A novel Y-specific long non-coding RNA associated with cellular lipid accumulation in HepG2 cells and Atherosclerosis-related genes
- Molina, Elsa, Chew, Guat, Myers, Stephen, Clarence, Elyse, Eales, James, Tomaszewski, Maciej, Charchar, Fadi
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
An investigation into the relationships between novel Y chromosome-linked long non-coding RNAs and coronary artery disease
- Authors: Molina, Elsa
- Date: 2016
- Type: Text , Thesis , PhD
- Full Text:
- Description: Coronary artery disease (CAD) is the most common type of cardiovascular disease and is one of the leading causes of morbidity and mortality globally. However, the pathogenesis of atherosclerosis which leads to CAD and results in heart attacks, heart failure and death is not well understood. In this context, studies have demonstrated a positive correlation between increased hepatic free fatty acids (FFAs) in atherosclerosis and CAD. Although CAD has welldefined environmental risk factors, genome-wide association studies (GWAS) have demonstrated a genetic influence on CAD. Previous studies have shown that genetic variation within the human Y chromosome is associated with an increased risk of developing CAD independent of traditional cardiovascular risk factors; possibly through a modulating effect of an adaptive immunity and inflammatory response by macrophages in men. However, no Y chromosome-linked gene has been investigated in this disease so far. Long non-coding RNAs (lncRNAs) have recently gained focused attention as a new class of regulatory RNA molecules involved in cardiovascular function and associated disease, particularly long intergenic noncoding RNAs (lincRNAs), the largest class within the lncRNA group so far. To date, Y chromosome-linked lincRNAs are poorly characterised and the potential link between these non-coding RNA molecules and CAD in men has not been investigated. In this context, I hypothesised that Y chromosome-linked lncRNAs may regulate pathways involved in lipid metabolism and trigger an over accumulation of FFAs in coronary arteries contributing to atherosclerosis, the underlying cause of CAD. The main objective of this thesis was to therefore further investigate the relationship between the Y chromosome, lncRNAs and CAD in light of the deficiencies within the literature to better understand the causative molecular mechanisms of CAD pathophysiology in men. In my first study (Chapter 2), I identified for the first time through gene expression analysis (real-time PCR) the expression of the following (unannotated in PubMed) Y chromosomelinked lincRNA transcripts: lnc-KDM5D-4:1, lnc-ZFY-1:1, lnc-ZFY-1:3, lnc-ZFY-2:1, lnc- RBMY1B-1:1, lnc-RBMY1B-1:4, lnc-RBMY1J-1:1, lnc-RBMY1J-1:2, and lnc-RBMY1J- 1:3, across 21 different normal, human tissues such as adipose, bladder, brain, cervix, colon, esophagus, heart, kidney, liver, lung, ovary, placenta, prostate, skeletal muscle, small intestine, spleen, testes, thymus, thyroid, trachea, and white blood cells (WBCs) (leukocytes). I found that Y-linked lincRNAs were expressed at low levels (with the lowest CT number equal at 24.5) with a high tissue-specificity for some. Also, the Y-linked RNA gene lnc-KDM5D-4 was widely expressed across male tissues while the Y-linked RNA gene lnc-RBMY1J-1 was specific to the testes. Furthermore, this study presents the first evidence through gene expression analysis that the Y chromosome-linked lincRNA transcripts, lnc-KDM5D-4:1, lnc- ZFY-1:1, lnc-ZFY-1:3, lnc-ZFY-2:1, lnc-RBMY1B-1:1, lnc-RBMY1B-1:4, and lnc- RBMY1J-1:3 are expressed in male leukocytes. Hence, these lincRNAs could be potential non-protein coding gene candidates for CAD research. Knowing that the Y chromosome contributes to lipid levels in humans, to further explore the potential function of these Y-linked lincRNAs in CAD in men, I then studied their expression in a fatty liver context (steatosis-associated atherosclerosis) (Chapter 3). This was performed using the human hepatocellular liver carcinoma cell line, HepG2; the