A V Stanton

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (35)215.61 Total impact

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    ABSTRACT: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
    Nature Genetics 10/2014; · 29.65 Impact Factor
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    ABSTRACT: -Blood pressure (BP) is highly heritable, but our understanding of the genetic causes underlying variations in BP is incomplete. In this study we explored whether novel loci associated with BP could be identified using a genecentric approach in three community-based cohorts with accurate BP measurements.
    Circulation Cardiovascular Genetics 09/2014; · 6.73 Impact Factor
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    ABSTRACT: Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
    The American Journal of Human Genetics 02/2014; · 11.20 Impact Factor
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    ABSTRACT: Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
    Nature Genetics 04/2013; · 29.65 Impact Factor
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    ABSTRACT: Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
    Nature Genetics 04/2013; · 29.65 Impact Factor
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    ABSTRACT: Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
    Nature Genetics 04/2013; · 29.65 Impact Factor
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    ABSTRACT: Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 single nucleotide polymorphisms (SNPs) that capture variation in ∼2,100 candidate genes for cardiovascular phenotypes in 61,619 individuals of European ancestry from cohort studies in the US and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed ten previously known loci associated with SBP, DBP, MAP, or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P value<2.4 x 10(-6)). We then replicated these associations in an independent set of 65,886 individuals of European ancestry. Findings from eQTL analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease, left ventricular hypertrophy, or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
    Human Molecular Genetics 01/2013; · 6.68 Impact Factor
  • The Journal of Lipid Research 02/2012; · 4.73 Impact Factor
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    ABSTRACT: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 x 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery, and follow-up data identified SNPs significantly associated with BP at p < 8.56 x 10(-7) at four further loci (NPR3, FIFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
    American Journal of Human Genetics. 01/2011; 89(6):688-700.
  • Journal of Hypertension 01/2010; 28. · 4.22 Impact Factor
  • Atherosclerosis 11/2009; 207(1). · 3.71 Impact Factor
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    ABSTRACT: Fluid shear stress and mechanical wall stress may play a role in the formation of early atherosclerotic lesions, but these quantities are difficult to measure in vivo. Our objective was to quantify these parameters in normal subjects in a clinical setting, and to define regions of low wall shear stress and high mechanical stress. The right carotid bifurcations of five healthy male volunteers were investigated using a novel non-invasive technique which integrates magnetic resonance angiography, ultrasonography, tonometry and state-of-the-art computational fluid dynamics and solid mechanics models. Significant inter-subject variations in patterns as well as magnitude of wall shear stress and mechanical stress were found. In spite of individual variabilities, this study revealed that some regions of the artery wall are exposed simultaneously to low wall shear stress and high mechanical stress and that these regions correspond to areas where atherosclerotic plaque develops. The coexistence of regions of low wall shear stress and high tensile stress may be an important determinant of the formation of atheroma in human arteries.
    Journal of Biomechanics 11/2002; 35(10):1367-77. · 2.50 Impact Factor
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    ABSTRACT: Increased intima-media thickness of the common carotid artery predicts increased risk of myocardial infarction and stroke. Preliminary evidence suggests that a decrease in blood pressure (BP) is associated with diminished wall thickness. It is not known if all classes of anti-hypertensive agents have similar protective effects. In this double-blind parallel-group clinical trial, 69 previously untreated patients with hypertension were allocated randomly to 1 year of treatment with either amlodipine (5-10 mg daily) or lisinopril (5-20 mg daily). Doxazosin and bendrofluazide were added if required to achieve BP control. After 12 months of treatment, clinic BP, ambulatory BP and cardiac mass were reduced similarly by the two treatment regimens. Common carotid artery intima-media thickness decreased by 0.048 mm (95% confidence intervals -0.066, -0.031 mm) in the amlodipine-treated group, but decreased by only 0.027 mm (-0.046, -0.007 mm) in the lisinopril-treated group (P<0.05 for difference between treatments). Common carotid artery lumen diameter declined significantly only in patients treated with lisinopril [amlodipine, -0.02 mm (-0.14, 0.10 mm); lisinopril, -0.21 mm (-0.32, -0.11 mm); P<0.02], while intima-media area declined similarly in the two treatment groups [amlodipine -1.32 mm(2) (-1.91, -0.74 mm(2)), lisinopril -1.26 mm(2) (-1.80, -0.72 mm(2)); not significant]. The results confirm that a decrease in BP causes regression of structural changes in the carotid artery in hypertensive patients. The nature of the structural regression differed markedly between the two treatment regimens, in spite of similar decreases in BP. The calcium channel blocker induced greater regression of common carotid artery intima-media thickness than the angiotensin-converting enzyme inhibitor. However, carotid artery wall mass, as indicated by intima-media area, was reduced to a similar extent by the two treatments. It remains to be established whether such differences confer a prognostic advantage.
