Heteroplasmic mitochondrial DNA variants in cardiovascular diseases.

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cam.issuedOnline2022-04
dc.contributor.authorCalabrese, Claudia
dc.contributor.authorPyle, Angela
dc.contributor.authorGriffin, Helen
dc.contributor.authorCoxhead, Jonathan
dc.contributor.authorHussain, Rafiqul
dc.contributor.authorBraund, Peter S
dc.contributor.authorLi, Linxin
dc.contributor.authorBurgess, Annette
dc.contributor.authorMunroe, Patricia B
dc.contributor.authorLittle, Louis
dc.contributor.authorWarren, Helen R
dc.contributor.authorCabrera, Claudia
dc.contributor.authorHall, Alistair
dc.contributor.authorCaulfield, Mark J
dc.contributor.authorRothwell, Peter M
dc.contributor.authorSamani, Nilesh J
dc.contributor.authorHudson, Gavin
dc.contributor.authorChinnery, Patrick F
dc.contributor.orcidCalabrese, Claudia [0000-0002-8941-2620]
dc.contributor.orcidPyle, Angela [0000-0003-3860-4531]
dc.contributor.orcidCoxhead, Jonathan [0000-0002-6128-9560]
dc.contributor.orcidHussain, Rafiqul [0000-0002-1436-8944]
dc.contributor.orcidBraund, Peter S [0000-0001-8540-5709]
dc.contributor.orcidLi, Linxin [0000-0002-3636-8355]
dc.contributor.orcidBurgess, Annette [0000-0003-3442-8083]
dc.contributor.orcidMunroe, Patricia B [0000-0002-4176-2947]
dc.contributor.orcidLittle, Louis [0000-0002-4250-4181]
dc.contributor.orcidWarren, Helen R [0000-0003-0511-1386]
dc.contributor.orcidCabrera, Claudia [0000-0002-2205-5315]
dc.contributor.orcidRothwell, Peter M [0000-0001-9739-9211]
dc.contributor.orcidChinnery, Patrick F [0000-0002-7065-6617]
dc.date.accessioned2022-05-03T02:30:12Z
dc.date.available2022-05-03T02:30:12Z
dc.date.issued2022-04
dc.date.updated2022-05-03T02:30:12Z
dc.descriptionFunder: NIHR Oxford Biomedical Research Centre
dc.descriptionFunder: National Institute for Health Research (NIHR)
dc.descriptionFunder: Wolfson Foundation
dc.description.abstractMitochondria 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 play a role in the pathophysiology of hypertension.
dc.identifier.doi10.17863/CAM.84131
dc.identifier.eissn1553-7404
dc.identifier.issn1553-7390
dc.identifier.other35363781
dc.identifier.otherPMC9007378
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336708
dc.languageeng
dc.publisherPublic Library of Science (PLoS)
dc.publisher.urlhttp://dx.doi.org/10.1371/journal.pgen.1010068
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101239074
dc.sourceessn: 1553-7404
dc.subjectCardiovascular Diseases
dc.subjectDNA, Mitochondrial
dc.subjectHumans
dc.subjectHypertension
dc.subjectMitochondria
dc.subjectMitochondrial Diseases
dc.subjectMutation
dc.titleHeteroplasmic mitochondrial DNA variants in cardiovascular diseases.
dc.typeArticle
dcterms.dateAccepted2022-02-01
prism.issueIdentifier4
prism.publicationNamePLoS Genet
prism.volume18
pubs.funder-project-idWellcome Trust (212219/Z/18/Z)
pubs.funder-project-idMRC (MR/S035699/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/N01426X/1)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1371/journal.pgen.1010068
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