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Heteroplasmic mitochondrial DNA variants in cardiovascular diseases

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...

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Autores principales: Calabrese, Claudia, Pyle, Angela, Griffin, Helen, Coxhead, Jonathan, Hussain, Rafiqul, Braund, Peter S, Li, Linxin, Burgess, Annette, Munroe, Patricia B, Little, Louis, Warren, Helen R, Cabrera, Claudia, Hall, Alistair, Caulfield, Mark J, Rothwell, Peter M, Samani, Nilesh J, Hudson, Gavin, Chinnery, Patrick F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007378/
https://www.ncbi.nlm.nih.gov/pubmed/35363781
http://dx.doi.org/10.1371/journal.pgen.1010068
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author Calabrese, Claudia
Pyle, Angela
Griffin, Helen
Coxhead, Jonathan
Hussain, Rafiqul
Braund, Peter S
Li, Linxin
Burgess, Annette
Munroe, Patricia B
Little, Louis
Warren, Helen R
Cabrera, Claudia
Hall, Alistair
Caulfield, Mark J
Rothwell, Peter M
Samani, Nilesh J
Hudson, Gavin
Chinnery, Patrick F.
author_facet Calabrese, Claudia
Pyle, Angela
Griffin, Helen
Coxhead, Jonathan
Hussain, Rafiqul
Braund, Peter S
Li, Linxin
Burgess, Annette
Munroe, Patricia B
Little, Louis
Warren, Helen R
Cabrera, Claudia
Hall, Alistair
Caulfield, Mark J
Rothwell, Peter M
Samani, Nilesh J
Hudson, Gavin
Chinnery, Patrick F.
author_sort Calabrese, Claudia
collection PubMed
description 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 play a role in the pathophysiology of hypertension.
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spelling pubmed-90073782022-04-14 Heteroplasmic mitochondrial DNA variants in cardiovascular diseases Calabrese, Claudia Pyle, Angela Griffin, Helen Coxhead, Jonathan Hussain, Rafiqul Braund, Peter S Li, Linxin Burgess, Annette Munroe, Patricia B Little, Louis Warren, Helen R Cabrera, Claudia Hall, Alistair Caulfield, Mark J Rothwell, Peter M Samani, Nilesh J Hudson, Gavin Chinnery, Patrick F. PLoS Genet Research Article 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 play a role in the pathophysiology of hypertension. Public Library of Science 2022-04-01 /pmc/articles/PMC9007378/ /pubmed/35363781 http://dx.doi.org/10.1371/journal.pgen.1010068 Text en © 2022 Calabrese et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Calabrese, Claudia
Pyle, Angela
Griffin, Helen
Coxhead, Jonathan
Hussain, Rafiqul
Braund, Peter S
Li, Linxin
Burgess, Annette
Munroe, Patricia B
Little, Louis
Warren, Helen R
Cabrera, Claudia
Hall, Alistair
Caulfield, Mark J
Rothwell, Peter M
Samani, Nilesh J
Hudson, Gavin
Chinnery, Patrick F.
Heteroplasmic mitochondrial DNA variants in cardiovascular diseases
title Heteroplasmic mitochondrial DNA variants in cardiovascular diseases
title_full Heteroplasmic mitochondrial DNA variants in cardiovascular diseases
title_fullStr Heteroplasmic mitochondrial DNA variants in cardiovascular diseases
title_full_unstemmed Heteroplasmic mitochondrial DNA variants in cardiovascular diseases
title_short Heteroplasmic mitochondrial DNA variants in cardiovascular diseases
title_sort heteroplasmic mitochondrial dna variants in cardiovascular diseases
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007378/
https://www.ncbi.nlm.nih.gov/pubmed/35363781
http://dx.doi.org/10.1371/journal.pgen.1010068
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