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Human Y Chromosome Exerts Pleiotropic Effects on Susceptibility to Atherosclerosis

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journal contribution
posted on 21.05.2020, 13:42 by James M Eales, Akhlaq A Maan, Xiaoguang Xu, Tom Michoel, Pille Hallast, Chiara Batini, Daniel Zadik, Priscilla R Prestes, Elsa Molina, Matthew Denniff, Juliane Schroeder, Johan LM Bjorkegren, John Thompson, Pasquale Maffia, Tomasz J Guzik, Bernard Keavney, Mark A Jobling, Nilesh J Samani, Fadi J Charchar, Maciej Tomaszewski
OBJECTIVE: The male-specific region of the Y chromosome (MSY) remains one of the most unexplored regions of the genome. We sought to examine how the genetic variants of the MSY influence male susceptibility to coronary artery disease (CAD) and atherosclerosis. Approach and Results: Analysis of 129 133 men from UK Biobank revealed that only one of 7 common MSY haplogroups (haplogroup I1) was associated with CAD-carriers of haplogroup I1 had ≈11% increase in risk of CAD when compared with all other haplogroups combined (odds ratio, 1.11; 95% CI, 1.04-1.18; P=6.8×10-4). Targeted MSY sequencing uncovered 235 variants exclusive to this haplogroup. The haplogroup I1-specific variants showed 2.45- and 1.56-fold respective enrichment for promoter and enhancer chromatin states, in cells/tissues relevant to atherosclerosis, when compared with other MSY variants. Gene set enrichment analysis in CAD-relevant tissues showed that haplogroup I1 was associated with changes in pathways responsible for early and late stages of atherosclerosis development including defence against pathogens, immunity, oxidative phosphorylation, mitochondrial respiration, lipids, coagulation, and extracellular matrix remodeling. UTY was the only Y chromosome gene whose blood expression was associated with haplogroup I1. Experimental reduction of UTY expression in macrophages led to changes in expression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune costimulatory signal. CONCLUSIONS: Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through proatherosclerotic reprogramming of the transcriptome, partly through UTY.

Funding

The work described herein was supported by British Heart Foundation grants PG/16/49/32176 (to M. Tomaszewski), PG/12/9/29376 (to M. Tomaszewski), and RE/13/5/30177 (to T.J. Guzik and P. Maffia); National Institutes of Health R01 grant HL125863 (to J.L.M. Bjorkegren); Estonian Research Council grant PUT1036 (to P. Hallast); and European Research Council grant 726318 (to T.J. Guzik). C. Batini, P. Hallast, D. Zadik, and M.A. Jobling were supported by a Wellcome Trust Senior Fellowship grant to M.A. Jobling (087576). F.J. Charchar is supported by a National Health and Medical Research Council of Australia grant (APP 1123472).

History

Citation

Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39:2386–2401

Author affiliation

College of Life Sciences

Version

VoR (Version of Record)

Published in

Arteriosclerosis, Thrombosis, and Vascular Biology

Volume

39

Issue

11

Pagination

2386 - 2401

Publisher

American Heart Association

issn

1079-5642

eissn

1524-4636

Acceptance date

14/08/2019

Copyright date

2019

Language

English