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
- 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
- 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
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
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.
The emerging role of non-coding RNA in essential hypertension and blood pressure regulation
- Marques, Francine, Booth, Scott, Charchar, Fadi
- Authors: Marques, Francine , Booth, Scott , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Human Hypertension Vol. 29, no. 8 (2015), p. 459-467
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Unravelling the complete genetic predisposition to high blood pressure (BP) has proven to be challenging. This puzzle and the fact that coding regions of the genome account for less than 2% of the entire human DNA support the hypothesis that genetic mechanism besides coding genes are likely to contribute to BP regulation. Non-coding RNAs (ncRNAs) are emerging as key players of transcription regulation in both health and disease states. They control basic functions in virtually all cell types relevant to the cardiovascular system and, thus, a direct involvement with BP regulation is highly probable. Here, we review the literature about ncRNAs associated with human BP and essential hypertension, highlighting investigations, methodology and difficulties arising in the field. The most investigated ncRNAs so far are microRNAs (miRNAs), small ncRNAs that modulate gene expression by posttranscriptional mechanisms. We discuss studies that have examined miRNAs associated with BP in biological fluids, such as blood and urine, and tissues, such as vascular smooth muscle cells and the kidney. Furthermore, we review the interaction between miRNA binding sites and single nucleotide polymorphisms in genes associated with BP. In conclusion, there is a clear need for more human and functional studies to help elucidate the multifaceted roles of ncRNAs, in particular mid- and long ncRNAs in BP regulation. © 2015 Macmillan Publishers Limited All rights reserved.
- 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
- Reviewed:
- 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
Higher long-term adherence to statins in rural patients at high atherosclerotic risk
- Peverelle, Matthew, Baradi, Arul, Paleri, Sarang, Lee, Yun, Sultani, Rohullah, Toukhsati, Samia, Hare, David, Janus, Edward, Wilson, Andrew
- Authors: Peverelle, Matthew , Baradi, Arul , Paleri, Sarang , Lee, Yun , Sultani, Rohullah , Toukhsati, Samia , Hare, David , Janus, Edward , Wilson, Andrew
- Date: 2019
- Type: Text , Journal article
- Relation: Journal of Clinical Lipidology Vol. 13, no. 1 (2019), p. 163-169
- Full Text: false
- Reviewed:
- Description: Background: Rural patients with atherosclerotic cardiovascular disease (ASCVD) experience greater cardiovascular morbidity and mortality than their urban counterparts. Statin therapy is a key component of ASCVD treatment. The extent to which there may be regional differences in long-term adherence to statins is unknown. Objective: To assess long-term rates of adherence to statins in a high-risk ASCVD cohort, and whether regional differences exist between rural and urban patients. Methods: Follow-up was conducted in patients who underwent coronary angiography at a single tertiary center between 2009 and 2013. Adherence was defined as consumption of prescribed statin ≥6 days per week. Patients were divided into remoteness areas (RAs), classified as RA1 (major city), RA2 (inner regional), and RA3 (outer regional) based on the Australian Standard Geographical Classification. Results: Five hundred twenty-five patients (69% male, mean age 64 ± 11 years) were followed-up after a median of 5.3 years. Baseline characteristics were similar between RAs. Overall adherence was 83%; however, rural patients were significantly more adherent to their statin therapy (80% in RA1, 83% in RA2, and 93% in RA3, P =.04). Living in RA3 independently predicted greater statin adherence than living in RA1 (odds ratio: 2.75, 95% CI: 1.1–7.8, P =.03). All-cause mortality was significantly higher in RA3 than other regional areas (6% RA1, 12% RA2, and 18% RA3, P =.01). Conclusions: Despite higher all-cause mortality, rural patients with ASCVD demonstrate significantly greater long-term adherence to statins than urban patients. Other factors, such as reduced access to health care and delayed diagnosis may explain the gap in outcomes between rural and urban patients.
A guide to the short, long and circular RNAs in hypertension and cardiovascular disease
- Prestes, Priscilla, Maier, Michelle, Woods, Bradley, Charchar, Fadi
- Authors: Prestes, Priscilla , Maier, Michelle , Woods, Bradley , Charchar, Fadi
- Date: 2020
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 21, no. 10 (2020)
- Full Text:
- Reviewed:
- Description: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in adults in developed countries. CVD encompasses many diseased states, including hypertension, coronary artery disease and atherosclerosis. Studies in animal models and human studies have elucidated the contribution of many genetic factors, including non-coding RNAs. Non-coding RNAs are RNAs not translated into protein, involved in gene expression regulation post-transcriptionally and implicated in CVD. Of these, circular RNAs (circRNAs) and microRNAs are relevant. CircRNAs are created by the back-splicing of pre-messenger RNA and have been underexplored as contributors to CVD. These circRNAs may also act as biomarkers of human disease, as they can be extracted from whole blood, plasma, saliva and seminal fluid. CircRNAs have recently been implicated in various disease processes, including hypertension and other cardiovascular disease. This review article will explore the promising and emerging roles of circRNAs as potential biomarkers and therapeutic targets in CVD, in particular hypertension. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- Authors: Prestes, Priscilla , Maier, Michelle , Woods, Bradley , Charchar, Fadi
- Date: 2020
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 21, no. 10 (2020)
- Full Text:
- Reviewed:
- Description: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in adults in developed countries. CVD encompasses many diseased states, including hypertension, coronary artery disease and atherosclerosis. Studies in animal models and human studies have elucidated the contribution of many genetic factors, including non-coding RNAs. Non-coding RNAs are RNAs not translated into protein, involved in gene expression regulation post-transcriptionally and implicated in CVD. Of these, circular RNAs (circRNAs) and microRNAs are relevant. CircRNAs are created by the back-splicing of pre-messenger RNA and have been underexplored as contributors to CVD. These circRNAs may also act as biomarkers of human disease, as they can be extracted from whole blood, plasma, saliva and seminal fluid. CircRNAs have recently been implicated in various disease processes, including hypertension and other cardiovascular disease. This review article will explore the promising and emerging roles of circRNAs as potential biomarkers and therapeutic targets in CVD, in particular hypertension. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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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