human model of liver cells in CAD research. This study showed for the first time that the Y-linked lincRNA transcripts lnc-KDM5D-4:1, lnc-ZFY-1:1, lnc-ZFY-2:1, lnc-RBMY1B-1:1, and lncxix RBMY1B-1:4 were expressed in HepG2 cells, hence in hepatocellular carcinoma (HCC). Furthermore, this study demonstrated that lnc-KDM5D-4 is a nuclear-retained lincRNA using RNA fluorescence in situ hybridisation (RNA FISH), and is upregulated in palmitate-induced steatosis within hepatocytes (Fold Change = 2.16; p-value = 0.00216). The human Atherosclerosis RT2 Profiler™ PCR Array determined that the silencing of lnc-KDM5D-4 in HepG2 cells was triggering the upregulation of the inhibitor of apoptosis (IAP) gene baculoviral IAP repeat containing 3 (BIRC3) (Fold Change = 12.45, p-value = 0.000025), a well-described protein-coding gene expressed by vascular smooth muscle cells and macrophage foam cells of the inflamed vascular wall of atherosclerotic arteries. Furthermore, perilipin 2 (PLIN2), a gene known to be implicated in lipid metabolism, was also found upregulated. Therefore, this study provides the first evidence for the involvement of a Ychromosome- linked lincRNA, lnc-KDM5D-4, in steatosis-associated atherosclerosis and its retained-nuclear cellular localisation in human hepatocytes, suggesting a function which takes place in the cell nucleus and may play a role in regulating metabolic processes in the liver that are implicated in atherosclerosis. Having shown that a Y chromosome-linked lincRNA could be involved in the determination of lipid level and hence atherosclerosis in men, and to further explore the role of lnc-KDM5D- 4, the expression of this Y-linked lincRNA was studied in human coronary artery smooth muscle cells, especially in atherosclerotic coronary artery cells (Chapter 4). The expression of other non-coding RNAs were also studied such as the protein kinase, Y-linked, pseudogene (PRKY) - previously considered as a new functional candidate for the development of CAD. By analysing the transcriptome of human atherosclerotic and non-atherosclerotic coronary artery smooth muscle cells, I established evidence for the implication of the human Y chromosome in atherosclerosis and CAD. This study exposed the general underexpression of the transcripts from the Y chromosome in atherosclerotic cells implicating a loss or a repression of this chromosome in relation to CAD. Furthermore, this research determined by RNA sequencing a significant downregulation of seven transcripts from Y chromosome genes, including RPS4Y1, USP9Y, DDX3Y, TXLNGY, NLGN4Y and PRKY. RNA FISH determined the subcellular localisation of PRKY in smooth muscle cells by showing a nuclear and a cytoplasmic expression. Furthermore, qPCR gene expression analysis demonstrated that lnc- KDM5D-4 is significantly downregulated in atherosclerotic cells in comparison to the nonatherosclerotic cells. Together, these results showed that lnc-KDM5D-4 is a potential regulator of PLIN2 and BIRC3 genes. Therefore, the downregulation of lnc-KDM5D-4 in atherosclerotic coronary artery smooth muscle cells suggests that this downregulation could be linked to the inflammation of the vascular smooth muscle cells in pathophysiology of CAD via the inhibition of apoptosis of the vascular smooth muscle cells triggered by the upregulation of BIRC3 in these cells. Overall, this study is the first to emphasise a potential involvement of a Y-specific lincRNA, called lnc-KDM5D-4, as a potential contributor to physiology in males. Lnc-KDM5D-4 knockdown resulted in an upregulation of anti-apoptosis and lipid metabolism-related genes. Collectively, our data suggest that the male–specific lnc-KDM5D-4 may regulate key processes in cellular inflammation that trigger atherosclerosis and CAD in men. Accordingly, this data suggests that lnc-KDM5D-4 may provide a novel molecular biomarker for atherosclerotic arteries, and could potentially lead to revolutionary treatment modalities on Y-linked lincRNA as therapeutic agents to manipulate CAD-causing genes in men.
