only affecting a proportion of mtDNA molecules (heteroplasmic) also play a role. To address this question, we performed a high-depth (∼1000- fold) mtDNA sequencing of blood DNA in 1,399 individuals with hypertension (HTN), 1,946 with ischemic heart disease (IHD), 2,146 with ischemic stroke (IS), and 723 healthy controls. We show that the per individual burden of heteroplasmic single nucleotide variants (mtSNVs) increases with age. The age-effect was stronger for low-level heteroplasmies (heteroplasmic fraction, HF, 5-10%), likely reflecting acquired somatic events based on trinucleotide mutational signatures. After correcting for age and other confounders, intermediate heteroplasmies (HF 10-95%) were more common in hypertension, particularly involving non-synonymous variants altering the amino acid sequence of essential respiratory chain proteins. These findings raise the possibility that heteroplasmic mtSNVs in the pathophysiology of hypertension.

Publication metadata

Author(s): Calabrese C, Pyle A, Griffin H, Coxhead J, Hussain R, Braund PS, Li L, Burgess A, Munroe PB, Little L, Warren HR, Cabrera C, Hall A, Caulfield MJ, Rothwell PM, Samani NJ, Hudson G, Chinnery PF

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2022

Volume: 18

Issue: 4

Online publication date: 01/04/2022

Acceptance date: 01/02/2022

Date deposited: 05/05/2022

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science


DOI: 10.1371/journal.pgen.1010068

PubMed id: 35363781


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