Age acquired skewed X Chromosome Inactivation is associated with adverse health outcomes in humans

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 XX,46 females to balance the gene expression with XY,46 males. Age acquired XCI-skew describes the preferential inactivation of one X chromosome across a tissue, which is particularly prevalent in blood tissues of ageing females and yet its clinical consequences are unknown. Methods We assayed XCI in 1,575 females from the TwinsUK population cohort and employed prospective, cross-sectional, and intra-twin designs to characterise the relationship of XCI-skew with molecular, cellular, and organismal measures of ageing, and 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.