- Description: Doctor of Philosophy
- Authors: Molina, Elsa
- Date: 2016
- Type: Text , Thesis , PhD
- Full Text:
- Description: Coronary artery disease (CAD) is the most common type of cardiovascular disease and is one of the leading causes of morbidity and mortality globally. However, the pathogenesis of atherosclerosis which leads to CAD and results in heart attacks, heart failure and death is not well understood. In this context, studies have demonstrated a positive correlation between increased hepatic free fatty acids (FFAs) in atherosclerosis and CAD. Although CAD has welldefined environmental risk factors, genome-wide association studies (GWAS) have demonstrated a genetic influence on CAD. Previous studies have shown that genetic variation within the human Y chromosome is associated with an increased risk of developing CAD independent of traditional cardiovascular risk factors; possibly through a modulating effect of an adaptive immunity and inflammatory response by macrophages in men. However, no Y chromosome-linked gene has been investigated in this disease so far. Long non-coding RNAs (lncRNAs) have recently gained focused attention as a new class of regulatory RNA molecules involved in cardiovascular function and associated disease, particularly long intergenic noncoding RNAs (lincRNAs), the largest class within the lncRNA group so far. To date, Y chromosome-linked lincRNAs are poorly characterised and the potential link between these non-coding RNA molecules and CAD in men has not been investigated. In this context, I hypothesised that Y chromosome-linked lncRNAs may regulate pathways involved in lipid metabolism and trigger an over accumulation of FFAs in coronary arteries contributing to atherosclerosis, the underlying cause of CAD. The main objective of this thesis was to therefore further investigate the relationship between the Y chromosome, lncRNAs and CAD in light of the deficiencies within the literature to better understand the causative molecular mechanisms of CAD pathophysiology in men. In my first study (Chapter 2), I identified for the first time through gene expression analysis (real-time PCR) the expression of the following (unannotated in PubMed) Y chromosomelinked lincRNA transcripts: lnc-KDM5D-4:1, lnc-ZFY-1:1, lnc-ZFY-1:3, lnc-ZFY-2:1, lnc- RBMY1B-1:1, lnc-RBMY1B-1:4, lnc-RBMY1J-1:1, lnc-RBMY1J-1:2, and lnc-RBMY1J- 1:3, across 21 different normal, human tissues such as adipose, bladder, brain, cervix, colon, esophagus, heart, kidney, liver, lung, ovary, placenta, prostate, skeletal muscle, small intestine, spleen, testes, thymus, thyroid, trachea, and white blood cells (WBCs) (leukocytes). I found that Y-linked lincRNAs were expressed at low levels (with the lowest CT number equal at 24.5) with a high tissue-specificity for some. Also, the Y-linked RNA gene lnc-KDM5D-4 was widely expressed across male tissues while the Y-linked RNA gene lnc-RBMY1J-1 was specific to the testes. Furthermore, this study presents the first evidence through gene expression analysis that the Y chromosome-linked lincRNA transcripts, lnc-KDM5D-4:1, lnc- ZFY-1:1, lnc-ZFY-1:3, lnc-ZFY-2:1, lnc-RBMY1B-1:1, lnc-RBMY1B-1:4, and lnc- RBMY1J-1:3 are expressed in male leukocytes. Hence, these lincRNAs could be potential non-protein coding gene candidates for CAD research. Knowing that the Y chromosome contributes to lipid levels in humans, to further explore the potential function of these Y-linked lincRNAs in CAD in men, I then studied their expression in a fatty liver context (steatosis-associated atherosclerosis) (Chapter 3). This was performed using the human hepatocellular liver carcinoma cell line, HepG2; the human model of liver cells in CAD research. This study showed for the first time that the Y-linked lincRNA transcripts lnc-KDM5D-4:1, lnc-ZFY-1:1, lnc-ZFY-2:1, lnc-RBMY1B-1:1, and lncxix