Abstract
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 seven common MSY haplogroups (haplogroup I1) was associated with CAD – carriers of haplogroup I1 had approximately 11% increase in risk of CAD when compared to all other haplogroups combined (OR=1.11, 95%CI=1.04-1.18, P=6.8x10-466 ). 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 to 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 remodelling. Ubiquitously transcribed tetratricopeptide repeat containing, Y-linked (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 inexpression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune co-stimulatory signal.
Conclusion:
Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through pro-atherosclerotic reprogramming of the transcriptome, partly through UTY.
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 seven common MSY haplogroups (haplogroup I1) was associated with CAD – carriers of haplogroup I1 had approximately 11% increase in risk of CAD when compared to all other haplogroups combined (OR=1.11, 95%CI=1.04-1.18, P=6.8x10-466 ). 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 to 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 remodelling. Ubiquitously transcribed tetratricopeptide repeat containing, Y-linked (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 inexpression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune co-stimulatory signal.
Conclusion:
Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through pro-atherosclerotic reprogramming of the transcriptome, partly through UTY.
| Original language | English |
|---|---|
| Pages (from-to) | 2386–2401 |
| Journal | Arteriosclerosis, Thrombosis and Vascular Biology |
| Volume | 39 |
| DOIs | |
| Publication status | Published - 5 Sept 2019 |
