A meta-analysis of gene expression signatures of blood pressure and hypertension
- Authors: Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: PLoS Genetics Vol. 11, no. 3 (2015), p. 1-29
- Full Text:
- Reviewed:
- Description: Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension. **Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliate is provided in this record**
- Authors: Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: PLoS Genetics Vol. 11, no. 3 (2015), p. 1-29
- Full Text:
- Reviewed:
- Description: Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension. **Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliate is provided in this record**
Telomere dynamics during aging in polygenic left ventricular hypertrophy
- Marques, Francine, Booth, Scott, Prestes, Priscilla, Curl, Claire, Delbridge, Lea, Lewandowski, Paul, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Booth, Scott , Prestes, Priscilla , Curl, Claire , Delbridge, Lea , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 48, no. 1 (2016), p. 42-49
- Full Text:
- Reviewed:
- Description: Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. © 2016 the American Physiological Society.
- Authors: Marques, Francine , Booth, Scott , Prestes, Priscilla , Curl, Claire , Delbridge, Lea , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 48, no. 1 (2016), p. 42-49
- Full Text:
- Reviewed:
- Description: Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. © 2016 the American Physiological Society.
Telomere length maintenance and cardio-metabolic disease prevention through exercise training
- Denham, Joshua, O'Brien, Brendan, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Sports Medicine Vol. 46, no. 9 (2016), p. 1213-1237
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Telomeres are tandem repeat DNA sequences located at distal ends of chromosomes that protect against genomic DNA degradation and chromosomal instability. Excessive telomere shortening leads to cellular senescence and for this reason telomere length is a marker of biological age. Abnormally short telomeres may culminate in the manifestation of a number of cardio-metabolic diseases. Age-related cardio-metabolic diseases attributable to an inactive lifestyle, such as obesity, type 2 diabetes mellitus and cardiovascular disease, are associated with short leukocyte telomeres. Exercise training prevents and manages the symptoms of many cardio-metabolic diseases whilst concurrently maintaining telomere length. The positive relationship between exercise training, physical fitness and telomere length raises the possibility of a mediating role of telomeres in chronic disease prevention via exercise. Further elucidation of the underpinning molecular mechanisms of how exercise maintains telomere length should provide crucial information on how physical activity can be best structured to combat the chronic disease epidemic and improve the human health span. Here, we synthesise and discuss the current evidence on the impact of physical activity and cardiorespiratory fitness on telomere dynamics. We provide the molecular mechanisms with a known role in exercise-induced telomere length maintenance and highlight unexplored, alternative pathways ripe for future investigations.
- Authors: Denham, Joshua , O'Brien, Brendan , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Sports Medicine Vol. 46, no. 9 (2016), p. 1213-1237
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Telomeres are tandem repeat DNA sequences located at distal ends of chromosomes that protect against genomic DNA degradation and chromosomal instability. Excessive telomere shortening leads to cellular senescence and for this reason telomere length is a marker of biological age. Abnormally short telomeres may culminate in the manifestation of a number of cardio-metabolic diseases. Age-related cardio-metabolic diseases attributable to an inactive lifestyle, such as obesity, type 2 diabetes mellitus and cardiovascular disease, are associated with short leukocyte telomeres. Exercise training prevents and manages the symptoms of many cardio-metabolic diseases whilst concurrently maintaining telomere length. The positive relationship between exercise training, physical fitness and telomere length raises the possibility of a mediating role of telomeres in chronic disease prevention via exercise. Further elucidation of the underpinning molecular mechanisms of how exercise maintains telomere length should provide crucial information on how physical activity can be best structured to combat the chronic disease epidemic and improve the human health span. Here, we synthesise and discuss the current evidence on the impact of physical activity and cardiorespiratory fitness on telomere dynamics. We provide the molecular mechanisms with a known role in exercise-induced telomere length maintenance and highlight unexplored, alternative pathways ripe for future investigations.
Renal nerves contribute to hypertension in Schlager BPH/2J mice
- Gueguen, Cindy, Jackson, Kristy, Marques, Francine, Eikelis, Nina, Phillips, Sarah, Stevenson, Emily, Charchar, Fadi, Lambert, Gavin, Davern, Pamela, Head, Geoffrey
- Authors: Gueguen, Cindy , Jackson, Kristy , Marques, Francine , Eikelis, Nina , Phillips, Sarah , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Davern, Pamela , Head, Geoffrey
- Date: 2019
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 42, no. 3 (2019), p. 306-318
- Full Text:
- Reviewed:
- Description: Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was −10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and −2.1 ± 2.2 mmHg in sham BPH/2J (P < 0.001, n = 8–10). RD had no effect in BPN/3J (P > 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (−12 vs −3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.
- Authors: Gueguen, Cindy , Jackson, Kristy , Marques, Francine , Eikelis, Nina , Phillips, Sarah , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Davern, Pamela , Head, Geoffrey
- Date: 2019
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 42, no. 3 (2019), p. 306-318
- Full Text:
- Reviewed:
- Description: Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was −10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and −2.1 ± 2.2 mmHg in sham BPH/2J (P < 0.001, n = 8–10). RD had no effect in BPN/3J (P > 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (−12 vs −3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.
Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- Pattaro, C, Teumer, A, Gorski, M, Chu, A.Y., Li, M, Mijatovic, V, Garnaas, M, Tin, A, Charchar, Fadi
- Authors: Pattaro, C , Teumer, A , Gorski, M , Chu, A.Y. , Li, M , Mijatovic, V , Garnaas, M , Tin, A , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Communications Vol. 7, no. (2016), p. 1-19
- Full Text:
- Reviewed:
- Description: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved. Please note that there are two hundred and six authors for this article and we have included only the Federation University Australia affiliate.
- Authors: Pattaro, C , Teumer, A , Gorski, M , Chu, A.Y. , Li, M , Mijatovic, V , Garnaas, M , Tin, A , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Communications Vol. 7, no. (2016), p. 1-19
- Full Text:
- Reviewed:
- Description: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved. Please note that there are two hundred and six authors for this article and we have included only the Federation University Australia affiliate.
Involvement of human monogenic cardiomyopathy genes in experimental polygenic cardiac hypertrophy
- Prestes, Priscilla, Marques, Francine, Lopez-Campos, Guillermo, Lewandowski, Paul, Delbridge, Lea, Charchar, Fadi, Harrap, Stephen
- Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Lewandowski, Paul , Delbridge, Lea , Charchar, Fadi , Harrap, Stephen
- Date: 2018
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 50, no. 9 (2018), p. 680-687
- Full Text:
- Reviewed:
- Description: Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.
- Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Lewandowski, Paul , Delbridge, Lea , Charchar, Fadi , Harrap, Stephen
- Date: 2018
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 50, no. 9 (2018), p. 680-687
- Full Text:
- Reviewed:
- Description: Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.
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.
Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
- Morris, Andrew, Le, Thu, Wu, Haojia, Akbarov, Artur, van der Most, Peter, Hemani, Gibran, Smith, George, Mahajan, Anubha, Gaulton, Kyle, Nadkarni, Girish, Valladares-Salgado, Adan, Wacher-Rodarte, Niels, Mychaleckyj, Josyf, Dueker, Nicole, Guo, Xiuqing, Hai, Yang, Haessler, Jeffrey, Kamatani, Yoichiro, Stilp, Adrienne, Zhu, Gu, Cook, James, Arnlov, Johan, Blanton, Susan, de Borst, Martin, Bottinger, Erwin, Buchanan, Thomas, Cechova, Sylvia, Charchar, Fadi, Chu, Pei-Lun, Damman, Jeffrey, Eales, James, Gharavi, Ali, Giedraitis, Vilmantas, Heath, Andrew, Ipp, Eli, Kiryluk, Krzysztof, Kramer, Holly, Kubo, Michiaki, Larsson, Anders, Lindgren, Cecilia, Lu, Yingchang, Madden, Pamela, Montgomery, Grant, Papanicolaou, George, Raffel, Leslie, Sacco, Ralph, Sanchez, Elena, Stark, Holger, Sundstrom, Johan, Taylor, Kent, Xiang, Anny, Zivkovic, Aleksandra, Lind, Lars, Ingelsson, Erik, Martin, Nicholas, Whitfield, John, Cai, Jianwen, Laurie, Cathy, Okada, Yukinori, Matsuda, Koichi, Kooperberg, Charles, Chen, Yii-Der, Rundek, Tatjana, Rich, Stephen, Loos, Ruth, Parra, Esteban, Cruz, Miguel, Rotter, Jerome, Snieder, Harold, Tomaszewski, Maciej, Humphreys, Benjamin, Franceschini, Nora
- Authors: Morris, Andrew , Le, Thu , Wu, Haojia , Akbarov, Artur , van der Most, Peter , Hemani, Gibran , Smith, George , Mahajan, Anubha , Gaulton, Kyle , Nadkarni, Girish , Valladares-Salgado, Adan , Wacher-Rodarte, Niels , Mychaleckyj, Josyf , Dueker, Nicole , Guo, Xiuqing , Hai, Yang , Haessler, Jeffrey , Kamatani, Yoichiro , Stilp, Adrienne , Zhu, Gu , Cook, James , Arnlov, Johan , Blanton, Susan , de Borst, Martin , Bottinger, Erwin , Buchanan, Thomas , Cechova, Sylvia , Charchar, Fadi , Chu, Pei-Lun , Damman, Jeffrey , Eales, James , Gharavi, Ali , Giedraitis, Vilmantas , Heath, Andrew , Ipp, Eli , Kiryluk, Krzysztof , Kramer, Holly , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia , Lu, Yingchang , Madden, Pamela , Montgomery, Grant , Papanicolaou, George , Raffel, Leslie , Sacco, Ralph , Sanchez, Elena , Stark, Holger , Sundstrom, Johan , Taylor, Kent , Xiang, Anny , Zivkovic, Aleksandra , Lind, Lars , Ingelsson, Erik , Martin, Nicholas , Whitfield, John , Cai, Jianwen , Laurie, Cathy , Okada, Yukinori , Matsuda, Koichi , Kooperberg, Charles , Chen, Yii-Der , Rundek, Tatjana , Rich, Stephen , Loos, Ruth , Parra, Esteban , Cruz, Miguel , Rotter, Jerome , Snieder, Harold , Tomaszewski, Maciej , Humphreys, Benjamin , Franceschini, Nora
- Date: 2019
- Type: Text , Journal article
- Relation: Nature Communications Vol. 10, no. 1 (2019), p. 1-14
- Full Text:
- Reviewed:
- Description: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
