Publications by authors named "Emma Hawe"

40 Publications

Impact of Patient Characteristics on Treatment Outcomes in Symptomatic Venous Thromboembolism: Results of HOKUSAI-VTE Randomized Trial Analysis.

TH Open 2020 Jul 23;4(3):e245-e254. Epub 2020 Sep 23.

Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.

 In patients with venous thromboembolism (VTE), direct oral anticoagulants (DOACs) such as edoxaban, apixaban, dabigatran, and rivaroxaban are more convenient, safer, and just as effective as vitamin K antagonists (VKAs). Limited information is known about the effects of patient characteristics on VTE efficacy and safety of DOACs compared with VKAs, without appropriate effect modifier adjustment comparisons of DOACs may be biased. This study considers the effect of variables that can modify the efficacy and safety of edoxaban and warfarin, using patient-level data.  The primary efficacy and safety outcomes in the HOKUSAI-VTE study were VTE recurrence and clinically relevant bleeding, respectively. Potential effect modifiers were age, creatinine clearance, and weight. The relationship between the percentage of time in international normalized ratio (INR) control and outcomes were considered for the warfarin arm. Univariate and multivariate regression were performed for each patient characteristic.  The relationship between treatment and VTE recurrence differed by age (interaction  = 0.007) and by creatinine clearance (  = 0.05). VTE recurrence differed by age for patients in the warfarin arm but not for those in the edoxaban arm and differed by INR control in the warfarin arm (  < 0.005). A stronger relationship between creatinine clearance and clinically relevant bleeding was found in the warfarin arm than in the edoxaban arm (  = 0.04). Clinically relevant bleeding differed by the percentage of time in INR control in the warfarin arm (  < 0.005). Age appeared to be a more important effect modifier than creatinine clearance in patients with VTE.  The finding that efficacy in older patients was greater for those taking edoxaban than for those taking warfarin in the HOKUSAI-VTE study needs further investigation. Modification of the treatment effect by age for those taking warfarin might bias estimates of comparative effectiveness among DOACs if VKAs are the reference treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1716496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553796PMC
July 2020

In Reply: Network Meta-analyses Are Not About a Single Treatment But About Sets of Regimens.

Clin Ther 2019 01 15;41(1):188-190. Epub 2018 Dec 15.

RTI Health Solutions, Manchester, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinthera.2018.11.011DOI Listing
January 2019

Cost-Effectiveness of Olaratumab in Combination with Doxorubicin for Patients with Soft Tissue Sarcoma in the United States.

Sarcoma 2018 26;2018:6703963. Epub 2018 Mar 26.

Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK.

Background: Standard first-line treatments for advanced soft tissue sarcoma (STS) have changed little for 40 years, and outcomes have been poor. Recently, the United States (US) Food and Drug Administration conditionally approved olaratumab in combination with doxorubicin (Olara + Dox) based on a randomized phase II trial that reported a significant 11.8-month improvement in median survival versus single-agent doxorubicin (Dox). The present study investigated the cost-effectiveness of Olara + Dox compared with Dox and five other standard-of-care regimens from the US payer perspective.

Methods: An economic model was constructed to estimate costs and outcomes over patients' lifetimes from start of therapy. Progression-free and overall survival were based on survival analysis of patient-level data and a meta-analysis. Adverse-event rates were based on trials. Costs were from published sources.

Results: Olara + Dox resulted in an estimated additional 1.27 life-years (LYs) compared with Dox, with an increase in total expected lifetime costs of $133,653. The incremental cost-effectiveness ratio (ICER) was estimated at $105,408 per LY gained; in a fully incremental analysis, all other regimens were dominated (higher costs and lower LYs or a higher ICER).

Conclusion: Olara + Dox is cost-effective for STS treatment compared with Dox and other standard-of-care regimens at willingness-to-pay thresholds of $150,000 per LY and above.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/6703963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892240PMC
March 2018

Comparative Efficacy of Treatments for Previously Treated Multiple Myeloma: A Systematic Literature Review and Network Meta-analysis.

