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[show abstract]
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ABSTRACT: Background Both platelet function and heart disease show strong genetic components, many of which remain to be elucidated. Materials and methods The roles of candidate polymorphisms in ten platelet-associated genes were compared between 1,237 Acute Coronary Syndrome
(ACS) cases (with myocardial infarction and unstable angina) and 386 controls, from an Irish Caucasian population. Additionally,
361 stable angina patients were investigated. Two genes of interest were followed up in a separate Irish study of 1,484 individuals
(577 with IHD and 907 unaffected). Results The GALNT4 (N-acetyl galactosaminyl transferase 4) 506I allele was significantly underrepresented in ACS (OR=0.66, CI=0.52–0.84; P=0.001; P=0.01 after correction for multiple testing), while the SULT1A1 (Sulphotransferase 1A1) 213H allele was associated with risk of ACS (OR=1.37, CI=1.08–1.74; P=0.01; P=0.1 after correction for multiple testing). Subsequent genotyping of further SNPs in GALNT4 in the family-based (IHD) group revealed that the 506I allele showed the same trend towards protecting against ACS but the
haplotypic test over the four commonest haplotypes was not significant (P=0.55). In contrast, the SULT1A1/SULT1A2 gene complex showed suggestive haplotypic association in the family-based study (P=0.07), with the greatest increase in risk conferred by the SULT1A2 235T allele (P=0.025). Conclusion We have identified two risk genes for cardiovascular disease, one of whose (GALNT4) effects may be on either platelet or
endothelial function through modifications of PSGL1 or other important glycosylated proteins. The role of sulphotransferases
(SULT1A1/2) in cardiovascular disease requires further exploration. Further validation of cardiovascular risks conferred by
both genes in other populations (including gene copy number variation) is warranted.
Journal of Thrombosis and Thrombolysis 04/2012; 27(2):175-184. · 1.48 Impact Factor
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R Y Khamis,
M Johns,
S Thom,
J Mayet,
E McConnell, A Stanton,
S Jeyapalan,
S Annon,
S Wrigley,
A Hughes,
D O Haskard
[show abstract]
[hide abstract]
ABSTRACT: Background We aimed to determine whether measurement of antibodies to modified LDL predicts cardiovascular events. Methods We studied ASCOT participants without diabetes with total cholesterol of ≤6.5 mmol/l and a total cholesterol/HDL ratio ≤4.5. IgG and IgM antibodies against malondialdehyde-modified LDL (MDA-LDL) and phosphorylcholine (PC) were measured by ELISA at baseline and after one year on atorvastatin (10 mg daily; n=100) or placebo (n=100). CRP, carotid intima-media thickness (CIMT), Framingham 10-year CVD Risk score (FRS) and total and LDL cholesterol (LDL) were determined. Results Antibody levels did not correlate with baseline LDL, or LDL, CRP or CIMT at 1 year. Atorvastatin reduced LDL by 1.44 mmol/l (p<0.001, 95% CI 1.31 to 1.58 adjusted for age and sex), but did not influence IgG or IgM antibodies against MDA-LDL (p=0.74 and p=0.38) or PC (p=0.26 and p=-0.556). However, following adjustment for classical risk factors, baseline IgG anti-MDA-LDL levels predicted protection from cardiovascular events (HR=0.22, 95% CI 0.052 to 0.92; p=0.04). There was also a trend for IgG anti-MDA-LDL being protective after adjustment for FRS, (HR=0.33, 95% CI 0.089 to 1.20; p=0.09). Conclusion IgG anti- MDA-LDL antibody levels are unrelated to LDL cholesterol levels, CRP, CIMT, and are not affected by treatment with atorvastatin. However, elevated levels are associated with significant protection against cardiovascular events and may be useful in clinical risk stratification for cardiovascular disease.
Heart (British Cardiac Society) 10/2011; 97(20):e7. · 4.22 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Both platelet function and heart disease show strong genetic components, many of which remain to be elucidated.
The roles of candidate polymorphisms in ten platelet-associated genes were compared between 1,237 Acute Coronary Syndrome (ACS) cases (with myocardial infarction and unstable angina) and 386 controls, from an Irish Caucasian population. Additionally, 361 stable angina patients were investigated. Two genes of interest were followed up in a separate Irish study of 1,484 individuals (577 with IHD and 907 unaffected).
