Physiology - Research Publications
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ItemCardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive-A New Preclinical Model(WILEY, 2018-06-05)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 Ca2+ operational levels and markedly increased L-type Ca2+ channel current. In HHR, prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed. CONCLUSIONS: Thus, the cardiomyocyte remodeling process in the etiology of this HFpEF model contrasts dramatically with the suppressed Ca2+ cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for HFpEF-and suggest a basis for new therapeutic strategies.
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ItemTrans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies(NATURE PORTFOLIO, 2019-01-03)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.
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ItemMolecular insights into genome-wide association studies of chronic kidney disease-defining traits(NATURE PUBLISHING GROUP, 2018-11-22)Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
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ItemMay Measurement Month 2017: Results of 39 national blood pressure screening programmes(OXFORD UNIV PRESS, 2019-04)Raised blood pressure is the biggest single risk factor responsible for mortality worldwide. Despite this, the majority of people with hypertension are unaware of having it, are untreated, or are on treatment but uncontrolled. May Measurement Month is a global campaign initiated by the International Society of Hypertension with the aim of raising awareness of high blood pressure. In the first year of the campaign in 2017, over 1.2 million people were screened in 80 countries across the world, finding over 100 000 people with hypertension who were not on treatment and over 150 000 people on anti-hypertensive treatment who were not controlled. The individual national results from 39 countries are presented in this supplement. In this article, we discuss the background to the campaign, along with some of the logistical and methodological challenges that were faced in setting up the campaign, and in collecting and analysing the data from such a large cross-sectional study. With the lessons learned from the 2017 campaign, the campaign was repeated in 2018 and is to be repeated again in 2019.
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ItemEpigenetic Modifications in Essential Hypertension(MDPI, 2016-04)Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world's leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual's risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development.
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ItemUrotensin-II System in Genetic Control of Blood Pressure and Renal Function(PUBLIC LIBRARY SCIENCE, 2013-12-31)Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.
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ItemThe Relation of Rapid Changes in Obesity Measures to Lipid Profile - Insights from a Nationwide Metabolic Health Survey in 444 Polish Cities(PUBLIC LIBRARY SCIENCE, 2014-01-31)OBJECTIVE: The impact of fast changes in obesity indices on other measures of metabolic health is poorly defined in the general population. Using the Polish accession to the European Union as a model of political and social transformation we examined how an expected rapid increase in body mass index (BMI) and waist circumference relates to changes in lipid profile, both at the population and personal level. METHODS: Through primary care centres in 444 Polish cities, two cross-sectional nationwide population-based surveys (LIPIDOGRAM 2004 and LIPIDOGRAM 2006) examined 15,404 and 15,453 adult individuals in 2004 and 2006, respectively. A separate prospective sample of 1,840 individuals recruited in 2004 had a follow-up in 2006 (LIPIDOGRAM PLUS). RESULTS: Two years after Polish accession to European Union, mean population BMI and waist circumference increased by 0.6% and 0.9%, respectively. This tracked with a 7.6% drop in HDL-cholesterol and a 2.1% increase in triglycerides (all p<0.001) nationwide. The direction and magnitude of the population changes were replicated at the personal level in LIPIDOGRAM PLUS (0.7%, 0.3%, 8.6% and 1.8%, respectively). However, increases in BMI and waist circumference were both only weakly associated with HDL-cholesterol and triglycerides changes prospectively. The relation of BMI to the magnitude of change in both lipid fractions was comparable to that of waist circumference. CONCLUSIONS: Moderate changes in obesity measures tracked with a significant deterioration in measures of pro-atherogenic dyslipidaemia at both personal and population level. These associations were predominantly driven by factors not measureable directly through either BMI or waist circumference.
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ItemA Novel Y-Specific Long Non-Coding RNA Associated with Cellular Lipid Accumulation in HepG2 cells and Atherosclerosis-related Genes(NATURE PORTFOLIO, 2017-12-01)There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
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ItemThe Y chromosome: a blueprint for men's health?(NATURE PUBLISHING GROUP, 2017-11)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.
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ItemLeukocyte telomere length variation due to DNA extraction method.(Springer Science and Business Media LLC, 2014-12-04)BACKGROUND: Telomere length is indicative of biological age. Shorter telomeres have been associated with several disease and health states. There are inconsistencies throughout the literature amongst relative telomere length measured by quantitative PCR (qPCR) and different extraction methods or kits used. We quantified whole-blood leukocyte telomere length using the telomere to single copy gene (T/S) ratio by qPCR in 20 young (18-25 yrs) men after extracting DNA using three common extraction methods: Lahiri and Nurnberger (high salt) method, PureLink Genomic DNA Mini kit (Life Technologies) and QiaAmp DNA Mini kit (Qiagen). Telomere length differences of DNA extracted from the three extraction methods was assessed by one-way analysis of variance (ANOVA). RESULTS: DNA purity differed between extraction methods used (P=0.01). Telomere length was impacted by the DNA extraction method used (P=0.01). Telomeres extracted using the Lahiri and Nurnberger method (mean T/S ratio: 2.43, range: 1.57-3.02) and PureLink Genomic DNA Mini Kit (mean T/S ratio: 2.57, range: 2.24-2.80) did not differ (P=0.13). Likewise, QiaAmp and Purelink-extracted telomeres were not statistically different (P=0.14). The Lahiri-extracted telomeres, however, were significantly shorter than those extracted using the QiaAmp DNA Mini Kit (mean T/S ratio: 2.71, range: 2.32-3.02; P=0.003). DNA purity was associated with telomere length. CONCLUSION: There are discrepancies between the length of leukocyte telomeres extracted from the same individuals according to the DNA extraction method used. DNA purity could be responsible for the discrepancy in telomere length but this will require validation studies. We recommend using the same DNA extraction kit when quantifying leukocyte telomere length by qPCR or when comparing different cohorts to avoid erroneous associations between telomere length and traits of interest.