Clin Ther 2018 03 28;40(3):480-494.e23. Epub 2018 Feb 28.

RTI Health Solutions, Manchester, United Kingdom.

Purpose: New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in the United States for patients with multiple myeloma (MM) who have received at least 1 prior line of therapy. However, few treatments have been compared in head-to-head clinical trials to determine the most efficacious therapy. In an update of the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) trial, median progression-free survival (PFS) for DRd was not reached; the hazard ratio compared with Rd was 0.41. In an update of the CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trial, median PFS for DVd was 16.7 months, compared with 7.1 months for Vd with a PFS hazard ratio of 0.31. A systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of treatments for previously treated patients with MM.

Methods: A systematic search of MEDLINE, EMBASE, BioSciences Information Service, and the Cochrane Library databases was conducted from initiation to September 2016. Abstracts published by international congresses (2014-2016) and bibliographies of pertinent systematic reviews and meta-analyses were also searched. Eligible studies consisted of randomized controlled trials (RCTs) or long-term follow-up studies with >1 treatment arm assessing the efficacy or safety of MM therapies. An NMA was conducted by using Bayesian fixed effect mixed-treatment comparisons. Outcomes considered were hazard ratios for PFS and odds ratios for overall response rate (ORR).

Findings: In total, 108 articles reporting 27 RCTs were included in the NMA. Data formed 2 evidence networks: RCTs with DRd and RCTs with DVd. Primary analysis of PFS found that DRd and DVd had a higher probability of being the best treatments (probability, 0.997 and 0.999, respectively) and had the lowest risk of progression or death than other treatments approved by the US Food and Drug Administration for the treatment of MM. Results from sensitivity analyses using time to progression as a proxy for missing PFS data were consistent. DRd and DVd also showed improved ORR compared with other treatments. Subgroup analyses of PFS in patients treated with only 1 prior therapy were like the results of the primary analyses.

Implications: This NMA provides comparative efficacy for MM treatments not studied in head-to-head RCTs. The NMA suggests that, compared with other approved MM treatments in the United States, DRd and DVd have a higher probability of providing the longest PFS in patients who have received at least 1 prior therapy and in patients who have received only 1 prior therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinthera.2018.01.014DOI Listing
March 2018

EQ-5D Utilities in Chronic Spontaneous/Idiopathic Urticaria.

Pharmacoeconomics 2016 May;34(5):521-7

RTI Health Solutions, 200 Park Offices Drive, Research Triangle Park, NC, 27709-2194, USA.

Objectives: To obtain utility estimates suitable for use in economic models for chronic spontaneous (idiopathic) urticaria (CSU).

Methods: Patient-level data from three randomized clinical trials-ASTERIA I, ASTERIA II and GLACIAL-were analysed. Health states were derived from the Urticaria Activity Score over 7 days (UAS7); higher scores denote greater activity. The health state score ranges were urticaria free: 0; well-controlled urticaria: 1-6; mild urticaria: 7-15; moderate urticaria: 16-27; and severe urticaria: 28-42. The mean EQ-5D utilities were calculated for each health state. A mixed model was used to predict the EQ-5D according to UAS7 health states in a pooled data set containing all treatment arms and time points from the three trials. Pooled trial data were validated through visual comparisons and interaction terms. Fixed and random effects for trials and patients were included, along with the following covariates: UAS7 health state at baseline (moderate or severe); presence of angioedema at baseline and during follow-up; duration of CSU; number of previous CSU medications; visit; current treatment; and patient age and sex.

Results: There was a consistent improvement in EQ-5D utilities as urticaria activity decreased. The mean utilities ranged from 0.710 (severe urticaria) to 0.780 (moderate urticaria), 0.829 (mild urticaria), 0.862 (well-controlled urticaria) and 0.894 (urticaria free). Sensitivity and subgroup analyses confirmed the robustness of the results.

