Roberts, AL;
Morea, A;
Amar, A;
Zito, A;
Moustafa, JSES;
Tomlinson, M;
Bowyer, RCE;
... Small, KS; + view all
(2022)
Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans.
eLife
, 11
, Article e78263. 10.7554/eLife.78263.
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Abstract
Background: Ageing is a heterogenous process characterised by cellular and molecular hallmarks, including changes to haematopoietic stem cells and is a primary risk factor for chronic diseases. X chromosome inactivation (XCI) randomly transcriptionally silences either the maternal or paternal X in each cell of 46, XX females to balance the gene expression with 46, XY males. Age acquired XCI-skew describes the preferential selection of cells across a tissue resulting in an imbalance of XCI, which is particularly prevalent in blood tissues of ageing females, and yet its clinical consequences are unknown. / Methods: We assayed XCI in 1575 females from the TwinsUK population cohort using DNA extracted from whole blood. We employed prospective, cross-sectional, and intra-twin study designs to characterise the relationship of XCI-skew with molecular and cellular measures of ageing, cardiovascular disease risk, and cancer diagnosis. / Results: We demonstrate that XCI-skew is independent of traditional markers of biological ageing and is associated with a haematopoietic bias towards the myeloid lineage. Using an atherosclerotic cardiovascular disease risk score, which captures traditional risk factors, XCI-skew is associated with an increased cardiovascular disease risk both cross-sectionally and within XCI-skew discordant twin pairs. In a prospective 10 year follow-up study, XCI-skew is predictive of future cancer incidence. / Conclusions: Our study demonstrates that age acquired XCI-skew captures changes to the haema-topoietic stem cell population and has clinical potential as a unique biomarker of chronic disease risk.
| Type: | Article |
|---|---|
| Title: | Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.7554/eLife.78263 |
| Publisher version: | http://doi.org/10.7554/eLife.78263 |
| Language: | English |
| Additional information: | Copyright © Roberts et al. This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry > Epidemiology and Applied Clinical Research |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10170130 |
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