- Authors: Morris, Andrew , Le, Thu , Wu, Haojia , Akbarov, Artur , van der Most, Peter , Hemani, Gibran , Smith, George , Mahajan, Anubha , Gaulton, Kyle , Nadkarni, Girish , Valladares-Salgado, Adan , Wacher-Rodarte, Niels , Mychaleckyj, Josyf , Dueker, Nicole , Guo, Xiuqing , Hai, Yang , Haessler, Jeffrey , Kamatani, Yoichiro , Stilp, Adrienne , Zhu, Gu , Cook, James , Arnlov, Johan , Blanton, Susan , de Borst, Martin , Bottinger, Erwin , Buchanan, Thomas , Cechova, Sylvia , Charchar, Fadi , Chu, Pei-Lun , Damman, Jeffrey , Eales, James , Gharavi, Ali , Giedraitis, Vilmantas , Heath, Andrew , Ipp, Eli , Kiryluk, Krzysztof , Kramer, Holly , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia , Lu, Yingchang , Madden, Pamela , Montgomery, Grant , Papanicolaou, George , Raffel, Leslie , Sacco, Ralph , Sanchez, Elena , Stark, Holger , Sundstrom, Johan , Taylor, Kent , Xiang, Anny , Zivkovic, Aleksandra , Lind, Lars , Ingelsson, Erik , Martin, Nicholas , Whitfield, John , Cai, Jianwen , Laurie, Cathy , Okada, Yukinori , Matsuda, Koichi , Kooperberg, Charles , Chen, Yii-Der , Rundek, Tatjana , Rich, Stephen , Loos, Ruth , Parra, Esteban , Cruz, Miguel , Rotter, Jerome , Snieder, Harold , Tomaszewski, Maciej , Humphreys, Benjamin , Franceschini, Nora
- Date: 2019
- Type: Text , Journal article
- Relation: Nature Communications Vol. 10, no. 1 (2019), p. 1-14
- Full Text:
- Reviewed:
- Description: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
Telomeres, aging and exercise : Guilty by association?
- Chilton, Warrick, O’Brien, Brendan, Charchar, Fadi
- Authors: Chilton, Warrick , O’Brien, Brendan , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 18, no. 12 (2017), p. 1-32
- Full Text:
- Reviewed:
- Description: Telomeres are repetitive tandem DNA sequences that cap chromosomal ends protecting genomic DNA from enzymatic degradation. Telomeres progressively shorten with cellular replication and are therefore assumed to correlate with biological and chronological age. An expanding body of evidence suggests (i) a predictable inverse association between telomere length, aging and age-related diseases and (ii) a positive association between physical activity and telomere length. Both hypotheses have garnered tremendous research attention and broad consensus; however, the evidence for each proposition is inconsistent and equivocal at best. Telomere length does not meet the basic criteria for an aging biomarker and at least 50% of key studies fail to find associations with physical activity. In this review, we address the evidence in support and refutation of the putative associations between telomere length, aging and physical activity. We finish with a brief review of plausible mechanisms and potential future research directions. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.
- Authors: Chilton, Warrick , O’Brien, Brendan , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 18, no. 12 (2017), p. 1-32
- Full Text:
- Reviewed:
- Description: Telomeres are repetitive tandem DNA sequences that cap chromosomal ends protecting genomic DNA from enzymatic degradation. Telomeres progressively shorten with cellular replication and are therefore assumed to correlate with biological and chronological age. An expanding body of evidence suggests (i) a predictable inverse association between telomere length, aging and age-related diseases and (ii) a positive association between physical activity and telomere length. Both hypotheses have garnered tremendous research attention and broad consensus; however, the evidence for each proposition is inconsistent and equivocal at best. Telomere length does not meet the basic criteria for an aging biomarker and at least 50% of key studies fail to find associations with physical activity. In this review, we address the evidence in support and refutation of the putative associations between telomere length, aging and physical activity. We finish with a brief review of plausible mechanisms and potential future research directions. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.
May measurement month 2018 : A pragmatic global screening campaign to raise awareness of blood pressure by the international society of hypertension
- Beaney, Thomas, Burrell, Louise, Castillo, Rafael, Charchar, Fadi, Cro, Suzie, Damasceno, Albertino, Kruger, Ruan, Nilsson, Peter, Prabhakaran, Dorairaj, Ramirez, Agustin, Schlaich, Markus, Schutte, Aletta, Tomaszewski, Maciej, Touyz, Rhian, Wang, Ji-Guang, Weber, Michael, Poulter, Neil
- Authors: Beaney, Thomas , Burrell, Louise , Castillo, Rafael , Charchar, Fadi , Cro, Suzie , Damasceno, Albertino , Kruger, Ruan , Nilsson, Peter , Prabhakaran, Dorairaj , Ramirez, Agustin , Schlaich, Markus , Schutte, Aletta , Tomaszewski, Maciej , Touyz, Rhian , Wang, Ji-Guang , Weber, Michael , Poulter, Neil
- Date: 2019
- Type: Text , Journal article , Review
- Relation: European Heart Journal Vol. 40, no. 25 (2019), p. 2006-2017
- Full Text:
- Reviewed:
- Description: Aims: Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results: Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion: May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk.