Conclusion: The results suggest that EQ-5D utility scores increase with decreasing urticaria activity. EQ-5D utility scores enable the health-related quality of life of CSU patients to be compared with that of patients with other diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40273-015-0375-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828466PMC
May 2016

PAYER PERSPECTIVES ON FUTURE ACCEPTABILITY OF COMPARATIVE EFFECTIVENESS AND RELATIVE EFFECTIVENESS RESEARCH.

Int J Technol Assess Health Care 2015 Jan;31(1-2):90-8

Office of Health Economics.

Objectives: Our objective was to gather perspectives from payers on how comparative effectiveness research (CER) in the United States and relative effectiveness (RE) research in Europe will impact evidentiary standards for access decisions of new drugs by 2020.

Methods: We conducted semi-structured interviews with fourteen senior officials representing public and private payers, health technology assessment groups, and pricing and reimbursement bodies in the United States and Europe. An online survey assessed current use of CER/RE evidence and potential trends that might influence its use for decision making by 2020. A semi-structured interview elicited payers' definitions of CER/RE and was structured around four hypothetical cases resembling drugs expected to be more common or poised to create policy challenges by 2020. Topics included acceptance of study designs and analytic methods associated with CER/RE. A systematic content review was done to extract relevant information.

Results: According to key informants, randomization will remain an essential component for assessing comparative or relative effectiveness. They anticipate greater use of policy levers such as conditional reimbursement or prior authorization to manage diffusion of new drugs. Case studies provided important insights into situations when certain types of CER evidence may be acceptable (e.g., observational data when differences between drugs are largely convenience).

Conclusions: Industry perceptions that CER/RE will change payers' evidentiary requirements in the future are consistent with our findings. Growing investment in payers' own data and increased reliance on policy tools to control diffusion of new drugs may also influence the type of evidence industry will be required to produce by 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0266462315000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505735PMC
January 2015

Higher IL-6 levels but not IL6 -174G>C or -572G>C genotype are associated with post-operative complication following coronary artery bypass graft (CABG) surgery.

Atherosclerosis 2009 May 4;204(1):196-201. Epub 2008 Sep 4.

Department of Surgery, University College London, London, UK.

Large increases in inflammatory markers, particularly IL-6, occur after cardiac surgery. However, despite interventions to reduce the inflammatory response, great variability still remains which could in part be attributable to genetic predisposition. Since increased IL-6 levels following surgery are also associated with poorer outcome we sought to determine whether baseline and post-operative levels of Interleukin-6 (IL-6) and functional common variants of the Interleukin-6 (IL6) gene are associated with post-operative outcome following coronary artery bypass grafting (CABG). Caucasian patients undergoing first-time elective CABG were studied. IL-6 levels were measured pre-, 6h and 24h following surgery and genotypes for IL6 gene variants -174G>C and -572G>C were obtained. Clinical data was collected daily until patient discharge. Patient outcome was categorised as with (ICUC, n=177) and without (NICUC, n=189) a post-operative complication during the ICU period and with (POC, n=215) and without (NC, n=151) a post-operative complication during hospitalisation. IL-6 levels pre- and at 24h were greater in POC and ICUC than NC and NICUC, respectively. Pre- IL-6 levels independently predicted (for 1 standard deviation increase in log IL-6) POC (OR 1.4, 95% CI 1.1-1.7, p=0.008) and ICUC (OR 1.3, 95% CI 1.0-1.6, p=0.02) outcomes. Overall, the IL6-572G>C had an effect over time on IL-6 levels (p=0.04) and on IL-6 levels in NC (P=0.008) and NICUC (p=0.006). However, no associations were found with the IL6 -572G>C or -174G>C variants on IL-6 levels at individual time-points or by outcome group. Thus, in conclusion, elevated pre-operative IL-6 levels, but not IL6 gene variants predict poor patient outcome following CABG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2008.08.032DOI Listing
May 2009

Ethnic variations in the experiences of mental health service users in England: results of a national patient survey programme.

Br J Psychiatry 2007 Oct;191:304-12

Healthcare Commission, 103-105 Bunhill Row, London EC1Y 8TG, UK.

