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1.  Genome-Wide Association Studies of Hypertension: Light at the End of the Tunnel 
Despite its significant genetic component, the study of hypertension by genome-wide association presents more challenges than other common complex diseases. Its high prevalence, heterogeneity, and somewhat unclear definition are the challenges that need to be overcome on one hand. On the other hand, there are issues of small effect sizes and pleiotropism that are not specific to hypertension alone but nonetheless magnify the problems of genetic dissection when coupled with phenotypic misclassification. We discuss issues of study design and summarise published genome-wide association studies (GWASs) of hypertension and blood pressure. With careful study design and analysis success is possible, as demonstrated by the recent large-scale studies. Following these, there is still further scope to advance the field through high fidelity phenotyping and deep sequencing.
doi:10.4061/2010/509581
PMCID: PMC2958365  PMID: 20981355
3.  Novel Biomarkers for Predicting Preeclampsia 
Trends in Cardiovascular Medicine  2008;18(5-24):186-194.
Preeclampsia is a major cause of maternal morbidity and mortality worldwide. Despite decades of research into the condition, the ability of clinicians to predict preeclampsia prior to the onset of symptoms has not improved significantly. In this review, we will examine the pathophysiology underlying preeclampsia and will look at potential biomarkers for early prediction and diagnosis. In addition, we will explore potential future areas of research into the condition.
doi:10.1016/j.tcm.2008.07.002
PMCID: PMC2577131  PMID: 18790389
4.  Mitochondrial reactive oxygen species enhance AMP-activated protein kinase activation in the endothelium of patients with coronary artery disease and diabetes 
The aim of the present study was to determine whether the endothelial dysfunction associated with CAD (coronary artery disease) and T2D (Type 2 diabetes mellitus) is concomitant with elevated mtROS (mitochondrial reactive oxygen species) production in the endothelium and establish if this, in turn, regulates the activity of endothelial AMPK (AMP-activated protein kinase). We investigated endothelial function, mtROS production and AMPK activation in saphenous veins from patients with advanced CAD. Endothelium-dependent vasodilation was impaired in patients with CAD and T2D relative to those with CAD alone. Levels of mitochondrial H2O2 and activity of AMPK were significantly elevated in primary HSVECs (human saphenous vein endothelial cells) from patients with CAD and T2D compared with those from patients with CAD alone. Incubation with the mitochondria-targeted antioxidant, MitoQ10 significantly reduced AMPK activity in HSVECs from patients with CAD and T2D but not in cells from patients with CAD alone. Elevated mtROS production in the endothelium of patients with CAD and T2D increases AMPK activation, supporting a role for the kinase in defence against oxidative stress. Further investigation is required to determine whether pharmacological activators of AMPK will prove beneficial in the attenuation of endothelial dysfunction in patients with CAD and T2D.
doi:10.1042/CS20120239
PMCID: PMC3903000  PMID: 23057846
AMP-activated protein kinase (AMPK); coronary artery disease (CAD); diabetes; endothelium; mitochondrion; oxidative stress; AICAR, 5-amino-4-imidazolecarboxamide riboside; AMPK, AMP-activated protein kinase; BMI, body mass index; CABG, coronary artery bypass graft; CAD, coronary artery disease; CaMKK, Ca2+/calmodulin-dependent kinase kinase; CVD, cardiovascular disease; 2DG, 2-deoxy-D-glucose; DTPP, decyl triphenylphosphonium bromide; eNOS, endothelial nitric oxide synthase; GAPDH, encoding glyceraldehyde-3-phosphate dehydrogenase; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; HSVEC, human saphenous vein endothelial cell; HUVEC, human umbilical vein endothelial cell; LDL, low-density lipoprotein; ROS, reactive oxygen species; mtROS, mitochondrial ROS; PRKAA1, encoding the AMPK-α1 catalytic subunit; SOD, superoxide dismutase; T2D, Type 2 diabetes; vWF, von Willebrand factor
5.  Upregulation of junctional adhesion molecule-A is a putative prognostic marker of hypertension 
Cardiovascular Research  2012;96(3):552-560.