- Authors: Beaney, Thomas , Burrell, Louise , Castillo, Rafael , Charchar, Fadi , Cro, Suzie , Damasceno, Albertino , Kruger, Ruan , Nilsson, Peter , Prabhakaran, Dorairaj , Ramirez, Agustin , Schlaich, Markus , Schutte, Aletta , Tomaszewski, Maciej , Touyz, Rhian , Wang, Ji-Guang , Weber, Michael , Poulter, Neil
- Date: 2019
- Type: Text , Journal article , Review
- Relation: European Heart Journal Vol. 40, no. 25 (2019), p. 2006-2017
- Full Text:
- Reviewed:
- Description: Aims: Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results: Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion: May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk.
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.
Cardiomyocyte functional etiology in heart failure with preserved ejection fraction is distinctive - A new preclinical model
- Curl, Claire, Danes, Vennetia, Bell, James, Raaijmakers, Antonia, Ip, Wendy, Chandramouli, Chanchal, Harding, Tristan, Porrello, Enzo, Erickson, Jeffrey, Charchar, Fadi, Kompa, Andrew, Edgley, Amanda, Crossman, David, Soeller, Christian, Mellor, Kimberley, Kalman, Jonathan, Harrap, Stephen, Delbridge, Lea
- Authors: Curl, Claire , Danes, Vennetia , Bell, James , Raaijmakers, Antonia , Ip, Wendy , Chandramouli, Chanchal , Harding, Tristan , Porrello, Enzo , Erickson, Jeffrey , Charchar, Fadi , Kompa, Andrew , Edgley, Amanda , Crossman, David , Soeller, Christian , Mellor, Kimberley , Kalman, Jonathan , Harrap, Stephen , Delbridge, Lea
- Date: 2018
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 7, no. 11 (2018), p. 1-32
- Full Text:
- Reviewed:
- Description: Background--Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. Methods and Results--The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca
- Authors: Curl, Claire , Danes, Vennetia , Bell, James , Raaijmakers, Antonia , Ip, Wendy , Chandramouli, Chanchal , Harding, Tristan , Porrello, Enzo , Erickson, Jeffrey , Charchar, Fadi , Kompa, Andrew , Edgley, Amanda , Crossman, David , Soeller, Christian , Mellor, Kimberley , Kalman, Jonathan , Harrap, Stephen , Delbridge, Lea
- Date: 2018
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 7, no. 11 (2018), p. 1-32
- Full Text:
- Reviewed:
- Description: Background--Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. Methods and Results--The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca
Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney
- Jiang, Xiao, Eales, James, Scannali, David, Prestes, Priscilla, Charchar, Fadi
- Authors: Jiang, Xiao , Eales, James , Scannali, David , Prestes, Priscilla , Charchar, Fadi
- Date: 2020
- Type: Text , Journal article
- Relation: European Heart Journal Vol. 41, no. 48 (2020), p. 4580-4588
- Full Text:
- Reviewed:
- Description: Aims Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. Methods and results We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 coexpression analysis. Conclusion Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection. © The Author(s) 2020. *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliates “James Eales", "Priscilla Prestes" and "Fadi Charchar” are provided in this record**
- Authors: Jiang, Xiao , Eales, James , Scannali, David , Prestes, Priscilla , Charchar, Fadi
- Date: 2020
- Type: Text , Journal article
- Relation: European Heart Journal Vol. 41, no. 48 (2020), p. 4580-4588
- Full Text:
- Reviewed:
- Description: Aims Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. Methods and results We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 coexpression analysis. Conclusion Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection. © The Author(s) 2020. *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliates “James Eales", "Priscilla Prestes" and "Fadi Charchar” are provided in this record**
May measurement month 2017 : an analysis of blood pressure screening results worldwide
- Beaney, Thomas, Schutte, Aletta, Tomaszewski, Maciej, Ariti, Cono, Burrell, Louise, Castillo, Rafael, Charchar, Fadi, Damasceno, Albertino, Kruger, Ruan, Lackland, Daniel, Nilsson, Peter, Prabhakaran, Dorairaj, Ramirez, Agustin, Schlaich, Markus, Wang, Jiguang, Weber, Michael, Poulter, Neil
- Authors: Beaney, Thomas , Schutte, Aletta , Tomaszewski, Maciej , Ariti, Cono , Burrell, Louise , Castillo, Rafael , Charchar, Fadi , Damasceno, Albertino , Kruger, Ruan , Lackland, Daniel , Nilsson, Peter , Prabhakaran, Dorairaj , Ramirez, Agustin , Schlaich, Markus , Wang, Jiguang , Weber, Michael , Poulter, Neil
- Date: 2018
- Type: Text , Journal article
- Relation: The Lancet Global Health Vol. 6, no. 7 (2018), p. e736-e743
- Full Text:
- Reviewed:
- Description: Background: Increased blood pressure is the biggest contributor to the global burden of disease and mortality. Data suggest that less than half of the population with hypertension is aware of it. May Measurement Month was initiated to raise awareness of the importance of blood pressure and as a pragmatic interim solution to the shortfall in screening programmes. Methods: This cross-sectional survey included volunteer adults (≥18 years) who ideally had not had their blood pressures measured in the past year. Each participant had their blood pressure measured three times and received a a questionnaire about demographic, lifestyle, and environmental factors. The primary objective was to raise awareness of blood pressure, measured by number of countries involved, number of people screened, and number of people who have untreated or inadequately treated hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, or on the basis of receiving antihypertensive medication). Multiple imputation was used to estimate the mean of the second and third blood pressure readings if these were not recorded. Measures of association were analysed using linear mixed models. Findings: Data were collected from 1 201 570 individuals in 80 countries. After imputation, of the 1 128 635 individuals for whom a mean of the second and third readings was available, 393 924 (34·9%) individuals had hypertension. 153 905 (17·3%) of 888 616 individuals who were not receiving antihypertensive treatment were hypertensive, and 105 456 (46·3%) of the 227 721 individuals receiving treatment did not have controlled blood pressure. Significant differences in adjusted blood pressures and hypertension prevalence were apparent between regions. Adjusted blood pressure was higher in association with antihypertensive medication, diabetes, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm than on the left arm, and blood pressure was highest on Saturdays. Interpretation: Inexpensive global screening of blood pressure is achievable using volunteers and convenience sampling. Pending the set-up of systematic surveillance systems worldwide, MMM will be repeated annually to raise awareness of blood pressure. Funding: International Society of Hypertension, Centers for Disease Control and Prevention, Servier Pharmaceutical Co.
