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
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- 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.
Male-specific region of the y chromosome and cardiovascular risk phylogenetic analysis and gene expression studies
- Bloomer, Lisa, Nelson, Christopher, Eales, James, Denniff, Matthew, Christofidou, Paraskevi, Debiec, Radoslaw, Moore, Jasbir, Consortium, Cardiogenics, Zukowska-Szczechowska, Ewa, Goodall, Alison, Thompson, John, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Bloomer, Lisa , Nelson, Christopher , Eales, James , Denniff, Matthew , Christofidou, Paraskevi , Debiec, Radoslaw , Moore, Jasbir , Consortium, Cardiogenics , Zukowska-Szczechowska, Ewa , Goodall, Alison , Thompson, John , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2013
- Type: Text , Journal article
- Relation: Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, no. 7 (2013), p. 1722-1727
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: Objective-Haplogroup I of male-specific region of the human Y chromosome is associated with 50% increased risk of coronary artery disease. It is not clear to what extent conventional cardiovascular risk factors and genes of the malespecific region may explain this association. Approach and Results-A total of 1988 biologically unrelated men from 4 white European populations were genotyped using 11 Y chromosome single nucleotide polymorphisms and classified into 13 most common European haplogroups. Approximately 75% to 93% of the haplotypic variation of the Y chromosome in all cohorts was attributable to I, R1a, and R1b1b2 lineages. None of traditional cardiovascular risk factors, including body mass index, blood pressures, lipids, glucose, C-reactive protein, creatinine, and insulin resistance, was associated with haplogroup I of the Y chromosome in the joint inverse variance meta-analysis. Fourteen of 15 ubiquitous single-copy genes of the male-specific region were expressed in human macrophages. When compared with men with other haplogroups, carriers of haplogroup I had 0.61- and 0.64-fold lower expression of ubiquitously transcribed tetratricopeptide repeat, Y-linked gene (UTY) and protein kinase, Y-linked, pseudogene (PRKY) in macrophages (P=0.0001 and P=0.002, respectively). Conclusions-Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors. © 2013 American Heart Association, Inc.
- Description: 2003011132
- Authors: Bloomer, Lisa , Nelson, Christopher , Eales, James , Denniff, Matthew , Christofidou, Paraskevi , Debiec, Radoslaw , Moore, Jasbir , Consortium, Cardiogenics , Zukowska-Szczechowska, Ewa , Goodall, Alison , Thompson, John , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2013
- Type: Text , Journal article
- Relation: Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, no. 7 (2013), p. 1722-1727
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Objective-Haplogroup I of male-specific region of the human Y chromosome is associated with 50% increased risk of coronary artery disease. It is not clear to what extent conventional cardiovascular risk factors and genes of the malespecific region may explain this association. Approach and Results-A total of 1988 biologically unrelated men from 4 white European populations were genotyped using 11 Y chromosome single nucleotide polymorphisms and classified into 13 most common European haplogroups. Approximately 75% to 93% of the haplotypic variation of the Y chromosome in all cohorts was attributable to I, R1a, and R1b1b2 lineages. None of traditional cardiovascular risk factors, including body mass index, blood pressures, lipids, glucose, C-reactive protein, creatinine, and insulin resistance, was associated with haplogroup I of the Y chromosome in the joint inverse variance meta-analysis. Fourteen of 15 ubiquitous single-copy genes of the male-specific region were expressed in human macrophages. When compared with men with other haplogroups, carriers of haplogroup I had 0.61- and 0.64-fold lower expression of ubiquitously transcribed tetratricopeptide repeat, Y-linked gene (UTY) and protein kinase, Y-linked, pseudogene (PRKY) in macrophages (P=0.0001 and P=0.002, respectively). Conclusions-Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors. © 2013 American Heart Association, Inc.
- Description: 2003011132
- Christofidou, Paraskevi, Nelson, Christopher, Nikpay, Majid, Qu, Liming, Li, Mingyao, Loley, Christina, Debiec, Radoslaw, Braund, Peter, Denniff, Matthew, Charchar, Fadi, Arjo, Ares Rocanin, Trégouët, David-Alexandre, Goodall, Alison, Cambien, Francois, Ouwehand, Willem, Roberts, Robert, Schunkert, Heribert, Hengstenberg, Christian, Reilly, Muredach, Erdmann, Jeanette, McPherson, Ruth, König, Inke, Thompson, John, Samani, Nilesh, Tomaszewski, Maciej
- Authors: Christofidou, Paraskevi , Nelson, Christopher , Nikpay, Majid , Qu, Liming , Li, Mingyao , Loley, Christina , Debiec, Radoslaw , Braund, Peter , Denniff, Matthew , Charchar, Fadi , Arjo, Ares Rocanin , Trégouët, David-Alexandre , Goodall, Alison , Cambien, Francois , Ouwehand, Willem , Roberts, Robert , Schunkert, Heribert , Hengstenberg, Christian , Reilly, Muredach , Erdmann, Jeanette , McPherson, Ruth , König, Inke , Thompson, John , Samani, Nilesh , Tomaszewski, Maciej
- Date: 2015
- Type: Text , Journal article
- Relation: American Journal of Human Genetics Vol. 97, no. 2 (2015), p. 228-237
- Full Text: false
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- Description: Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4-0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 x 10
Urotensin-II system in genetic control of blood pressure and renal function
- Debiec, Radoslaw, Christofidou, Paraskevi, Denniff, Matthew, Bloomer, Lisa, Bogdanski, Pawel, Wojnar, Lukasz, Musialik, Katarzyna, Charchar, Fadi, Thompson, John, Waterworth, Dawn, Song, Kijoung, Vollenweider, Peter, Waeber, Gerard, Zukowska-Szczechowska, Ewa, Samani, Nilesh, Lambert, David, Tomaszewski, Maciej
- Authors: Debiec, Radoslaw , Christofidou, Paraskevi , Denniff, Matthew , Bloomer, Lisa , Bogdanski, Pawel , Wojnar, Lukasz , Musialik, Katarzyna , Charchar, Fadi , Thompson, John , Waterworth, Dawn , Song, Kijoung , Vollenweider, Peter , Waeber, Gerard , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Lambert, David , Tomaszewski, Maciej
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS ONE Vol. 8, no. 12 (2013), p.
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- Reviewed:
- Description: Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed familybased analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p< 0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates. © 2013 Debiec et al.
- Authors: Debiec, Radoslaw , Christofidou, Paraskevi , Denniff, Matthew , Bloomer, Lisa , Bogdanski, Pawel , Wojnar, Lukasz , Musialik, Katarzyna , Charchar, Fadi , Thompson, John , Waterworth, Dawn , Song, Kijoung , Vollenweider, Peter , Waeber, Gerard , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Lambert, David , Tomaszewski, Maciej
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS ONE Vol. 8, no. 12 (2013), p.
- Full Text:
- Reviewed:
- Description: Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed familybased analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p< 0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates. © 2013 Debiec et al.
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