Loss of Y Chromosome in Blood Is Associated With Major Cardiovascular Events During Follow-Up in Men After Carotid Endarterectomy

Abstract

L oss of the Y chromosome (LOY) in blood cells was already described in the 1960s and affects ≈15% of the male population of older age.1 Only recently, LOY was associated with a higher risk of (nonhematological) cancer and overall mortality. 2,3 This relationship was speculated to be because of smoking and a disrupted tumor immunosurveillance. See Editorial by Dumanski et al See Clinical PerspectiveThe Y chromosome exhibited an immuneregulatory function by acting as a global transexpression quantitative trait locus in mice. 8 The Y chromosome directly mediated changes in the transcriptome of CD4 + T cells and macrophages, contributing to altered gene expression and alternative splicing. A role in global immune response was also found in the monocyte and macrophage transcriptome results of males with haplotype I that exhibited a 50% greater risk of myocardial infarction. 9 Comparison of gene expression data between haplotype I and other haplotypes revealed pathways that are related to inflammation and immunity, revealing downregulation of adaptive immunity and upregulation of inflammatory response in haplotype I carriers.Background-Recent studies found an immune regulatory role for Y chromosome and a relationship between loss of Y chromosome (LOY) in blood cells and a higher risk of cancer and mortality. Given involvement of immune cells in atherosclerosis, we hypothesized that LOY is associated with the severity of atherosclerotic plaque characteristics and outcome in men undergoing carotid endarterectomy. Methods and Results-LOY was quantified in blood and plaque from raw intensity genotyping data in men within the Athero-Express biobank study. Plaques were dissected, and the culprit lesions used for histology and the measurement of inflammatory proteins. We tested LOY for association with (inflammatory) atherosclerotic plaque phenotypes and cytokines and assessed the association of LOY with secondary events during 3-year follow-up. Of 366 patients with carotid endarterectomy, 61 exhibited some degree of LOY in blood. LOY was also present in atherosclerotic plaque lesions (n=8/242, 3%). LOY in blood was negatively associated with age (β=−0.03/10 y; r 2 =0.07; P=1.6×10 -7 ) but not with cardiovascular disease severity at baseline. LOY in blood was associated with a larger atheroma size (odds ratio, 2.15; 95% confidence interval, 1.06-4.76; P=0.04); however, this association was not significant after correction for multiple testing. LOY was independently associated with secondary major cardiovascular events (hazard ratio=2.28; 95% confidence interval, 1.11-4.67; P=0.02) in blood when corrected for confounders. Conclusions-In this hypothesis-generating study, LOY in blood is independently associated with secondary major cardiovascular events in a severely atherosclerotic population. Our data could indicate that LOY affects secondary outcome via other mechanisms than inflammation in the atherosclerotic plaque. (Circ

Immune cells lacking Y chromosome have widespread dysregulation of autosomal genes

“…LOY has already been shown as the most common post-zygotic mutation considering data from blood DNA alone [23,28]. Furthermore, LOY also occurs in other tissues [17,23], but these two reports only scratched the surface of the topic and studies of other tissues/cell types should follow in order to establish the frequency of LOY in adult and aging men across the soma. Moreover, as we show here, LOY occurs frequently in blood as oligo-clonal expansions and this could be best explained by independent mutations occurring in progenitors for different lineages of hematopoietic cells, resulting in more than one expanding LOY-clone circulating in blood.…”

“…Hence, LOY as a male specific risk factor, showing reproducible associations with various common disorders, could help explaining this difference.LOY in blood is the most frequent post-zygotic mutation, detectable in 20% of the UK Biobank male population [21], reaching 40% in 80 years old males [22], and 57% in 93 years old males [23]. Furthermore, LOY is not restricted to the hematopoietic system, since it has also been described in other non-cancerous tissues, although with much lower frequencies [17,23]. Our understanding of why LOY occurs is also limited.…”

Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

“…Previous studies have demonstrated robust associations with age, sex (clonal mosaicism is more frequent in males), smoking and inherited germline genetic predisposition 2,4,[10][11][12][13][14][15] . Recent epidemiological studies have challenged the view that LOY in the hematopoietic system is a phenotypically neutral event, with epidemiological associations observed with various forms of cancer 13,[16][17][18][19][20] , autoimmune conditions 21,22 , age-related macular degeneration 23 , cardiovascular disease 24 , Alzheimer's disease 25 , type 2 diabetes 15 , obesity 15 , and all-cause mortality 15,16 . The extent to which such observations represent a causal association, reverse causality or confounding is unclear.…”

Intra-individual changes in the frequency of mosaic loss of chromosome Y over time estimated with a new method

“…For over 50 years it has been known that LOY is a frequent event in cells of the hematopoietic system(2) and LOY in leukocytes was long viewed as a neutral event related to normal aging without phenotypical consequences(3). However, recent studies suggest the opposite as LOY has been found to be associated with increased risk for all-cause mortality(4, 5) as well as a growing list of diverse diseases and outcomes such as various forms of cancer(4, 6-9), autoimmune conditions(10, 11), Alzheimer’s disease(12), major cardiovascular events(13, 14), suicide completion(15), schizophrenia(16), diabetes(14) as well as age-related macular degeneration (AMD)(17).…”