RBMY1B-1:4 were expressed in HepG2 cells, hence in hepatocellular carcinoma (HCC). Furthermore, this study demonstrated that lnc-KDM5D-4 is a nuclear-retained lincRNA using RNA fluorescence in situ hybridisation (RNA FISH), and is upregulated in palmitate-induced steatosis within hepatocytes (Fold Change = 2.16; p-value = 0.00216). The human Atherosclerosis RT2 Profiler™ PCR Array determined that the silencing of lnc-KDM5D-4 in HepG2 cells was triggering the upregulation of the inhibitor of apoptosis (IAP) gene baculoviral IAP repeat containing 3 (BIRC3) (Fold Change = 12.45, p-value = 0.000025), a well-described protein-coding gene expressed by vascular smooth muscle cells and macrophage foam cells of the inflamed vascular wall of atherosclerotic arteries. Furthermore, perilipin 2 (PLIN2), a gene known to be implicated in lipid metabolism, was also found upregulated. Therefore, this study provides the first evidence for the involvement of a Ychromosome- linked lincRNA, lnc-KDM5D-4, in steatosis-associated atherosclerosis and its retained-nuclear cellular localisation in human hepatocytes, suggesting a function which takes place in the cell nucleus and may play a role in regulating metabolic processes in the liver that are implicated in atherosclerosis. Having shown that a Y chromosome-linked lincRNA could be involved in the determination of lipid level and hence atherosclerosis in men, and to further explore the role of lnc-KDM5D- 4, the expression of this Y-linked lincRNA was studied in human coronary artery smooth muscle cells, especially in atherosclerotic coronary artery cells (Chapter 4). The expression of other non-coding RNAs were also studied such as the protein kinase, Y-linked, pseudogene (PRKY) - previously considered as a new functional candidate for the development of CAD. By analysing the transcriptome of human atherosclerotic and non-atherosclerotic coronary artery smooth muscle cells, I established evidence for the implication of the human Y chromosome in atherosclerosis and CAD. This study exposed the general underexpression of the transcripts from the Y chromosome in atherosclerotic cells implicating a loss or a repression of this chromosome in relation to CAD. Furthermore, this research determined by RNA sequencing a significant downregulation of seven transcripts from Y chromosome genes, including RPS4Y1, USP9Y, DDX3Y, TXLNGY, NLGN4Y and PRKY. RNA FISH determined the subcellular localisation of PRKY in smooth muscle cells by showing a nuclear and a cytoplasmic expression. Furthermore, qPCR gene expression analysis demonstrated that lnc- KDM5D-4 is significantly downregulated in atherosclerotic cells in comparison to the nonatherosclerotic cells. Together, these results showed that lnc-KDM5D-4 is a potential regulator of PLIN2 and BIRC3 genes. Therefore, the downregulation of lnc-KDM5D-4 in atherosclerotic coronary artery smooth muscle cells suggests that this downregulation could be linked to the inflammation of the vascular smooth muscle cells in pathophysiology of CAD via the inhibition of apoptosis of the vascular smooth muscle cells triggered by the upregulation of BIRC3 in these cells. Overall, this study is the first to emphasise a potential involvement of a Y-specific lincRNA, called lnc-KDM5D-4, as a potential contributor to physiology in males. Lnc-KDM5D-4 knockdown resulted in an upregulation of anti-apoptosis and lipid metabolism-related genes. Collectively, our data suggest that the male–specific lnc-KDM5D-4 may regulate key processes in cellular inflammation that trigger atherosclerosis and CAD in men. Accordingly, this data suggests that lnc-KDM5D-4 may provide a novel molecular biomarker for atherosclerotic arteries, and could potentially lead to revolutionary treatment modalities on Y-linked lincRNA as therapeutic agents to manipulate CAD-causing genes in men.
