Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784686835183648768 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9007378 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT calabreseclaudia heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT pyleangela heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT griffinhelen heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT coxheadjonathan heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT hussainrafiqul heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT braundpeters heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT lilinxin heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT burgessannette heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT munroepatriciab heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT littlelouis heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT warrenhelenr heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT cabreraclaudia heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT hallalistair heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT caulfieldmarkj heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT rothwellpeterm heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT samaninileshj heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT hudsongavin heteroplasmicmitochondrialdnavariantsincardiovasculardiseases AT chinnerypatrickf heteroplasmicmitochondrialdnavariantsincardiovasculardiseases |