Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans

Roberts, Amy L.; Morea, Alessandro; Amar, Ariella; Zito, Antonino; El-Sayed Moustafa, Julia S.; Tomlinson, Max; Bowyer, Ruth C. E.; Zhang, Xinyan; Christiansen, Colette; Costeira, Ricardo; Steves, Claire J.; Mangino, Massimo; Bell, Jordana T.; Wong, Chloe C. Y.; Vyse, Timothy J. and Small, Kerrin S. (2022). Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans. eLife, 11, article no. e78263.

DOI: https://doi.org/10.7554/eLife.78263

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 haematopoietic stem cell population and has clinical potential as a unique biomarker of chronic disease risk.