    Clinical Science 12/2001; 101(5):455-64. · 5.63 Impact Factor
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    ABSTRACT: Quantification of retinal vascular change is difficult and manual measurements of vascular features are slow and subject to observer bias. These problems may be overcome using computer algorithms. Three automated methods and a manual method for measurement of arteriolar diameters from digitised red-free retinal photographs were compared. 60 diameters (in pixels) measured by manual identification of vessel edges in red-free retinal images were compared with diameters measured by (1) fitting vessel intensity profiles to a double Gaussian function by non-linear regression, (2) a standard edge detection algorithm (Sobel), and (3) determination of points of maximum intensity variation by a sliding linear regression filter (SLRF). Method agreement was analysed using Bland-Altman plots and the repeatability of each method was assessed. Diameter estimations obtained using the SLRF method were the least scattered although diameters obtained were approximately 3 pixels greater than those measured manually. The SLRF method was the most repeatable and the Gaussian method less so. The Sobel method was the least consistent owing to frequent misinterpretation of the light reflex as the vessel edge. Of the three automated methods compared, the SLRF method was the most consistent (defined as the method producing diameter estimations with the least scatter) and the most repeatable in measurements of retinal arteriolar diameter. Application of automated methods of retinal vascular analysis may be useful in the assessment of cardiovascular and other diseases.
    British Journal of Ophthalmology 02/2001; 85(1):74-9. · 2.81 Impact Factor
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    ABSTRACT: The optimal design of vascular networks maximizes circulatory efficiency while minimizing power costs. We investigated the effects of acute changes in vascular tone on retinal arteriolar network geometry. Six hypertensive and six normotensive subjects each breathed air, 5% CO(2) (with 12% O(2)), and 100% O(2) for 5 min periods in random order. Retinal photographs were taken at the end of each test period. Bifurcation angles and arteriolar diameters were measured using operator-directed image analysis, and junction exponents were calculated. Arteriolar diameters narrowed on breathing O(2). The magnitude of this change was significantly greater in normotensive than in hypertensive subjects. Angles narrowed in normotensive subjects, but not significantly in hypertensive subjects. Arteriolar diameters increased significantly on breathing CO(2) in normotensive but not in hypertensive subjects, but there were no changes in angles. Despite changes in diameter, junction exponents did not change under any conditions. Vascular reactivity in the retinal arteriolar bed appears to be diminished in hypertensive subjects. The failure of junction exponents to change, despite alterations in diameter, suggests that arteriolar diameters at retinal bifurcations adhere to optimality principles when exposed to acute vasoactive stress. As vasoconstriction is associated with the narrowing of bifurcation angles, previous observations showing narrowed angles in hypertensive subjects could be explained by increased tone in the retinal arteriolar bed.
    Clinical Science 01/2001; 99(6):483-8. · 5.63 Impact Factor
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    ABSTRACT: The pulsatile flow in an anatomically realistic compliant human carotid bifurcation was simulated numerically. Pressure and mass flow waveforms in the carotid arteries were obtained from an individual subject using non-invasive techniques. The geometry of the computational model was reconstructed from magnetic resonance angiograms. Maps of time-average wall shear stress, contours of velocity in the flow field as well as wall movement and tensile stress on the arterial wall are all presented. Inconsistent with previous findings from idealised geometry models, flow in the carotid sinus is dominated by a strong helical flow accompanied by a single secondary vortex motion. This type of flow is induced primarily by the asymmetry and curvature of the in vivo geometry. Flow simulations have been carried out under the rigid wall assumption and for the compliant wall, respectively. Comparison of the results demonstrates the quantitative influence of the vessel wall motion. Generally there is a reduction in the magnitude of wall shear stress, with its degree depending on location and phase of the cardiac cycle. The region of slow or reversed flow was greater, in both spatial and temporal terms in the compliant model, but the global characteristics of the flow and stress patterns remain unchanged. The analysis of mechanical stresses on the vessel surface shows a complicated stress field. Stress concentration occurs at both the anterior and posterior aspects of the proximal internal bulb. These are also regions of low wall shear stress. The comparison of computed and measured wall movement generally shows good agreement.