The GALNT4 (N-acetyl galactosaminyl transferase 4) 506I allele was significantly underrepresented in ACS (OR = 0.66, CI = 0.52-0.84; P = 0.001; P = 0.01 after correction for multiple testing), while the SULT1A1 (Sulphotransferase 1A1) 213H allele was associated with risk of ACS (OR = 1.37, CI = 1.08-1.74; P = 0.01; P = 0.1 after correction for multiple testing). Subsequent genotyping of further SNPs in GALNT4 in the family-based (IHD) group revealed that the 506I allele showed the same trend towards protecting against ACS but the haplotypic test over the four commonest haplotypes was not significant (P = 0.55). In contrast, the SULT1A1/SULT1A2 gene complex showed suggestive haplotypic association in the family-based study (P = 0.07), with the greatest increase in risk conferred by the SULT1A2 235T allele (P = 0.025).
We have identified two risk genes for cardiovascular disease, one of whose (GALNT4) effects may be on either platelet or endothelial function through modifications of PSGL1 or other important glycosylated proteins. The role of sulphotransferases (SULT1A1/2) in cardiovascular disease requires further exploration. Further validation of cardiovascular risks conferred by both genes in other populations (including gene copy number variation) is warranted.
Journal of Thrombosis and Thrombolysis 03/2008; 27(2):175-84. · 1.48 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: There are two distinct models to explain how genetic variants contributing to cardiovascular disease may have arisen. Firstly, variants may result from random, initially neutral, mutations whose effects are largely revealed in post-reproductive individuals in industrialized societies. Alternatively, the introduced variants may confer an adaptive advantage in certain circumstances. Resistance to pathogens is one of the strongest selection pressures on human proteins. To determine whether this evolutionary pressure has made a large contribution to heart disease we tested whether seventeen polymorphisms in fourteen innate-immunity genes, with documented evidence of modulating response to pathogens, had an impact on heart disease. Genotyping was performed in 1,598 CAD subjects (ACS or stable angina) and 332 controls. The TLR4 399Ile allele had the greatest impact on ACS risk (uncorrected p = 0.006); however there was no evidence overall that the resistance alleles cumulatively influenced the risk of ACS compared to controls or stable angina patients (p = 0.12, and p = 0.40, respectively). We did note a significant interaction between age at onset of disease and combined resistance allele carriership when the ACS and non-thrombotic, stable angina groups were compared (p = 0.04, 16 d.f.). This suggests that innate immunity factors could have a greater impact on thrombus formation among younger CAD patients.
Annals of Human Genetics 12/2006; 70(Pt 6):934-45. · 2.57 Impact Factor
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ABSTRACT: The prevalence of white-coat hypertension (WCH) is considerable in patients referred with elevated office blood pressure. Failure to recognise this phenomenon can lead to the inappropriate use of antihypertensive medications. We undertook this study to determine the profile of patients with WCH.
Baseline clinic and daytime ambulatory blood pressures were available from 5716 patients referred over a 22-year period. Individuals were considered to have WCH if they had an elevated clinic blood pressure measurement greater than 140/90 mmHg and normal daytime mean ambulatory blood pressure. Mean age was 53.6 years and 53.2% were female.
The overall prevalence of white-coat hypertension was 15.4%. A higher prevalence was seen amongst older adults, females, and non-smokers.
Multivariate logistic regression analysis confirmed these characteristics as independent predictors of WCH.
Blood Pressure Monitoring 01/2005; 9(6):307-9. · 1.52 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: A method of vessel tracking has been developed for quantification
of vessel diameters of retinal images. This method utilises twin
Gaussian functions to model the distribution of grey level over a vessel
cross section. The diameter of the vessel at the cross section can then
be calculated using the functions. The variation of vessel diameter in
the direction of vessel longitude axis has been described by a tracking
technique based on parameters of modelled intensity distribution curves
over every cross section. This enables us to obtain an average diameter
over any length of a vessel and to develop more parameters for diagnosis
and study of vascular diseases
Image Processing, 2001. Proceedings. 2001 International Conference on; 11/2001
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Journal of Human Hypertension 09/2001; 15 Suppl 1:S75-7. · 2.80 Impact Factor
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Journal of Human Hypertension 09/2001; 15 Suppl 1:S13-8. · 2.80 Impact Factor
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Journal of Human Hypertension 09/2001; 15 Suppl 1:S47-51. · 2.80 Impact Factor
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ABSTRACT: A computerised system is presented for the automatic quantification of blood vessel topography in retinal images. This system utilises digital image processing techniques to provide more reliable and comprehensive information for the retinal vascular network. It applies strategies and algorithms for measuring vascular trees and includes methods for locating the centre of a bifurcation, detecting vessel branches, estimating vessel diameter, and calculating angular geometry at a bifurcation. The performance of the system is studied by comparison with manual measurements and by comparing measurements between red-free images and fluorescein images. In general an acceptable degree of accuracy and precision was seen for all measurements, although the system had difficulty dealing with very noisy images and small or especially tortuous blood vessels.