- Authors: Beaney, Thomas , Schutte, Aletta , Tomaszewski, Maciej , Ariti, Cono , Burrell, Louise , Castillo, Rafael , Charchar, Fadi , Damasceno, Albertino , Kruger, Ruan , Lackland, Daniel , Nilsson, Peter , Prabhakaran, Dorairaj , Ramirez, Agustin , Schlaich, Markus , Wang, Jiguang , Weber, Michael , Poulter, Neil
- Date: 2018
- Type: Text , Journal article
- Relation: The Lancet Global Health Vol. 6, no. 7 (2018), p. e736-e743
- Full Text:
- Reviewed:
- Description: Background: Increased blood pressure is the biggest contributor to the global burden of disease and mortality. Data suggest that less than half of the population with hypertension is aware of it. May Measurement Month was initiated to raise awareness of the importance of blood pressure and as a pragmatic interim solution to the shortfall in screening programmes. Methods: This cross-sectional survey included volunteer adults (≥18 years) who ideally had not had their blood pressures measured in the past year. Each participant had their blood pressure measured three times and received a a questionnaire about demographic, lifestyle, and environmental factors. The primary objective was to raise awareness of blood pressure, measured by number of countries involved, number of people screened, and number of people who have untreated or inadequately treated hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, or on the basis of receiving antihypertensive medication). Multiple imputation was used to estimate the mean of the second and third blood pressure readings if these were not recorded. Measures of association were analysed using linear mixed models. Findings: Data were collected from 1 201 570 individuals in 80 countries. After imputation, of the 1 128 635 individuals for whom a mean of the second and third readings was available, 393 924 (34·9%) individuals had hypertension. 153 905 (17·3%) of 888 616 individuals who were not receiving antihypertensive treatment were hypertensive, and 105 456 (46·3%) of the 227 721 individuals receiving treatment did not have controlled blood pressure. Significant differences in adjusted blood pressures and hypertension prevalence were apparent between regions. Adjusted blood pressure was higher in association with antihypertensive medication, diabetes, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm than on the left arm, and blood pressure was highest on Saturdays. Interpretation: Inexpensive global screening of blood pressure is achievable using volunteers and convenience sampling. Pending the set-up of systematic surveillance systems worldwide, MMM will be repeated annually to raise awareness of blood pressure. Funding: International Society of Hypertension, Centers for Disease Control and Prevention, Servier Pharmaceutical Co.