Aims
Establishing biochemical markers of pre-hypertension and early hypertension could help earlier diagnostics and therapeutic intervention. We assess dynamics of junctional adhesion molecule-A (JAM-A) expression in rat models of hypertension and test whether JAM-A expression could be driven by angiotensin (ANG) II and whether JAM-A contributes to the progression of hypertension. We also compare JAM-A expression in normo- and hypertensive humans.
Methods and results
In pre-hypertensive and spontaneously hypertensive rats (SHRs), JAM-A protein was overexpressed in the brainstem microvasculature, lung, liver, kidney, spleen, and heart. JAM-A upregulation at early and late stages was even greater in the stroke-prone SHR. However, JAM-A was not upregulated in leucocytes and platelets of SHRs. In Goldblatt 2K-1C hypertensive rats, JAM-A expression was augmented before any increase in blood pressure, and similarly JAM-A upregulation preceded hypertension caused by peripheral and central ANG II infusions. In SHRs, ANG II type 1 (AT1) receptor antagonism reduced JAM-A expression, but the vasodilator hydralazine did not. Body-wide downregulation of JAM-A with Vivo-morpholinos in juvenile SHRs delayed the progression of hypertension. In the human saphenous vein, JAM-A mRNA was elevated in hypertensive patients with untreated hypertension compared with normotensive patients but reduced in patients treated with renin–angiotensin system antagonists.
Conclusion
Body-wide upregulation of JAM-A in genetic and induced models of hypertension in the rat precedes the stable elevation of arterial pressure. JAM-A upregulation may be triggered by AT1 receptor-mediated signalling. An association of JAM-A with hypertension and sensitivity to blockers of ANG II signalling were also evident in humans. We suggest a prognostic and possibly a pathogenic role of JAM-A in arterial hypertension.
doi:10.1093/cvr/cvs273
PMCID: PMC3500047  PMID: 22918977
Adhesion molecules; JAM-A; Hypertension; Angiotensin; Vasculature
6.  Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function 
Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
doi:10.1164/rccm.201102-0192OC
PMCID: PMC3398416  PMID: 21965014
FEV1; FVC; genome-wide association study; modeling risk
7.  Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome 
Lancet  2012;379(9819):915-922.
Summary
Background
A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.
Methods
We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.
Findings
Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.
Interpretation
The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.
Funding
British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.
doi:10.1016/S0140-6736(11)61453-0
PMCID: PMC3314981  PMID: 22325189
8.  Differences in the Evolution of the Ischemic Penumbra in Stroke-Prone Spontaneously Hypertensive and Wistar-Kyoto Rats 
Background and Purpose
Stroke-prone spontaneously hypertensive rats (SHRSP) are a highly pertinent stroke model with increased sensitivity to focal ischemia compared with the normotensive reference strain (Wistar-Kyoto rats; WKY). Study aims were to investigate temporal changes in the ischemic penumbra in SHRSP compared with WKY.
Methods
Permanent middle cerebral artery occlusion was induced with an intraluminal filament. Diffusion- (DWI) and perfusion- (PWI) weighted magnetic resonance imaging was performed from 1 to 6 hours after stroke, with the PWI-DWI mismatch used to define the penumbra and thresholded apparent diffusion coefficient (ADC) maps used to define ischemic damage.
Results
There was significantly more ischemic damage in SHRSP than in WKY from 1 to 6 hours after stroke. The perfusion deficit remained unchanged in WKY (39.9±6 mm2 at 1 hour, 39.6±5.3 mm2 at 6 hours) but surprisingly increased in SHRSP (43.9±9.2 mm2 at 1 hour, 48.5±7.4 mm2 at 6 hours; P=0.01). One hour after stroke, SHRSP had a significantly smaller penumbra (3.4±5.8 mm2) than did WKY (9.7±3.8, P=0.03). In WKY, 56% of the 1-hour penumbra area was incorporated into the ADC lesion by 6 hours, whereas in SHRSP, the small penumbra remained static owing to the temporal increase in both ADC lesion size and perfusion deficit.
Conclusions
First, SHRSP have significantly more ischemic damage and a smaller penumbra than do WKY within 1 hour of stroke; second, the penumbra is recruited into the ADC abnormality over time in both strains; and third, the expanding perfusion deficit in SHRSP predicts more tissue at risk of infarction. These results have important implications for management of stroke patients with preexisting hypertension and suggest ischemic damage could progress at a faster rate and over a longer time frame in the presence of hypertension.
doi:10.1161/STROKEAHA.109.559021
PMCID: PMC3145096  PMID: 19797186
ischemic penumbra; stroke; hypertension; magnetic resonance imaging
9.  Genetics of hypertension: From experimental animals to humans 
Biochimica et Biophysica Acta  2010;1802(12):1299-1308.
