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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.
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
URL: https://doi.org/10.1371/journal.pgen.1010068
DOI: 10.1371/journal.pgen.1010068
PubMed id: 35363781
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