May measurement month 2019 the global blood pressure screening campaign of the International Society of Hypertension
- Beaney, Thomas, Schutte, Aletta, Stergiou, George, Borghi, Claudio, Burger, Dylan, Charchar, Fadi, Cro, Suzie, Diaz, Alejandro, Damasceno, Albertino, Espeche, Walter, Jose, Arun, Khan, Nadia, Kokubo, Yoshihiro, Maheshwari, Anuj, Marin, Marcos, More, Arun, Neupane, Dinesh, Nilsson, Peter, Patil, Mansi, Prabhakaran, Dorairaj, Ramirez, Agustin, Rodriguez, Pablo, Schlaich, Markus, Steckelings, Ulrike, Tomaszewski, Maciej, Unger, Thomas, Wainford, Richard, Wang, Jiguang, Williams, Bryan, Poulter, Neil, M. M. M. Investigators
- Authors: Beaney, Thomas , Schutte, Aletta , Stergiou, George , Borghi, Claudio , Burger, Dylan , Charchar, Fadi , Cro, Suzie , Diaz, Alejandro , Damasceno, Albertino , Espeche, Walter , Jose, Arun , Khan, Nadia , Kokubo, Yoshihiro , Maheshwari, Anuj , Marin, Marcos , More, Arun , Neupane, Dinesh , Nilsson, Peter , Patil, Mansi , Prabhakaran, Dorairaj , Ramirez, Agustin , Rodriguez, Pablo , Schlaich, Markus , Steckelings, Ulrike , Tomaszewski, Maciej , Unger, Thomas , Wainford, Richard , Wang, Jiguang , Williams, Bryan , Poulter, Neil , M. M. M. Investigators
- Date: 2020
- Type: Text , Journal article
- Relation: Hypertension Vol. 76, no. 2 (Aug 2020), p. 333-341
- Full Text:
- Reviewed:
- Description: Elevated blood pressure remains the single biggest risk factor contributing to the global burden of disease and mortality. May Measurement Month is an annual global screening campaign aiming to improve awareness of blood pressure at the individual and population level. Adults (>= 18 years) recruited through opportunistic sampling were screened at sites in 92 countries during May 2019. Ideally, 3 blood pressure readings were measured for each participant, and data on lifestyle factors and comorbidities were collected. Hypertension was defined as a systolic blood pressure >= 140 mm Hg, or a diastolic blood pressure >= 90 mm Hg (mean of the second and third readings) or taking antihypertensive medication. When necessary, multiple imputation was used to estimate participants' mean blood pressure. Mixed-effects models were used to evaluate associations between blood pressure and participant characteristics. Of 1 508 130 screenees 482 273 (32.0%) had never had a blood pressure measurement before and 513 337 (34.0%) had hypertension, of whom 58.7% were aware, and 54.7% were on antihypertensive medication. Of those on medication, 57.8% were controlled to <140/90 mm Hg, and 28.9% to <130/80 mm Hg. Of all those with hypertension, 31.7% were controlled to <140/90 mm Hg, and 350 825 (23.3%) participants had untreated or inadequately treated hypertension. Of those taking antihypertensive medication, half were taking only a single drug, and 25% reported using aspirin inappropriately. This survey is the largest ever synchronized and standardized contemporary compilation of global blood pressure data. This campaign is needed as a temporary substitute for systematic blood pressure screening in many countries worldwide.
- Authors: Beaney, Thomas , Schutte, Aletta , Stergiou, George , Borghi, Claudio , Burger, Dylan , Charchar, Fadi , Cro, Suzie , Diaz, Alejandro , Damasceno, Albertino , Espeche, Walter , Jose, Arun , Khan, Nadia , Kokubo, Yoshihiro , Maheshwari, Anuj , Marin, Marcos , More, Arun , Neupane, Dinesh , Nilsson, Peter , Patil, Mansi , Prabhakaran, Dorairaj , Ramirez, Agustin , Rodriguez, Pablo , Schlaich, Markus , Steckelings, Ulrike , Tomaszewski, Maciej , Unger, Thomas , Wainford, Richard , Wang, Jiguang , Williams, Bryan , Poulter, Neil , M. M. M. Investigators
- Date: 2020
- Type: Text , Journal article
- Relation: Hypertension Vol. 76, no. 2 (Aug 2020), p. 333-341
- Full Text:
- Reviewed:
- Description: Elevated blood pressure remains the single biggest risk factor contributing to the global burden of disease and mortality. May Measurement Month is an annual global screening campaign aiming to improve awareness of blood pressure at the individual and population level. Adults (>= 18 years) recruited through opportunistic sampling were screened at sites in 92 countries during May 2019. Ideally, 3 blood pressure readings were measured for each participant, and data on lifestyle factors and comorbidities were collected. Hypertension was defined as a systolic blood pressure >= 140 mm Hg, or a diastolic blood pressure >= 90 mm Hg (mean of the second and third readings) or taking antihypertensive medication. When necessary, multiple imputation was used to estimate participants' mean blood pressure. Mixed-effects models were used to evaluate associations between blood pressure and participant characteristics. Of 1 508 130 screenees 482 273 (32.0%) had never had a blood pressure measurement before and 513 337 (34.0%) had hypertension, of whom 58.7% were aware, and 54.7% were on antihypertensive medication. Of those on medication, 57.8% were controlled to <140/90 mm Hg, and 28.9% to <130/80 mm Hg. Of all those with hypertension, 31.7% were controlled to <140/90 mm Hg, and 350 825 (23.3%) participants had untreated or inadequately treated hypertension. Of those taking antihypertensive medication, half were taking only a single drug, and 25% reported using aspirin inappropriately. This survey is the largest ever synchronized and standardized contemporary compilation of global blood pressure data. This campaign is needed as a temporary substitute for systematic blood pressure screening in many countries worldwide.
The y chromosome : A blueprint for men's health?
- Maan, Akhlaq, Eales, James, Akbarov, Artur, Rowland, Joshua, Xu, Xiaoguang, Jobling, Mark, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Maan, Akhlaq , Eales, James , Akbarov, Artur , Rowland, Joshua , Xu, Xiaoguang , Jobling, Mark , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2017
- Type: Text , Journal article , Review
- Relation: European Journal of Human Genetics Vol. 25, no. 11 (2017), p. 1181-1188
- Full Text:
- Reviewed:
- Description: The Y chromosome has long been considered a genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome. © 2017 The Author(s).
- Authors: Maan, Akhlaq , Eales, James , Akbarov, Artur , Rowland, Joshua , Xu, Xiaoguang , Jobling, Mark , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2017
- Type: Text , Journal article , Review
- Relation: European Journal of Human Genetics Vol. 25, no. 11 (2017), p. 1181-1188
- Full Text:
- Reviewed:
- Description: The Y chromosome has long been considered a genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome. © 2017 The Author(s).