Background: Minority ethnic groups in the UK are reported to have a poor experience of mental health services, but comparative information is scarce.

Aims: To examine ethnic differences in patients' experience of community mental health services.

Method: Trusts providing mental health services in England conducted surveys in 2004 and 2005 of users of community mental health services. Multiple regression was used to examine ethnic differences in responses.

Results: About 27 000 patients responded to each of the surveys, of whom 10% were of minority ethnic origin. In the 2004 survey, age, living alone, the 2004 survey, age, living alone, detention and hospital admissions were stronger predictors of patient experience than ethnicity. Self-reported mental health status had the strongest explanatory effect. In the 2005 survey, the main negative differences relative to the White British were for Asians.

Conclusions: Ethnicity had a smaller effect on patient experience than other variables. Relative to the White British, the Black group did not report negative experiences whereas the Asian group were most likely to respond negatively. However, there is a need for improvements in services for minority ethnic groups, including access to talking therapies and better recording of ethnicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1192/bjp.bp.106.032417DOI Listing
October 2007

The association of left ventricular mass with blood pressure, cigarette smoking and alcohol consumption; data from the LARGE Heart study.

Int J Cardiol 2007 Aug 31;120(1):52-8. Epub 2006 Oct 31.

Centre for Cardiovascular Genetics, BHF Laboratories, Royal Free and University College Medical School, 5 University Street, London, UK.

Background: Left ventricular mass is a risk factor for cardiovascular morbidity and mortality. Although factors associated with elevated left ventricular mass have been sought and studied extensively in elderly and in diseased subjects, few studies have examined the young and healthy. The aim of this study was to examine the possible influence of lifestyle on left ventricular mass in a large group of young men.

Methods: Left ventricular mass was assessed using cardiovascular magnetic resonance in 541 healthy Caucasian male army recruits. Anthropometric, lifestyle and blood pressure data were collected.

Results: Mean unadjusted left ventricular mass and left ventricular mass indexed to body surface area were 163.8+/-24.9 g and 86.6+/-10.2 g m(-2) respectively. In univariate analysis, age, height, weight, alcohol consumption, systolic blood pressure, diastolic blood pressure and indices of physical activity were positively associated with unadjusted left ventricular mass (all P<0.02). By contrast, smoking was associated with lower mean left ventricular mass; never smoked 167.5+/-25.8 g vs ex-smokers 159.1+/-25.2 g vs current smokers 161.0+/-23.1 g (P=0.007). Multivariate analysis revealed weight, systolic blood pressure, smoking status and indices of physical activity to be independent predictors of left ventricular mass.

Conclusions: Our data confirm an association of age, body weight, height, physical activity, diastolic and systolic blood pressure with left ventricular mass. In addition, unexpectedly, we have found smoking is associated with lower left ventricular mass in a large sample of young healthy men. Although the latter association may result from confounding effects, such an interesting observation deserves further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2006.08.043DOI Listing
August 2007

+9/+9 Homozygosity of the bradykinin receptor gene polymorphism is associated with reduced fat-free mass in chronic obstructive pulmonary disease.

Am J Clin Nutr 2006 Apr;83(4):912-7

Respiratory Muscle Laboratory, Royal Brompton Hospital, Fulham Road, London SW3 6NP, United Kingdom.

Background: The etiology of muscle wasting in chronic obstructive pulmonary disease (COPD) is incompletely understood. We previously showed that the D rather than the I polymorphic variant of the angiotensin-converting enzyme (ACE) gene is associated with preserved quadriceps strength in COPD. If the ACE D allele influences skeletal muscle through increased ACE-related kinin degradation [and reduced activity at the bradykinin type 2 receptor (BK(2)R)], we might expect a similar association with the +9 BK(2)R genotype in this population as well.

Objective: The objective was to test the hypothesis that the BK(2)R gene polymorphism is a determinant of fat-free mass and quadriceps strength in patients with COPD.

