Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
- Authors: Charchar, Fadi
- Date: 2011
- Type: Text , Journal article
- Relation: Nature Vol. 478, no. 7367 (2011), p. 103-109
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- Description: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140mmg Hg systolic blood pressure ≥90mmg Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3 GUCY1B3, NPR3 C5orf23, ADM, FURIN FES, GOSR2, GNAS EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. © 2011 Macmillan Publishers Limited. All rights reserved. Please note that there are two hundred and six authors for this article therefore only the Federation University Australia affiliate is provided in this record.
- Description: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140mmg Hg systolic blood pressure ≥90mmg Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3 GUCY1B3, NPR3 C5orf23, ADM, FURIN FES, GOSR2, GNAS EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. © 2011 Macmillan Publishers Limited. All rights reserved. Please note that there are two hundred and six authors for this article and we have included only the University of Ballarat Affiliate.
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
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- 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**
Circulating microRNAs and hypertension - From new insights into blood pressure regulation to biomarkers of cardiovascular risk
- Authors: Romaine, Simon , Charchar, Fadi , Samani, Nilesh , Tomaszewski, Maciej
- Date: 2016
- Type: Text , Journal article
- Relation: Current Opinion in Pharmacology Vol. 27, no. (2016), p. 1-7
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
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- Description: Hypertension is a leading cause of cardiovascular morbidity and mortality worldwide, yet the molecular mechanisms underpinning the development of high blood pressure remain incompletely understood. MicroRNAs are small, non-coding RNA molecules approximately 22 nucleotides in length that act as post-transcriptional regulators of gene expression. We highlight, through a review of recent literature, that studies on circulating microRNAs have provided novel insights into blood pressure regulation. They have also complemented tissue-based and animal-based experiments in shedding new light on our understanding of established pathways in hypertension, such as the renin-angiotensin system. Despite a number of challenges, we believe microRNAs herald particular potential in becoming effective biomarkers of target-organ damage in hypertension. © 2016 Elsevier Ltd. All rights reserved.
The emerging role of non-coding RNA in essential hypertension and blood pressure regulation
- 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.