A modified MTS proliferation assay for suspended cells to avoid the interference by hydralazine and β-Mercaptoethanol
- Wang, Yutang, Nguyen, Dinh, Anesi, Jack, Kelly, Jason, Ahmady, Fahima, Charchar, Fadi
- Authors: Wang, Yutang , Nguyen, Dinh , Anesi, Jack , Kelly, Jason , Ahmady, Fahima , Charchar, Fadi
- Date: 2021
- Type: Text , Journal article
- Relation: Assay and Drug Development Technologies Vol. 19, no. 3 (2021), p. 184-190. https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay is one of the most commonly used tests of cell proliferation. Hydralazine has been reported to interfere with the performance of the MTS assay when used on adherent cells. This study aimed to investigate whether hydralazine interferes with the performance of the MTS assay on suspended cells. THP-1 (a monocytic leukemia cell line) cells were cultured in the presence or absence of hydralazine (0, 10, 50, 100, and 500 μM) for 2 or 24 h. Cell numbers were analyzed using the MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established by centrifuging the cells and replacing the test medium with fresh culture medium immediately before the addition of the MTS reagent. Culture of THP-1 cells with hydralazine at concentrations of 50, 100, and 500 μM for 2 h increased absorbance (p < 0.001) in the standard MTS assay, whereas both the trypan blue exclusion assay and microscopy suggested no change in cell numbers. Culture of THP-1 cells with 100 and 500 μm hydralazine for 24 h increased absorbance (p < 0.05) in the standard MTS assay; however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (100 and 500 μM) increased absorbance in a time- and concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy using THP-1 cells. In addition, the modified MTS assay produced reliable results when K562 and Jurkat cells were incubated with hydralazine or β-mercaptoethanol (βME). In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and βME when assessing suspended cells. © Copyright 2021, Mary Ann Liebert, Inc., publishers 2021. *Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliates “Yutang Wang, Dinh Nguyen, Jack Anesi, Jason Kelly, Fahima Ahmady, Fadi Charchar" is provided in this record**
- Authors: Wang, Yutang , Nguyen, Dinh , Anesi, Jack , Kelly, Jason , Ahmady, Fahima , Charchar, Fadi
- Date: 2021
- Type: Text , Journal article
- Relation: Assay and Drug Development Technologies Vol. 19, no. 3 (2021), p. 184-190. https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay is one of the most commonly used tests of cell proliferation. Hydralazine has been reported to interfere with the performance of the MTS assay when used on adherent cells. This study aimed to investigate whether hydralazine interferes with the performance of the MTS assay on suspended cells. THP-1 (a monocytic leukemia cell line) cells were cultured in the presence or absence of hydralazine (0, 10, 50, 100, and 500 μM) for 2 or 24 h. Cell numbers were analyzed using the MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established by centrifuging the cells and replacing the test medium with fresh culture medium immediately before the addition of the MTS reagent. Culture of THP-1 cells with hydralazine at concentrations of 50, 100, and 500 μM for 2 h increased absorbance (p < 0.001) in the standard MTS assay, whereas both the trypan blue exclusion assay and microscopy suggested no change in cell numbers. Culture of THP-1 cells with 100 and 500 μm hydralazine for 24 h increased absorbance (p < 0.05) in the standard MTS assay; however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (100 and 500 μM) increased absorbance in a time- and concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy using THP-1 cells. In addition, the modified MTS assay produced reliable results when K562 and Jurkat cells were incubated with hydralazine or β-mercaptoethanol (βME). In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and βME when assessing suspended cells. © Copyright 2021, Mary Ann Liebert, Inc., publishers 2021. *Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliates “Yutang Wang, Dinh Nguyen, Jack Anesi, Jason Kelly, Fahima Ahmady, Fadi Charchar" is provided in this record**
Plasma lipocalin-2/NGAL is stable over 12 weeks and is not modulated by exercise or dieting
- Nakai, Michael, Prestes, Priscilla, O’Brien, Brendan, Charchar, Fadi, Marques, Francine
- Authors: Nakai, Michael , Prestes, Priscilla , O’Brien, Brendan , Charchar, Fadi , Marques, Francine
- Date: 2021
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18–55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise. © 2021, The Author(s). *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Priscilla Prestes, Brendan O'Brien, Fadi Charchar and Francine Marques” is provided in this record** .
- Authors: Nakai, Michael , Prestes, Priscilla , O’Brien, Brendan , Charchar, Fadi , Marques, Francine
- Date: 2021
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18–55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise. © 2021, The Author(s). *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Priscilla Prestes, Brendan O'Brien, Fadi Charchar and Francine Marques” is provided in this record** .
DNA copy number variations – Do these big mutations have a big effect on cardiovascular risk?