Computer Methods and Programs in Biomedicine 11/2000; 63(2):133-46. · 1.52 Impact Factor
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N Chapman,
A Mohamudally,
A Cerutti, A Stanton,
A A Sayer,
C Cooper,
D Barker,
A Rauf,
J Evans,
R Wormald,
P Sever,
A Hughes,
S Thom
[show abstract]
[hide abstract]
ABSTRACT: Low birth weight is associated with hypertension and increased cardiovascular mortality, but the mechanism of this association is not known. Hypertension is accompanied by abnormalities of the microvasculature including rarefaction.
To test the hypothesis that low birth weight is associated with an alteration in microvascular architecture.
A stratified random sample of 100 men aged 64-74 years was selected from a cohort of men whose birth weights were known. They were of relatively high or low birth weight ('high' > or = 3700 g, 'low' < or = 3200 g) and high or low systolic blood pressure (high > or = 160 mmHg, low < or = 140 mmHg).
Retinal arteriolar geometry was defined in terms of arteriolar bifurcation angles and junction exponents (a measure of the relative diameters of parent and daughter vessels), measured from photographic diapositives using operator-directed image analysis.
Members of low-birth-weight groups had significantly narrower bifurcation angles than did members of high-birth-weight groups (74 +/- 1 degree versus 78 +/- 1 degree, P= 0.017 by analysis of variance). There was no significant difference between angles in members of groups with high and low blood pressures. Neither birth weight nor blood pressure grouping affected junction exponents.
Narrower bifurcation angles are associated with increased circulatory energy costs and may be related to a lower than normal microvascular density. Our finding of differences in retinal microvascular architecture might reflect a persistent alteration in vascular architecture as a result of an impairment of foetal development and could provide a mechanistic link between low birth weight and subsequently increased cardiovascular risk.
Journal of Hypertension 12/1997; 15(12 Pt 1):1449-53. · 4.02 Impact Factor
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ABSTRACT: The results of previous studies on the effects of antihypertensive agents on circadian blood pressure patterns are inconclusive, possibly due to the lack of a simple, objective, universally accepted method of quantifying circadian blood pressure profiles. In order to investigate for differences in the effects of antihypertensive drugs on circadian changes we utilised a recently described modified cumulative sums technique to quantify circadian alteration magnitude (CAM). CAM is simply calculated as the difference between crest and trough blood pressures, the mean blood pressures of the 6-h periods of highest and lowest sustained pressures respectively. The records from all 24-h ambulatory blood pressure monitoring performed over a 7 year period on subjects either on no medication (1208), or on treatment with a single first-line antihypertensive agent (578), were examined retrospectively. A sample (n = 40) stratified for trough diastolic blood pressure, age and sex was randomly selected from each of the following 5 groups: subjects on no medication, and subjects being treated with bendrofluazide, atenolol, class 2 calcium-channel blockers or captopril alone. Untreated subjects, those on bendrofluazide and those on a class 2 calcium channel blocker had similar circadian patterns. Subjects on atenolol therapy (25.9 +/- 1.7/18.3 +/- 1.3, systolic CAM +/- SE/diastolic CAM +/- SE) had attenuated circadian changes (p < 0.05) when compared to the untreated group (29.8 +/- 1.8/23.6 +/- 1.1), while those on captopril (34.9 +/- 2.4/25.7 +/- 1.8) exhibited markedly increased systolic and diastolic circadian blood pressure swings, which differed from those of the atenolol treated group (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Pressure 01/1994; 2(4):289-95. · 1.43 Impact Factor
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Postgraduate Medical Journal 05/1993; 69(810):255-67. · 1.94 Impact Factor
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[hide abstract]
ABSTRACT: This population study included 399 subjects, of whom 370 (93%) showed a significant diurnal blood pressure (BP) rhythm. The nocturnal BP fall was normally distributed and averaged 16 +/- 9 mm Hg systolic and 14 +/- 7 mm Hg diastolic (mean +/- SD). The amplitude of the diurnal BP curve followed a positively skewed distribution, with a mean of 16 +/- 5 mm Hg for systolic BP and 14 +/- 4 mm Hg for diastolic BP. The daily BP maximum occurred at 15:54 +/- 4:47 for systolic BP and at 15:11 +/- 4:20 for diastolic BP. Thirty-four subjects were reexamined after a median interval of 350 days. The test for the presence of a significant diurnal rhythm was discordant in only two subjects. Repeatability (twice the standard deviation of the differences between paired recordings expressed as a percentage of the mean) varied from 11 to 25% for the 24 h, daytime, and overnight BP, and from 76 to 138% for the parameters describing the diurnal BP rhythm. In nine subjects with an initial night/day ratio of mean BP less than 0.78, the nighttime BP was significantly increased at the repeat examination, whereas the opposite tendency was observed in nine subjects with an initial ratio greater than 0.87. In conclusion, the distribution of the nocturnal BP fall is unimodal. The reproducibility of the ambulatory BP is satisfactory for the level of BP and for the presence of a diurnal BP rhythm, but not for the parameters of the diurnal BP curve. Thus, one 24 h recording is insufficient to fully characterize an individual's diurnal BP profile.