Essential hypertension affects 20 to 30% of the population worldwide and contributes significantly to cardiovascular mortality and morbidity. Heridability of blood pressure is around 15 to 40% but there are also substantial environmental factors affecting blood pressure variability. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Animal models of hypertension, particularly in the rat, have led to the discovery of quantitative trait loci harbouring one or several hypertension related genes, but translation of these findings into human essential hypertension remains challenging. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models.
doi:10.1016/j.bbadis.2009.12.006
PMCID: PMC2977068  PMID: 20035862
GWAS, Genome-wide association study; QTL, Quantitative trait locus; SHR, Spontaneously hypertensive rat; SHRSP, Stroke-prone spontaneously hypertensive rat; SNP, Single nucleotide polymorphism; WTCCC, Wellcome Trust Case Control Consortium; Hypertension; Genetics; Rodents; Human
10.  Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology 
PLoS ONE  2010;5(9):e13051.
Background
The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).
Methodology/Principal Findings
Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92–95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81–94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81–88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed.
Conclusions/Significance
These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling.
doi:10.1371/journal.pone.0013051
PMCID: PMC2946909  PMID: 20927192
11.  Gene expression profiling in whole blood of patients with coronary artery disease 
Owing to the dynamic nature of the transcriptome, gene expression profiling is a promising tool for discovery of disease-related genes and biological pathways. In the present study, we examined gene expression in whole blood of 12 patients with CAD (coronary artery disease) and 12 healthy control subjects. Furthermore, ten patients with CAD underwent whole-blood gene expression analysis before and after the completion of a cardiac rehabilitation programme following surgical coronary revascularization. mRNA and miRNA (microRNA) were isolated for expression profiling. Gene expression analysis identified 365 differentially expressed genes in patients with CAD compared with healthy controls (175 up- and 190 down-regulated in CAD), and 645 in CAD rehabilitation patients (196 up- and 449 down-regulated post-rehabilitation). Biological pathway analysis identified a number of canonical pathways, including oxidative phosphorylation and mitochondrial function, as being significantly and consistently modulated across the groups. Analysis of miRNA expression revealed a number of differentially expressed miRNAs, including hsa-miR-140-3p (control compared with CAD, P=0.017), hsa-miR-182 (control compared with CAD, P=0.093), hsa-miR-92a and hsa-miR-92b (post- compared with pre-exercise, P<0.01). Global analysis of predicted miRNA targets found significantly reduced expression of genes with target regions compared with those without: hsa-miR-140-3p (P=0.002), hsa-miR-182 (P=0.001), hsa-miR-92a and hsa-miR-92b (P=2.2×10−16). In conclusion, using whole blood as a ‘surrogate tissue’ in patients with CAD, we have identified differentially expressed miRNAs, differentially regulated genes and modulated pathways which warrant further investigation in the setting of cardiovascular function. This approach may represent a novel non-invasive strategy to unravel potentially modifiable pathways and possible therapeutic targets in cardiovascular disease.
doi:10.1042/CS20100043
PMCID: PMC2922838  PMID: 20528768
coronary artery disease (CAD); gene expression; microRNA (miRNA); mitochondrion; oxidative phosphorylation; rehabilitation programme; ATP5I, ATP synthase, H+ transporting, mitochondrial F0 complex, subunit E; ATP5L, ATP synthase, H+ transporting, mitochondrial F0 complex, subunit G; CABG, coronary artery bypass graft; CAD, coronary artery disease; CASP3, caspase 3; COX7C, cytochrome c oxidase subunit VIIc, CRP, C-reactive protein; FDR, False Discovery Rate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; miRNA, microRNA; NDUFA1, NADH dehydrogenase (ubiquinone) 1α subcomplex 1; NDUFB3, NADH dehydrogenase (ubiquinone) 1β subcomplex 3; qRT-PCR, quantitative real-time PCR; ROS, reactive oxygen species; UQCRQ, ubiquinol-cytochrome c reductase, complex III subunit VII; UTR, untranslated region
12.  Reduced LDL-cholesterol levels in patients with coronary artery disease are paralelled by improved endothelial function: An observational study in patients from 2003 and 2007 
Atherosclerosis  2010;211(1):271-277.
