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

Abstract

BackgroundAgeing 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.FundingKSS acknowledges funding from the Medical Research Council (MR/M004422/1 and MR/R023131/1). JTB acknowledges funding from the ESRC (ES/N000404/1). MM acknowledges funding from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.

Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

“…Overall, ever-smokers had no increased risk of mLOX (P=0.56); however, an increased risk was observed among ever-smokers for acquiring expanded mLOX with cell fraction ≥5% (OR=1.3 [1.2-1.5], P=6.9×10 -5 ) (Supplementary Table S3 and Figure S4-5). The relationship between smoking and skewed X-inactivation has not been established, as smoking was suggested as a modulator for skewed XCI in the whole-blood tissue for women older than age 55 7 but not associated in the TwinsUK cohort 35 . No associations were observed between BMI and mLOX (Supplementary…”

“…) (Supplementary Table S3 and Figure S4-5). The relationship between smoking and skewed X-inactivation has not been established, as smoking was suggested as a modulator for skewed XCI in the whole-blood tissue for women older than age 55 7 but not associated in the TwinsUK cohort 35 . No associations were observed between BMI and mLOX (Supplementary Table S4).…”