American Journal of Hypertension 07/1992; 5(6 Pt 1):386-92. · 3.18 Impact Factor
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[hide abstract]
ABSTRACT: The plotting of cumulative sums (cusums), a technique of proven value in the detection of trends in data collected at intervals of time, may be modified to analyze circadian blood pressure patterns quantitatively. Mean 24-hour ambulatory blood pressure is taken as the reference value and is subtracted from each pressure value. The products of the remainders and the corresponding time intervals are summed in sequence and are plotted against time to form a modified cusum plot. The slope of the plot over any given time period equals the difference between mean blood pressure during that period and mean 24-hour blood pressure. Crest and trough blood pressures (the mean blood pressures of the 6-hour periods of highest and lowest pressures) may be identified as the 6-hour periods where plot slopes are most steeply ascending and descending, respectively. The magnitude of the circadian blood pressure change, defined as the difference between crest and trough blood pressure, is calculated from the difference between crest and trough plot slopes. The height of the cusum plot, which reflects pressure alteration extent and duration, may also be used as a measure of circadian pattern. The modified cusums technique and cusum-derived statistics are illustrated using ambulatory blood pressure profiles of hypothetical and actual hypertensive subjects. Independence from fixed time periods improves precision and reproducibility. Cusum-derived statistics are simply calculated from raw ambulatory data and should prove useful in the quantitative analysis of circadian blood pressure profiles.
Hypertension 02/1992; 19(1):93-101. · 6.21 Impact Factor
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[hide abstract]
ABSTRACT: Conventional clinic measurement of blood pressure is influenced by many factors that make the technique unsuitable for the assessment of antihypertensive drug efficacy. The major drawback of conventional measurement is that it cannot indicate the duration of drug effect or the influence of antihypertensive drugs on nocturnal blood pressure. Noninvasive 24-hour ambulatory blood pressure measurement has a number of advantages over conventional measurement: it provides a profile of blood pressure over the 24-hour period; it detects white coat responders; it is free of regression to the mean and the placebo response, thereby making it possible to consider efficacy studies which need not have a placebo phase; it enables considerably more observations than is possible with clinic measurement by increasing the power of studies, which may reduce significantly the numbers of patients needed for antihypertensive drug studies. Twenty-four-hour ambulatory blood pressure measurement offers the opportunity to study antihypertensive drugs in fewer patients with greater accuracy than is possible with conventional clinic measurement and should be a mandatory requirement for such studies.
American Heart Journal 04/1991; 121(3 Pt 2):999-1006. · 4.65 Impact Factor
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International Journal of Eating Disorders 01/1990; 9:565-569. · 2.95 Impact Factor
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M. B. Lanktree,
Y. Guo,
M. Murtaza,
J. T. Glessner,
S. D. Bailey,
N. C. Onland-Moret,
G. Lettre,
H. Ongen,
R. Rajagopalan,
T. Johnson, [......],
W. Koenig,
T. R. Gaunt,
S. S. Anand,
Y. T. van der Schouw,
N. Soranzo,
G. A. Fitzgerald,
A. Reiner,
R. A. Hegele,
H. Hakonarson,
B. J. Keating
[show abstract]
[hide abstract]
ABSTRACT: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 x 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
American journal of human genetics. 88(1):6-18.
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S. Padmanabhan,
O. Melander,
T. Johnson,
A.M. Di Blasio,
W.K. Lee,
D. Gentilini,
C.E. Hastie,
C. Menni,
M.C. Monti,
C. Delles, [......],
D. Graham,
R.A. McDonald,
J.P. Pell,
N. Sattar,
P. Welsh,
P. Munroe,
M.J. Caulfield,
A. Zanchetti,
A.F. Dominiczak,
BPgen Consortium Global
[show abstract]
[hide abstract]
ABSTRACT: Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk
6.
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S Padmanabhan,
O Melander,
T Johnson,
A M Di Blasio,
W K Lee,
D Gentilini,
C E Hastie,
C Menni,
M C Monti,
C Delles, [......],
D Graham,
R A McDonald,
J P Pell,
N Sattar,
P Welsh,
P Munroe,
M J Caulfield,
A Zanchetti,
A F Dominiczak,
BPgen Consortium Global
[show abstract]
[hide abstract]
ABSTRACT: {Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96]
Plos Genetics. 6(10).