Objective
Recent guidelines recommend more aggressive lipid-lowering in secondary prevention protocols. We examined whether this resulted in improved endothelial function.
Methods
We studied saphenous vein specimens of patients undergoing surgical coronary revascularisation in 2007 and compared results with those of patients examined in 2003. Endothelium-dependent vasodilation was assessed by relaxation to calcium ionophore A23187, and vascular superoxide production by lucigenin enhanced chemiluminescence.
Results
Statin dose increased from 26 ± 16 mg/d in 2003 to 37 ± 17 mg/d in 2007 (P < 0.001), and total (4.0 ± 0.9 mmol/L vs 4.8 ± 1.0 mmol/L) and LDL-cholesterol levels (2.0 ± 0.7 mmol/L vs 3.0 ± 0.9 mmol/L) were lower in 2007 compared to 2003 (P < 0.001; n = 90 each). Endothelium-dependent vasodilation was greater in 2007 (44 ± 15%) compared to 2003 (28 ± 12%; n = 36 each; P < 0.001). Vascular superoxide derived from endothelial NO synthase (eNOS) was lower in 2007 than in 2003 (reduction by NG-nitro-l-arginine-methyl ester, 0.29 ± 0.21 nmol/(mg min) vs 0.09 ± 0.20 nmol/(mg min); P = 0.002). In linear regression analysis, LDL-cholesterol levels have been shown to be the major determinant of endothelial function in the combined 2003 and 2007 cohort.
Conclusion
Intensive lipid-lowering is associated with improved endothelial function and reduced superoxide production from eNOS. Further improvement in vascular function could be achieved by targeting other sources of superoxide including xanthine oxidase.
doi:10.1016/j.atherosclerosis.2010.01.014
PMCID: PMC2946556  PMID: 20138279
Cholesterol; Endothelial function; Coronary disease; Statins; Oxidative stress
13.  Predictive response-relevant clustering of expression data provides insights into disease processes 
Nucleic Acids Research  2010;38(20):6831-6840.
This article describes and illustrates a novel method of microarray data analysis that couples model-based clustering and binary classification to form clusters of `response-relevant' genes; that is, genes that are informative when discriminating between the different values of the response. Predictions are subsequently made using an appropriate statistical summary of each gene cluster, which we call the `meta-covariate' representation of the cluster, in a probit regression model. We first illustrate this method by analysing a leukaemia expression dataset, before focusing closely on the meta-covariate analysis of a renal gene expression dataset in a rat model of salt-sensitive hypertension. We explore the biological insights provided by our analysis of these data. In particular, we identify a highly influential cluster of 13 genes—including three transcription factors (Arntl, Bhlhe41 and Npas2)—that is implicated as being protective against hypertension in response to increased dietary sodium. Functional and canonical pathway analysis of this cluster using Ingenuity Pathway Analysis implicated transcriptional activation and circadian rhythm signalling, respectively. Although we illustrate our method using only expression data, the method is applicable to any high-dimensional datasets. Expression data are available at ArrayExpress (accession number E-MEXP-2514) and code is available at http://www.dcs.gla.ac.uk/inference/metacovariateanalysis/.
doi:10.1093/nar/gkq550
PMCID: PMC2978340  PMID: 20571087
14.  CE-MS analysis of the human urinary proteome for biomarker discovery and disease diagnostics 
Owing to its availability, ease of collection, and correlation with pathophysiology of diseases, urine is an attractive source for clinical proteomics. However, many proteomic studies have had only limited clinical impact, due to factors such as modest numbers of subjects, absence of disease controls, small numbers of defined biomarkers, and diversity of analytical platforms. Therefore, it is difficult to merge biomarkers from different studies into a broadly applicable human urinary proteome database. Ideally, the methodology for defining the biomarkers should combine a reasonable analysis time with high resolution, thereby enabling the profiling of adequate samples and recognition of sufficient features to yield robust diagnostic panels. Capillary electrophoresis coupled to mass spectrometry (CE-MS), which was used to analyze urine samples from healthy subjects and patients with various diseases, is a suitable approach for this task. The database of these datasets compiled from the urinary peptides enabled the diagnosis, classification, and monitoring of a wide range of diseases. CE-MS exhibits excellent performance for biomarker discovery and allows subsequent biomarker sequencing independent of the separation platform. This approach may elucidate the pathogenesis of many diseases, and better define especially renal and urological disorders at the molecular level.
doi:10.1002/prca.200800024
PMCID: PMC2815342  PMID: 20130789
Capillary electrophoresis; database; mass spectrometry; proteomics; urine
15.  Capillary electrophoresis–mass spectrometry as a powerful tool in biomarker discovery and clinical diagnosis: an update of recent developments 
Mass spectrometry reviews  2009;28(5):703-724.
Proteome analysis has emerged as a powerful technology to decipher biological processes. One of the main goals is to discover biomarkers for diseases from tissues and body fluids. However, the complexity and wide dynamic range of protein expression present an enormous challenge to separation technologies and mass spectrometry (MS). In this review, we examine the limitations of proteomics, and aim towards the definition of the current key prerequisites. We focus on capillary electrophoresis coupled to mass spectrometry (CE-MS), because this technique continues to show great promise. We discuss CE-MS from an application point of view, and evaluate its merits and vices for biomarker discovery and clinical applications. Finally, we present several examples on the use of CE-MS to determine urinary biomarkers and implications for disease diagnosis, prognosis, and therapy evaluation.
doi:10.1002/mas.20205
PMCID: PMC2720435  PMID: 18973238
Capillary electrophoresis; mass spectrometry; biomarker; urine; clinical proteomics; peptides
16.  Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function 
Journal of Hypertension  2014;32(3):555-564.
Objective:
Mitochondria-derived reactive oxygen species (ROS) play important roles in the development of cardiovascular disease highlighting the need for novel targeted therapies. This study assessed the potential therapeutic benefit of combining the mitochondria-specific antioxidant, MitoQ10, with the low-dose angiotensin receptor blocker (ARB), losartan, on attenuation of hypertension and left ventricular hypertrophy. In parallel, we investigated the impact of MitoQ10 on cardiac hypertrophy in a neonatal cardiomyocyte cell line.
Methods and results:
Eight-week-old male stroke-prone spontaneously hypertensive rats (SHRSPs, n = 8–11) were treated with low-dose losartan (2.5 mg/kg per day); MitoQ10 (500 μmol/l); a combination of MitoQ10 and losartan (M + L); or vehicle for 8 weeks. Systolic pressure and pulse pressure were significantly lower in M + L rats (167.1 ± 2.9 mmHg; 50.2 ± 2.05 mmHg) than in untreated SHRSP (206.6 ± 9 mmHg, P < 0.001; 63.7 ± 2.7 mmHg, P = 0.001) and demonstrated greater improvement than MitoQ10 or low-dose losartan alone, as measured by radiotelemetry. Left ventricular mass index was significantly reduced from 22.8 ± 0.74 to 20.1 ± 0.61 mg/mm in the combination group (P < 0.05). Picrosirius red staining showed significantly reduced cardiac fibrosis in M + L rats (0.82 ± 0.22 A.U.) compared with control (5.94 ± 1.35 A.U., P < 0.01). In H9c2 neonatal rat cardiomyocytes, MitoQ10 significantly inhibited angiotensin II mediated hypertrophy in a dose-dependent manner (500 nmol/l MitoQ10 153.7 ± 3.1 microns vs. angiotensin II 200.1 ± 3.6 microns, P < 0.001).
Conclusion:
Combining MitoQ10 and low-dose losartan provides additive therapeutic benefit, significantly attenuating development of hypertension and reducing left ventricular hypertrophy. In addition, MitoQ10 mediates a direct antihypertrophic effect on rat cardiomyocytes in vitro. MitoQ10 has potential as a novel therapeutic intervention in conjunction with current antihypertensive drugs.
doi:10.1097/HJH.0000000000000054
PMCID: PMC3914904  PMID: 24309493
cardiac fibrosis; cardiac hypertrophy; hypertension; mitochondria; reactive oxygen species
17.  Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB–FKBPL–NOTCH4 region of chromosome 6p21.3 
Human Molecular Genetics  2012;21(18):4138-4150.
Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)–HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10−72), CFH (complement factor H) (P =2.3 × 10−47), C2 (complement component 2)–CFB (complement factor B) (P =5.2 × 10−9), C3 (complement component 3) (P =2.2 × 10−3) and CFI (P =3.6 × 10−3) and with more recently reported risk loci at VEGFA (P =1.2 × 10−3) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)–FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10−7, replication P =3.0 × 10−4, combined P =1.3 × 10−9, odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3–1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10−8, replication P =3.8 × 10−5, combined P =2.0 × 10−11, OR = 1.3, 95% CI = 1.2–1.4). These associations remained significant in conditional analyses which included the adjacent C2–CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.
doi:10.1093/hmg/dds225
PMCID: PMC3428154  PMID: 22694956
18.  Impaired renal function impacts negatively on vascular stiffness in patients with coronary artery disease 
BMC Nephrology  2013;14:173.
Background
Chronic kidney disease (CKD) and coronary artery disease (CAD) are independently associated with increased vascular stiffness. We examined whether renal function contributes to vascular stiffness independently of CAD status.
Methods
We studied 160 patients with CAD and 169 subjects without CAD. The 4-variable MDRD formula was used to estimate glomerular filtration rate (eGFR); impaired renal function was defined as eGFR <60 mL/min. Carotid-femoral pulse wave velocity (PWV) was measured with the SphygmoCor® device. Circulating biomarkers were assessed in plasma using xMAP® multiplexing technology.
Results
Patients with CAD and impaired renal function had greater PWV compared to those with CAD and normal renal function (10.2 [9.1;11.2] vs 7.3 [6.9;7.7] m/s; P < 0.001). In all patients, PWV was a function of eGFR (β = −0.293; P < 0.001) even after adjustment for age, sex, systolic blood pressure, body mass index and presence or absence of CAD. Patients with CAD and impaired renal function had higher levels of adhesion and inflammatory molecules including E-selectin and osteopontin (all P < 0.05) compared to those with CAD alone, but had similar levels of markers of oxidative stress.
Conclusions
Renal function is a determinant of vascular stiffness even in patients with severe atherosclerotic disease. This was paralleled by differences in markers of cell adhesion and inflammation. Increased vascular stiffness may therefore be linked to inflammatory remodeling of the vasculature in people with impaired renal function, irrespective of concomitant atherosclerotic disease.
doi:10.1186/1471-2369-14-173
PMCID: PMC3751647  PMID: 23937620
Coronary artery disease; Chronic kidney disease; Vascular stiffness
19.  Genome-wide association study using a high-density SNP-array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of eNOS 
Hypertension  2011;59(2):248-255.
Essential hypertension is a multi-factorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a two-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions.
The discovery phase consisted of 1,865 cases and 1,750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1,385 cases and 1,246 controls that were genotyped with a custom array of 14,055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial nitric oxide synthase (eNOS) gene (odds ratio 1.54; 95% CI 1.37-1.73; combined p=2.58·10−13). A meta-analysis, using other in-silico/de novo genotyping data for a total of 21714 subjects, resulted in an overall odds ratio of 1.34 (95% CI 1.25-1.44, p=1.032·10−14). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI 0.16-3.66) for systolic and 1.40 (95% CI 0.25-2.55) for diastolic blood pressure. We identified in-silico a potential binding site for ETS transcription-factors directly next to rs3918226, suggesting a potential modulation of eNOS expression. Biological evidence links eNOS with hypertension, as it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
doi:10.1161/HYPERTENSIONAHA.111.181990
PMCID: PMC3272453  PMID: 22184326
genetic epidemiology; risk factors; genetics-association studies; nitric oxide; Essential Hypertension
20.  Polymorphisms in the WNK1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion 
PLoS ONE  2009;4(4):e5003.
WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p<10−7). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (>10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.
doi:10.1371/journal.pone.0005003
PMCID: PMC2661139  PMID: 19347040
21.  Generation Scotland: the Scottish Family Health Study; a new resource for researching genes and heritability 
BMC Medical Genetics  2006;7:74.
Background
Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland.
Methods/Design
Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process.
Discussion
As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population.
doi:10.1186/1471-2350-7-74
PMCID: PMC1592477  PMID: 17014726

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