- Prestes, Priscilla, Maier, Michelle, Charchar, Fadi
- Authors: Prestes, Priscilla , Maier, Michelle , Charchar, Fadi
- Date: 2019
- Type: Text , Journal article , Editorial
- Relation: International Journal of Cardiology Vol. 298, no. (2019), p. 116-117
- Full Text:
- Reviewed:
- Description: In simple terms, copy number variations or CNVs are replications or deletions in the DNA which, in humans, changes it from the normal number of two gene copies. These CNVs are caused by inherited or de novo structural changes such as duplications, insertions or deletions of repeated portions of genetic material (Fig. 1). These duplications can vary from one to ten or more copies and range in size from 50 DNA base pairs to several million [1]. Since their discovery in 1987 by Nakamura et al. [2], when they were initially named variable number tandem repeats, many studies have investigated their association with rare and common human diseases. Throughout evolution, some of these changes in copy number were beneficial such as the globin gene number duplication, while others such as the CNVs that cause Huntington's disease were not. In 2004, two landmark studies by Iafrate et al. [3] and Sebat et al. [4] found that large-scale copy-number variations, ranging in size from 100 kb to 2 Mb are common throughout the human genome, and that a high proportion of them are in known genes. These findings roused several association studies between CNVs and disease
- Authors: Prestes, Priscilla , Maier, Michelle , Charchar, Fadi
- Date: 2019
- Type: Text , Journal article , Editorial
- Relation: International Journal of Cardiology Vol. 298, no. (2019), p. 116-117
- Full Text:
- Reviewed:
- Description: In simple terms, copy number variations or CNVs are replications or deletions in the DNA which, in humans, changes it from the normal number of two gene copies. These CNVs are caused by inherited or de novo structural changes such as duplications, insertions or deletions of repeated portions of genetic material (Fig. 1). These duplications can vary from one to ten or more copies and range in size from 50 DNA base pairs to several million [1]. Since their discovery in 1987 by Nakamura et al. [2], when they were initially named variable number tandem repeats, many studies have investigated their association with rare and common human diseases. Throughout evolution, some of these changes in copy number were beneficial such as the globin gene number duplication, while others such as the CNVs that cause Huntington's disease were not. In 2004, two landmark studies by Iafrate et al. [3] and Sebat et al. [4] found that large-scale copy-number variations, ranging in size from 100 kb to 2 Mb are common throughout the human genome, and that a high proportion of them are in known genes. These findings roused several association studies between CNVs and disease
Establishment of sex difference in circulating uric acid is associated with higher testosterone and lower sex hormone-binding globulin in adolescent boys
- Wang, Yutang, Charchar, Fadi
- Authors: Wang, Yutang , Charchar, Fadi
- Date: 2021
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Men have higher circulating levels of uric acid than women. This sex difference is suspected to be a result of suppressive effects of estradiol on uric acid. If so, estradiol would be inversely associated with circulating uric acid. This study aimed to test this hypothesis. This cross-sectional study included 9472 participants (weighted sample size of 184,342,210) aged 12–80 years from the 2013 to 2016 US National Health and Nutrition Examination Survey. Associations of sex hormones with uric acid were analyzed using weighted least squares regression, adjusting for demographic characteristics, lifestyle risk factors, and comorbidities. Neither free nor bioavailable estradiol was inversely associated with circulating uric acid in adolescent boys or girls, or adult men or women, or perimenopausal women after full adjustment. The sex difference in uric acid was established during adolescence as a result of a dramatic increase in uric acid in adolescent boys. During adolescence, the increase in estradiol in girls over time was accompanied by a relatively unchanged level of uric acid. All three fractions of estradiol (free, bioavailable, and total) were positively associated with uric acid in adolescent boys and girls after full adjustment. In adolescent boys, all three fractions of testosterone were positively associated with serum uric acid, and sex hormone-binding globulin was inversely associated with uric acid after full adjustment. These results suggest that estradiol is not inversely associated with circulating uric acid in adolescents and the establishment of sex difference in circulating uric acid during adolescence is associated with higher testosterone and lower sex hormone-binding globulin in adolescent boys. © 2021, The Author(s).
- Authors: Wang, Yutang , Charchar, Fadi
- Date: 2021
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Men have higher circulating levels of uric acid than women. This sex difference is suspected to be a result of suppressive effects of estradiol on uric acid. If so, estradiol would be inversely associated with circulating uric acid. This study aimed to test this hypothesis. This cross-sectional study included 9472 participants (weighted sample size of 184,342,210) aged 12–80 years from the 2013 to 2016 US National Health and Nutrition Examination Survey. Associations of sex hormones with uric acid were analyzed using weighted least squares regression, adjusting for demographic characteristics, lifestyle risk factors, and comorbidities. Neither free nor bioavailable estradiol was inversely associated with circulating uric acid in adolescent boys or girls, or adult men or women, or perimenopausal women after full adjustment. The sex difference in uric acid was established during adolescence as a result of a dramatic increase in uric acid in adolescent boys. During adolescence, the increase in estradiol in girls over time was accompanied by a relatively unchanged level of uric acid. All three fractions of estradiol (free, bioavailable, and total) were positively associated with uric acid in adolescent boys and girls after full adjustment. In adolescent boys, all three fractions of testosterone were positively associated with serum uric acid, and sex hormone-binding globulin was inversely associated with uric acid after full adjustment. These results suggest that estradiol is not inversely associated with circulating uric acid in adolescents and the establishment of sex difference in circulating uric acid during adolescence is associated with higher testosterone and lower sex hormone-binding globulin in adolescent boys. © 2021, The Author(s).