    Journal of Biomechanics 09/2000; 33(8):975-84. · 2.50 Impact Factor
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    ABSTRACT: Increased intima-media thickness (IMT) of the common carotid artery is associated with many cardiovascular risk factors and predicts increased risk of myocardial infarction and stroke. Preliminary evidence suggests that lowering of BP may reduce IMT and retard progression of atherosclerosis. It is not known if all classes of antihypertensive agents have similar protective effects on the vasculature. In this double blind single centre study, 69 previously untreated hypertensive patients were randomized to treatment with a calcium antagonist, amlodipine (A) (5–10mg daily, n=35), or to treatment with an ACE inhibitor, lisinopril (L) (5–20mg daily, n=34). Doxazosin (1–8 mg daily) and bendrofluazide (2.5–5 mg daily) were added as required so as to achieve a target clinic BP of less than 140 mm Hg systolic and less than 90 mm Hg diastolic. Non-invasive measurements of right and left distal CC IMT, lumen diameter (D), and intima media area (IMA) were made, using high resolution ultrasonography. Baseline CC IMT, D, IMA and BP did not differ between the two treatment groups. Mean differences (95% confidence intervals) from baseline at 14 weeks, 26 weeks and at study end are shown: (See Table)Despite similar BP lowering, previously untreated hypertensive patients treated with amlodipine showed earlier and greater regression of common carotid IMT than patients treated with lisinopril. However, carotid wall mass, as measured by IMA, was reduced to a similar extent in the two treatment groups. Vascular regression in the amlodipine treated patients was solely due to a reduction in wall thickness, whilst both IMT and vascular diameter decreased in those patients treated with lisinopril. It remains to be established whether the greater reduction in common carotid IMT achieved in amlodipine treated patients confers additional prognostic advantage.
    American Journal of Hypertension 06/2000; · 3.40 Impact Factor
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    ABSTRACT: Afro-Caribbeans have a greater prevalence of diabetes, hypertension, left ventricular hypertrophy and obesity compared with White Europeans. In spite of this, they have a lower prevalence of ischaemic heart disease. An increased carotid intima-media thickness (IMT) has recently been found to be associated with the majority of known cardiovascular risk factors, including left ventricular hypertrophy. It is widely believed that intima-media thickening may represent an early marker for the development of atheroma. Afro-Caribbean subjects with their clustering of cardiovascular risk factors may be expected to have an increased IMT compared with White Europeans. In order to test this hypothesis 32 age, sex and blood pressure matched Black and White hypertensives underwent bilateral common carotid and femoral ultrasonography and echocardiography.The Afro-Caribbean group had a significantly greater left ventricular mass index compared with the White Europeans (mean±SEM 137±7.3 versus 115±8.5 g/m2, p
    American Journal of Hypertension 06/2000; · 3.40 Impact Factor
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    ABSTRACT: The carotid bifurcation is a common site for clinically significant atherosclerosis, and the development of this disease may be influenced by the local hemodynamic environment. It has been shown that vessel geometry and pulsatile flow conditions are the predominant factors that determine the detailed blood flow patterns at the carotid bifurcation. This study was initiated to quantify the velocity profiles and wall shear stress (WSS) distributions in an anatomically true model of the human carotid bifurcation using data acquired from magnetic resonance (MR) imaging scans of an individual subject. A numerical simulation approach combining the image processing and computational fluid dynamics (CFD) techniques was developed. Individual vascular anatomy and pulsatile flow conditions were all incorporated into the computer model. It was found that the geometry of the carotid bifurcation was highly complex, involving helical curvature and out-of-plane branching. These geometrical features resulted in patterns of flow and wall shear stress significantly different from those found in simplified planar carotid bifurcation models. Comparisons between the predicted flow patterns and MR measurement demonstrated good quantitative agreement.
    Journal of Magnetic Resonance Imaging 04/2000; 11(3):299-311. · 2.79 Impact Factor
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    ABSTRACT: Am J Hypertens (2000) 13, 192A–193A; doi:10.1016/S0895-7061(00)00678-6 B017: A comparison of manual and 3 automated methods of determining retinal arteriolar diameters J.N. Chapman1, N. Witt1, A.V. Stanton1, X. Gau1, S.A. Thom1 and A.D. Hughes11Clinical Pharmacology, School of Medicine at NHLI, ICSTM, St Mary's Hospital, London, UK
    American Journal of Hypertension 03/2000; · 3.40 Impact Factor

Publication Stats

593 Citations
215.61 Total Impact Points

Institutions

  • 2013
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 1999–2001
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1996–2001
    • Imperial College London
      • Department of Chemical Engineering
      Londinium, England, United Kingdom
  • 1995–2000
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom