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M den Hoed,
J Luan,
C Langenberg,
C Cooper,
A A Sayer,
K Jameson,
M Kumari,
M Kivimaki, A D Hingorani,
A Grøntved,
K-T Khaw,
U Ekelund,
N J Wareham,
R J F Loos
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ABSTRACT: Background:Meta-analysis of case-control genome-wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes.Objective:We aimed to validate association of these variants with obesity-related traits in population-based samples.Design:Genotypes and anthropometric traits were available in up to 31 083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r (2)>0.8), with the odds of being overweight and obese, as well as with body mass index (BMI), percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age(2) in adults and for sex, age, age group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods.Results:We had 80% power to detect odds ratios of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P>0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (β=0.013 s.d./allele, P=0.040), but not with any of the remaining obesity-related traits (P>0.3).Conclusion:Overall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population.International Journal of Obesity advance online publication, 20 March 2012; doi:10.1038/ijo.2012.34.
International journal of obesity (2005) 03/2012; · 4.34 Impact Factor
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N Yiannakouris,
J A Cooper,
S Shah,
F Drenos,
H A Ireland,
J W Stephens,
K-W Li,
R Elkeles,
I F Godsland,
M Kivimaki, A D Hingorani,
M Kumari,
P J Talmud,
S E Humphries
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ABSTRACT: BACKGROUND AND AIMS: A recent genome-wide association study identified rs2943641C > T, 500 kb from the insulin receptor substrate-1 gene (IRS1), as a type-2 diabetes (T2D) susceptibility locus. We aimed to replicate this association by meta-analysis and examine whether common variants within IRS1, present on the HumanCVD BeadChip, were associated with T2D risk. METHODS AND RESULTS: We genotyped rs2943641 in 2389 prevalent or incident T2D patients and 6494 controls from two prospective and three case studies based in UK and in the European Atherosclerosis Research Study-II (EARSII; n = 714). Thirty-three IRS1 variants had been genotyped in the prospective Whitehall-II study (n = 4752) using the HumanCVD BeadChip. In a fixed-effects meta-analysis of the UK study cohorts rs2943641T allele was associated with 6% lower risk of T2D (p = 0.18), with T-allele carriers having an odds ratio (OR) of 0.89 (95% confidence interval [CI]: 0.80-1.00, p = 0.056) compared to CC subjects. The T-allele was also associated with lower fasting insulin and homeostasis model assessment index of insulin resistance in Whitehall-II and with lower post-load insulin after an oral glucose tolerance test in EARSII (all p < 0.05). None of the IRS1 variants on the chip showed linkage disequilibrium with rs2943641. In silico analysis with follow-up genotyping (total n = 9313) identified that the rare allele of the IRS1 promoter variant rs6725556A > G showed association with reduced T2D risk (OR per G-allele: 0.82, 95%CI: 0.69-0.96, p = 0.015). CONCLUSIONS: We confirm the association of rs2943641T with T2D protection. There is a possible independent effect on risk of a putative IRS1 promoter variant.
Nutrition, metabolism, and cardiovascular diseases: NMCD 09/2011; · 3.52 Impact Factor
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International Journal of Clinical Practice 08/2011; 65(8):912. · 2.41 Impact Factor
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P J Talmud,
J A Cooper,
T Gaunt,
M V Holmes,
S Shah,
J Palmen,
F Drenos,
T Shah,
M Kumari,
M Kivimaki,
J Whittaker,
D A Lawlor,
I N Day, A D Hingorani,
J P Casas,
S E Humphries
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ABSTRACT: We quantified the effect of ADRA2A (encoding α-2 adrenergic receptor) variants on metabolic traits and type 2 diabetes risk, as reported in four studies.
Genotype data for ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 were analysed in >17,000 individuals (1,307 type 2 diabetes cases) with regard to metabolic traits and type 2 diabetes risk. Two studies (n = 9,437), genotyped using the Human Cardiovascular Disease BeadChip, provided 12 additional ADRA2A SNPs.
Rs553668 was associated with per allele effects on fasting glucose (0.03 mmol/l, p = 0.016) and type 2 diabetes risk (OR 1.17, 95% CI 1.04-1.31; p = 0.01). No significant association was observed with rs10885122. Of the 12 SNPs, several showed associations with metabolic traits. Overall, after variable selection, rs553668 was associated with type 2 diabetes risk (OR 1.38, 95% CI 1.09-1.73; p = 0.007). rs553668 (per allele difference 0.036 mmol/l, 95% CI 0.008-0.065) and rs17186196 (per allele difference 0.066 mmol/l, 95% CI 0.017-0.115) were independently associated with fasting glucose, and rs17186196 with fasting insulin and HOMA of insulin resistance (4.3%, 95% CI 0.6-8.1 and 4.9%, 95% CI 1.0-9.0, respectively, per allele). Per-allele effects of rs491589 on systolic and diastolic blood pressure were 1.19 mmHg (95% CI 0.43-1.95) and 0.61 mmHg (95% CI 0.11-1.10), respectively, and those of rs36022820 on BMI 0.58 kg/m(2) (95% CI 0.15-1.02).
Multiple ADRA2A SNPs are associated with metabolic traits, blood pressure and type 2 diabetes risk. The α-2 adrenergic receptor should be revisited as a therapeutic target for reduction of the adverse consequences of metabolic trait disorders and type 2 diabetes.
Diabetologia 04/2011; 54(7):1710-9. · 6.81 Impact Factor
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ABSTRACT: The UK National Health Service (NHS) currently spends in excess of £250 million per annum on angiotensin II receptor blockers (ARBs) for the treatment of hypertension and heart failure; with candesartan currently dominating the market. With the recent introduction of generic losartan, we set out to directly compare the branded market leader to its now cheaper alternative. The primary objectives were to compare the blood pressure (BP) lowering efficacy and cardiovascular outcomes of candesartan and losartan in the treatment of essential hypertension and chronic heart failure, respectively. The secondary objective was to model their comparative incremental cost-effectiveness in a UK NHS setting. The Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2), which contains the Hypertension and Heart Group's specialist register, Medline (1950-February 2010), and Embase (1980-February 2010) were included in the search strategy. Selection criteria were randomised studies of candesartan versus losartan in adults (> 18 years). The main outcome measures were as follows: Hypertension: mean change from baseline in trough (24 h postdose) systolic and diastolic BP. Heart failure: composite of cardiovascular death and hospital admission for management of heart failure. Two reviewers applied inclusion criteria, assessed trial quality, and extracted data. Eight (three of which met inclusion criteria) and zero trials compared candesartan directly with losartan in the treatment of hypertension and heart failure, respectively. A between-treatment difference of -1.96 mmHg [95% confidence interval (CI) -2.40 to -1.51] for trough diastolic BP and -3.00 mmHg (95% CI -3.79 to -2.22) for trough systolic BP in favour of candesartan was observed. Based on this differential, a 10-year Markov model estimates the cost per quality-adjusted life-year gained to exceed £40,000 for using candesartan in place of generic losartan. Candesartan reduces BP to a slightly greater extent when compared with losartan, however, such difference is unlikely to be cost-effective based on current acquisition costs, perceived NHS affordability thresholds and use of combination regimens. We could find no robust evidence supporting the superiority of candesartan over losartan in the treatment of heart failure. We therefore recommend using generic losartan as the ARB of choice which could save the UK NHS approximately £200 million per annum in drug costs.
International Journal of Clinical Practice 03/2011; 65(3):253-63. · 2.41 Impact Factor
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ABSTRACT: Evidence for the associations of single nucleotide polymorphisms (SNPs) in the F7 gene and factor (F)VII levels and with risk of coronary heart disease (CHD) is inconsistent. We examined whether F7 tagging SNPs (tSNPs) and haplotypes were associated with FVII levels, coagulation activation markers (CAMs) and CHD risk in two cohorts of UK men.
Genotypes for eight SNPs and baseline levels of FVIIc, FVIIag and CAMs (including FVIIa) were determined in 2773 healthy men from the Second Northwick Park Heart Study (NPHS-II). A second cohort, Whitehall II study (WH-II, n = 4055), was used for replication analysis of FVIIc levels and CHD risk.
In NPHS-II the minor alleles of three SNPs (rs555212, rs762635 and rs510317; haplotype H2) were associated with higher levels of FVIIag, FVIIc and FVIIa, whereas the minor allele for two SNPs (I/D323 and rs6046; haplotype H5) was associated with lower levels. Adjusted for classic risk factors, H2 carriers had a CHD hazard ratio of 1.34 [95% confidence interval (CI): 1.12-1.59; independent of FVIIc], whereas H5 carriers had a CHD risk of 1.29 (95% CI: 1.01-1.56; not independent of FVIIc) and significantly lower CAMs. Effects of haplotypes on FVIIc levels were replicated in WH-II, as was the association of H5 with higher CHD risk [pooled-estimate odds ratio (OR) 1.16 (1.00-1.36), P = 0.05], but surprisingly, H2 exhibited a reduced risk for CHD.
tSNPs in the F7 gene strongly influence FVII levels. The haplotype associated with low FVIIc level, with particularly reduced functional activity, was consistently associated with increased risk for CHD, whereas the haplotype associated with high FVIIc level was not.
Journal of Thrombosis and Haemostasis 11/2010; 8(11):2394-403. · 5.73 Impact Factor
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H A Ireland,
J A Cooper,
P J Talmud, A D Hingorani,
M Kivimki,
M Kumari,
R Morris,
I Tzoulaki,
J Price,
F G Fowkes,
S E Humphries
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ABSTRACT: Rationale for the study Endothelial protein C receptor (EPCR) is involved in the regulation of thrombin generation and inflammation. PROCR gene variant rs867186 codes for an amino acid substitution (Ser219Gly) within the membrane spanning region of EPCR. The minor allele of the variant has been identified as functional, and associated with increased shedding of EPCR from the endothelial surface.1 Previous analysis has also shown increased coagulation activated markers in those with the Gly allele1.2 Furthermore, while heterozygotes for this variant may be protected from coronary heart disease (CHD), homozygotes had a threefold elevation in CHD risk in a prospective cohort (NPHSII).1 In a case-control study of CHD (HIFMECH), there was a suggestion that the EPCR genotype interacts with factors present in metabolic syndrome, to increase CHD risk.1 Methodology NPHSII was analysed to further assess the CHD risk associated with EPCR Ser219Gly in those who have been identified as diabetic, or as having 'metabolic syndrome', during 15 years' follow-up. Results Individuals who were Gly/Gly and had 'metabolic syndrome' had a fourfold increase in CHD risk compared with Ser/Ser (HR=4.72, CI 1.69 to 13.4) p=0.006; or an eightfold increase in risk above those who were Ser/Ser without metabolic syndrome (HR=8.02, CI 2.89 to 22.2) p=0.006. No Gly/Gly individuals without metabolic syndrome had a CHD event. Conclusions Homozygotes for the Gly allele are present at a frequency of approximately 1%. If the findings in the study can be replicated, the variant would constitute a considerable CHD risk in 1% of diabetics. Replication studies are under way in three further, large prospective cohorts.
Heart (British Cardiac Society) 09/2010; 96(17):e24. · 4.22 Impact Factor
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ABSTRACT: Socioeconomic gradients in adiposity were not present during childhood for previous generations, but have emerged in contemporary children. It is unknown whether this translates to socioeconomic gradients in associated cardiovascular risk factors in children, with consequent implications for inequalities in coronary heart disease (CHD) and diabetes when these children reach adulthood.
Using data from 7772 participants aged 10-years from the Avon Longitudinal Study of Parents and Children, we examined the association between maternal education and a large number of cardiovascular risk factors (cholesterol, triglycerides, high-density lipoprotein, apolipoprotein, adiponectin, leptin, C-reactive protein (CRP), interleukin-6 (IL-6) and systolic and diastolic blood pressure), and examined whether inequalities were mediated by adiposity, measured by dual energy X-ray absorptiometry (DXA)-assessed total fat mass.
There were socioeconomic differences in a number of the cardiovascular risk factors (apolipoprotein B, systolic and diastolic blood pressure, CRP, leptin and IL-6). Inequalities were greater in girls than boys. Inequalities in CRP and leptin were completely mediated by adiposity. Inequalities in other cardiovascular risk factors were partially mediated by adiposity.
This study showed important socioeconomic inequalities in adiposity and associated cardiovascular risk factors in a contemporary UK population of 10-year-old children. Differences between contemporary children and previous generations in the socioeconomic patterning of cardiovascular risk factors suggest future adults may have greater inequalities in diabetes and CHD than current adults. These findings highlight the importance of interventions aimed at preventing obesity in childhood, particularly among those of lower socioeconomic position.
International journal of obesity (2005) 03/2010; 34(7):1149-59. · 4.34 Impact Factor
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ABSTRACT: The hepatocyte-derived acute-phase reactant C-reactive protein (CRP) has been the subject of intense research over the last 2 decades for its possible role in the pathogenesis of cardiovascular diseases. This research has spawned interest in the use of the blood concentration of CRP for predicting a first coronary heart disease (CHD) event, which has been made possible with the development of high-sensitivity CRP (hsCRP) assays that can measure the typically low concentrations of CRP that circulate in the absence of an overt infective or inflammatory episode, and as a potential causal factor that might be targeted therapeutically. The research has encompassed observational and genetic epidemiology, basic science studies with cells and tissues, experiments with animal models and humans, and randomized trials (although not of specific CRP-lowering therapies as yet).
We focus on investigations of the potential role of small differences in basal hsCRP concentration seen in healthy individuals and the relationship of such differences to the long-term risk of a first CHD event, rather than on research devoted to the high acute-phase CRP concentrations, which occur after acute atherothrombotic events and can influence the severity of ischemic tissue damage and the subsequent prognosis. We concentrate mainly on research findings at the translational interface and draw on evidence from human observational and genetic epidemiology, as well as from randomized trials.
As the field matures from one of discovery to an evaluative science, the development of possible clinical applications requires a sharpening of focus on and a critical appraisal of the strengths and deficiencies of the accumulated evidence. Such assessments require attention to both the current state of affairs and the design of future research, so that the existing uncertainties about the utility of CRP in predicting CHD and its role in causing this disease can be resolved.
Clinical Chemistry 01/2009; 55(2):239-55. · 7.91 Impact Factor
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ABSTRACT: Modestly elevated baseline concentrations of C-reactive protein (CRP), the classical acute phase protein, are associated with the long-term risk of coronary heart disease in general populations, whilst the major acute phase response of CRP following myocardial infarction is associated with death and cardiac complications. The pathogenic and clinical significance of these associations is controversial. Here we critically review the evidence and describe large-scale epidemiological studies, novel experiments and possible specific therapies which will rigorously inform the debate. We distinguish between the potential pathogenicity of high acute phase circulating CRP concentrations in individuals with substantial tissue damage and modest but persistent increases in baseline values in generally healthy subjects.
Journal of Internal Medicine 11/2008; 264(4):295-314. · 5.48 Impact Factor
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ABSTRACT: To determine whether maternal serum concentrations of placental growth factor (PlGF) and soluble endoglin (sEng) are altered in women who subsequently develop pre-eclampsia (PE) or have small-for-gestational-age (SGA) infants, and whether these changes are associated with maternal endothelial dysfunction.
Maternal serum PlGF and sEng were measured in two groups of pregnant women at 23-25 weeks' gestation: Group A (n = 40), with normal uterine artery Doppler waveforms and Group B (n = 43) with abnormal Doppler. Maternal endothelial dysfunction was assessed by flow-mediated dilatation (FMD) of the brachial artery. Comparisons between groups were performed using one-way analysis of variance.
In Group B, 16 women had normal outcome, 15 delivered SGA infants and 12 developed PE. Women who developed PE had lower levels of PlGF (154.8 +/- 150.8 vs. 423.3 +/- 230.5 pg/mL; P < 0.001) (data given as mean +/- SD) and higher levels of sEng (8.1 (7.0-14.1) vs. 6.5 (4.9-7.9) pg/mL; P < 0.05) (data given as median (interquartile range)) than Group A. Similar were the findings in women who delivered SGA infants. In women who subsequently developed PE, there was no correlation between FMD and either PlGF or sEng.
Maternal serum concentrations of PlGF and sEng are altered in women who develop PE. However, these alterations do not correlate directly with maternal endothelial dysfunction.
Ultrasound in Obstetrics and Gynecology 09/2008; 32(7):871-6. · 3.01 Impact Factor
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Oral Diseases 04/2008; 14(2):102-4. · 2.49 Impact Factor
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ABSTRACT: Antiphospholipid antibodies are associated with increased risk of thrombosis, particularly as in antiphospholipid syndrome. This study aims to determine the acute effects of anticardiolipin antibodies on nitric oxide production and vascular function.
Ex vivo aortic rings from male Sprague Dawley rats were incubated with IgG monoclonal anticardiolipin antibody (IS4) or a non-specific IgG control. In organ baths, response to phenylephrine and acetlycholine was determined alone and with nitro-L-arginine methyl ester (L-NAME), 1,400 W, D-arginine, L-arginine, sodium nitroprusside and cardiolipin. In vivo antibodies were injected into anaesthetised, spontaneously breathing male Sprague Dawley rats. Haemodynamic variables and serum nitric oxide were measured. Immunohistochemistry for iNOS and eNOS was performed in kidney vessels.
Phenylepherine contraction was decreased in the IS4 group compared to controls (p < 0.001). L-NAME, 1,400 W and cardiolipin, abolished this effect. L-Arginine caused significant relaxation in the IS4 group (p = 0.005). Mean arterial pressure in rats injected with IS4 was reduced compared to IgG and saline controls (p < 0.001). NO in plasma increased significantly after IS4 administration (p < 0.001). Immunohistochemistry showed increased iNOS expression in kidney arteries in the IS4 group, with no change in eNOS.
Anticardiolipin antibodies induce NO production acutely via increased expression of iNOS in both ex vivo and in vivo models.
Atherosclerosis 04/2006; 185(2):246-53. · 3.79 Impact Factor
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Heart (British Cardiac Society) 11/2005; 91(10):1275-7. · 4.22 Impact Factor
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ABSTRACT: To investigate whether the tau H1 haplotype is a genetic risk factor in Parkinson's disease and to report a meta-analysis on all previously published data
and results: In a sample of 580 patients with Parkinson's disease and 513 controls there was an increased risk of Parkinson's disease for both the tau H1 haplotype (p<or=0.0064; odds ratio (OR) 1.34 (95% confidence interval (CI), 1.04 to 1.72)) and the H1H1 genotype (p<or=0.0047; OR 1.42 (1.1 to 1.83)). Under a fixed effect model, the summary OR for this showed that individuals homozygous for the H1 allele were 1.57 times more likely to develop Parkinson's disease than individuals carrying the H2 allele (95% CI 1.33 to 1.85; p<0.00001). The population attributable risk for the tau variant, for the main comparison of H1H1 against H2 carriers, was 24.8% for all studies combined.
Homozygosity for the tau H1 is associated with an increased risk of Parkinson's disease. This adds to the growing body of evidence that common genetic variation contributes to the pathogenesis of this disorder.
Journal of Neurology Neurosurgery & Psychiatry 07/2004; 75(7):962-5. · 4.76 Impact Factor
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D J Brull,
N. Serrano,
F Zito,
L. Jones,
H E Montgomery,
A Rumley,
P Sharma,
G.D.O. Lowe,
M J World,
S E Humphries, A D Hingorani
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ABSTRACT: Objective - C- reactive protein ( CRP) concentrations are predictive of cardiovascular disease, and levels are heritable, in part. We identified novel polymorphisms in the CRP gene and assessed their influence on CRP level. Methods and Results - CRP was measured in 250 male army recruits before and after strenuous exercise and perioperatively in 193 coronary artery bypass graft ( CABG) patients. Two novel polymorphisms were identified in the CRP gene, - 717G gt A in the promoter and + 1444C gt T in the 3' UTR. Among army recruits, CRP was higher in + 1444TT homozygotes than + 1444 C- allele carriers at baseline ( 1.04 +/- 0.38 versus 0.55 +/- 0.06, P = 0.014) and at all time points after exercise ( 2.35 +/- 0.68 versus 1.07 +/- 0.12, 2.11 +/- 0.53 versus 0.88 +/- 0.09, and 1.77 -/+ 0.44 versus 0.71 -/+ 0.09, P = 0.034, P = 0.007, and P = 0.013, at 2, 48, and 96 hours after exercise, respectively). In the CABG patients, mean CRP ( mg/ L) rose from 1.97 -/+ 0.36 at baseline to 167.2 +/- 5.0 72 hours postoperatively. Genotype did not influence CRP at baseline; however, peak post- CABG CRP levels were higher in + 1444TT homozygotes compared with + 1444C- allele carriers ( 198 +/- 17 versus 164 +/- 5, P = 0.03). Conclusions - The CRP gene + 1444C gt T variant influences basal and stimulated CRP level. These findings have implications both for the prediction and pathogenesis of coronary heart disease.
Arteriosclerosis Thrombosis and Vascular Biology 12/2003; · 6.37 Impact Factor
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ABSTRACT: Synthesis of the vasodilator nitric oxide (NO) can be inhibited by the endogenous methylarginines L-NMMA and ADMA. ADMA is elevated in a number of cardiovascular disorders in which NO availability is reduced. Elimination of ADMA from the body occurs primarily by enzymatic breakdown through the action of DDAH, of which two isoforms exist, DDAH1 and DDAH2. In this study we have identified a core promoter region of the DDAH2 gene, and transcription factor sites that play an important role in the regulation of DDAH2 expression. Using PCR-SSCP analysis we also identified six common polymorphisms. One of these polymorphisms (an insertion/deletion at position -871) within the core promoter element influenced basal transcription. The discovery of a functional polymorphism within the DDAH2 promoter suggests that there may be common, individual differences in the ability to metabolise ADMA in vivo, that in turn, might underlie susceptibility to cardiovascular disease.
Biochemical and Biophysical Research Communications 11/2003; 310(3):836-43. · 2.48 Impact Factor
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ABSTRACT: An endothelial nitric oxide synthase (eNOS) gene polymorphism (Glu298Asp) has been associated with cardiovascular disease. We investigated whether carriage of the polymorphism was associated with functional changes in the endothelium, and how genotype altered the harmful and beneficial impact of environmental influences on the endothelium. Endothelium-dependent, flow-mediated brachial artery dilatation (FMD) and endothelium-independent dilatation response to glyceryl trinitrate were measured using high-resolution ultrasound in 248 subjects (131 female, 117 male, aged 20 to 28) genotyped for the Glu298Asp polymorphism. Vascular function was compared between genotype groups and interactions with the proatherogenic risk factor, smoking, and the antiatherogenic influence of n-3 fatty acids (n-3FA) were investigated. Vascular function was not related to genotype in the group as a whole or within sexes. However, among males, smoking was associated with lower FMD in Asp298 carriers (nonsmokers 0.125+/-0.085 mm versus smokers 0.070+/-0.060 mm, P=0.006) but not in Glu298 homozygotes (nonsmokers 0.103+/-0.090 mm versus smokers 0.124+/-0.106, P=0.5). In the whole group, n-3FA levels were positively related to FMD in Asp298 carriers (reg coeff=0.023 mm/%, P=0.04, r=0.20) but not in Glu298 homozygotes (reg coeff=-0.019 mm/%, P=0.1). These differences between genotype groups were significant in interaction models. The Glu298Asp polymorphism is associated with differences in endothelial responses to both smoking and n-3 FA in healthy young subjects. These findings raise the possibility of genotype-specific prevention strategies in cardiovascular disease.
Circulation Research 07/2002; 90(11):1153-8. · 9.49 Impact Factor
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ABSTRACT: A common polymorphism of the endothelial NO synthase gene that predicts a Glu298Asp amino acid substitution in the mature protein has been associated with cardiovascular disorders in which NO bioactivity is impaired. However, the influence of this polymorphism on endothelial function is unknown. Healthy pregnancy is associated with enhanced endothelium-dependent, flow-mediated dilation (FMD) of the brachial artery, a response mediated by NO. In this study, we investigated the effect of the endothelial NO synthase Glu298Asp polymorphism on endothelium-dependent vasodilation in early pregnancy, making the hypothesis that any genotype-dependent differences in NO generation would be more marked during pregnancy, when the production of NO is upregulated. FMD of the brachial artery was recorded during the first trimester in 139 healthy women with normal singleton pregnancies genotyped for the Glu298Asp variant of endothelial NO synthase. Maternal FMD exhibited a codominant inverse relation with the number of Asp298 alleles (r=-0.21, P=0.01). Among homozygotes for endothelial NO synthase Asp298, FMD (7.99+/-1.46%) was significantly lower than that observed among individuals homozygous for endothelial NO synthase Glu298 (10.12+/-3.44) (P=0.002). In a backward stepwise multiple regression analysis, vessel size (P<0.0001) and Glu298Asp polymorphism (P=0.01) were significantly and independently correlated with FMD. Our findings indicate that the endothelial NO synthase Glu298Asp polymorphism is associated with differences in endothelium-dependent dilation at 12-week gestation and are the first to implicate genetic factors in the normal vascular adaptation to pregnancy. They also provide a potential mechanism linking the endothelial NO synthase polymorphism with the development of cardiovascular disorders and have implications for understanding the genetic basis of preeclampsia.
Hypertension 12/2001; 38(6):1289-93. · 6.21 Impact Factor
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The Lancet 12/2001; 358(9295):1814. · 38.28 Impact Factor