- Description: Doctor of Philosophy
Coronary artery disease : Why we should consider the Y chromosome
- Molina, Elsa, Clarence, Elyse, Ahmady, Farah, Chew, Guatsiew, Charchar, Fadi
- Authors: Molina, Elsa , Clarence, Elyse , Ahmady, Farah , Chew, Guatsiew , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Heart Lung and Circulation Vol. 25, no. 8 (Aug 2016), p. 791-801
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality globally. In the last few years our understanding of the genetic and molecular mechanisms that promote CAD in individuals has increased with the advent of the genome era. This complex inflammatory disease has well-defined environmental risk factors. However, in the last 10 years, studies including genome-wide association studies (GWAS) have clearly demonstrated a genetic influence on CAD. Recently, studies on the human Y chromosome have also demonstrated that genetic variation within the male-specific region of the Y chromosome (MSY) could play a part in determining cardiovascular risk in men, confirming the notion that the increased risk for CAD in men cannot be fully explained through common CAD risk factors. Here, we review the literature about the pathophysiology of CAD, its potential causes and environmental risk factors known so far. Furthermore, we review the genetics of CAD, especially the latest discoveries regarding the implication of the Y chromosome, the most underexplored portion of the human genome to date, highlighting methods and difficulties arising in this research field, and discussing the importance of considering the Y chromosome in CAD research.
- Authors: Molina, Elsa , Clarence, Elyse , Ahmady, Farah , Chew, Guatsiew , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Heart Lung and Circulation Vol. 25, no. 8 (Aug 2016), p. 791-801
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality globally. In the last few years our understanding of the genetic and molecular mechanisms that promote CAD in individuals has increased with the advent of the genome era. This complex inflammatory disease has well-defined environmental risk factors. However, in the last 10 years, studies including genome-wide association studies (GWAS) have clearly demonstrated a genetic influence on CAD. Recently, studies on the human Y chromosome have also demonstrated that genetic variation within the male-specific region of the Y chromosome (MSY) could play a part in determining cardiovascular risk in men, confirming the notion that the increased risk for CAD in men cannot be fully explained through common CAD risk factors. Here, we review the literature about the pathophysiology of CAD, its potential causes and environmental risk factors known so far. Furthermore, we review the genetics of CAD, especially the latest discoveries regarding the implication of the Y chromosome, the most underexplored portion of the human genome to date, highlighting methods and difficulties arising in this research field, and discussing the importance of considering the Y chromosome in CAD research.
Human Y Chromosome Exerts Pleiotropic Effects on Susceptibility to Atherosclerosis
- Eales, James, Maan, Akhlaq, Xu, Xiaoguang, Michoel, Tom, Hallast, Pille, Batini, C, Zadik, Daniel, Prestes, Priscilla, Molina, Elsa, Denniff, Matthew, Schroeder, Juliane, Bjorkegren, Johan, Thompson, John, Maffia, Pasquale, Guzik, Tomasz, Keavney, Bernard, Jobling, Mark, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Eales, James , Maan, Akhlaq , Xu, Xiaoguang , Michoel, Tom , Hallast, Pille , Batini, C , Zadik, Daniel , Prestes, Priscilla , Molina, Elsa , Denniff, Matthew , Schroeder, Juliane , Bjorkegren, Johan , Thompson, John , Maffia, Pasquale , Guzik, Tomasz , Keavney, Bernard , Jobling, Mark , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2019
- Type: Text , Journal article
- Relation: Arteriosclerosis, thrombosis, and vascular biology Vol. 39, no. 11 (2019), p. 2386-2401
- Full Text:
- Reviewed:
- Description: 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.
- Authors: Eales, James , Maan, Akhlaq , Xu, Xiaoguang , Michoel, Tom , Hallast, Pille , Batini, C , Zadik, Daniel , Prestes, Priscilla , Molina, Elsa , Denniff, Matthew , Schroeder, Juliane , Bjorkegren, Johan , Thompson, John , Maffia, Pasquale , Guzik, Tomasz , Keavney, Bernard , Jobling, Mark , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2019
- Type: Text , Journal article
- Relation: Arteriosclerosis, thrombosis, and vascular biology Vol. 39, no. 11 (2019), p. 2386-2401
- Full Text:
- Reviewed:
- Description: 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.
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