Design: In a cross-sectional design we determined BK(2)R genotype, fat-free mass, and quadriceps strength in 110 COPD patients with a mean (+/-SD) predicted forced expiratory volume in 1 s of 34.3 +/- 16.4% and in 104 healthy age-matched control subjects.

Results: The mean (+/-SD) fat-free mass index (in kg/m(2)) was significantly lower in 37 patients homozygous for the +9 allele than in carriers of the -9 allele (15.7 +/- 1.8 compared with 16.7 +/- 2.3; P = 0.038); the same pattern was true for quadriceps maximal voluntary force (30.8 +/- 10.4 and 36.4 +/- 12.8 kg; P = 0.02), respectively. No significant effect of BK(2)R genotype on inspiratory muscle strength or on any variable in control subjects was observed. There was no interaction between the effect of the BK(2)R and ACE genotypes on quadriceps strength.

Conclusions: The genotype associated with reduced BK(2)R expression is associated with reduced fat-free mass and quadriceps strength in COPD. However, alterations in the activity at the BK(2)R do not seem to account for the previously identified association of quadriceps strength with ACE genotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/83.4.912DOI Listing
April 2006

Insight into the nature of the CRP-coronary event association using Mendelian randomization.

Int J Epidemiol 2006 Aug 24;35(4):922-31. Epub 2006 Mar 24.

Centre for Clinical Pharmacology, Department of Medicine, BHF Laboratories at University College London, UCL, London, UK.

Background: It is unclear wheather the association between C-reactive protein (CRP) and incident coronary events is free from bias and confounding. Individuals homozygous for a +1444C>T polymorphism in the CRP gene have higher circulating concentrations of CRP. Since the distribution of this polymorphism occurs at random during gamete formation, its association with coronary events should not be biased or confounded.

Methods: We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4,659 European men from six studies (genotype-intermediate phenotype studies). We used this difference together with data from previous observational studies to compute an expected odds ratio (OR) for non-fatal myocardial infarction (MI) among individuals homozygous for the T allele. We then performed four new genetic association studies (6,201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies).

Results: CRP was 0.68 mg/l [95% confidence interval (95% CI) 0.31-1.10; P = 0.0001] higher among subjects homozygous for the +1444-T allele, with no confounding by a range of covariates. The expected ORs among TT subjects for non-fatal MI corresponding to this difference in CRP was 1.20 (95% CI 1.07-1.38) using the Reykjavik Heart study data and 1.25 (1.09-1.43) for all observational studies to 2004. The estimate for the observed adjusted-OR for non-fatal MI among TT subjects was 1.01 (95% CI 0.74-1.38), lower than both expected ORs.

Conclusions: A common CRP gene polymorphism is associated with important differences in CRP concentrations, free from confounding. The null association of this variant with coronary events suggests possible residual confounding (or reverse causation) in the CRP-coronary event association in observational studies, though the confidence limits are still compatible with a modest causal effect. Additional studies of genotype (or haplotype) and coronary events would help clarify whether or not the link between CRP and coronary events in observational studies is causal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyl041DOI Listing
August 2006

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing.

J Mol Med (Berl) 2006 Mar 31;84(3):203-14. Epub 2005 Dec 31.

Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, Rayne Building, 5 University Street, London WC1E 6JJ, UK.

As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15+/-1.62 vs LDLR=9.13+/-1.16 vs APOB=10.26+/-2.07 mmol/l p<0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71+/-2.39 mmol/l vs 9.88+/-2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p<0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00109-005-0019-zDOI Listing
March 2006

The microsatellite polymorphism of heme oxygenase-1 is associated with baseline plasma IL-6 level but not with restenosis after coronary in-stenting.

Chin Med J (Engl) 2005 Sep;118(18):1525-32

Cardiovascular Department, Second Affiliated Hospital of Jiangxi Medical College, Nanchang 330006, China.

Background: Vascular smooth muscle cells (VSMCs) can express heme-oxygenase (HO), a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide (CO). VSMC-derived CO can suppress VSMC proliferation and may serve as an antiproliferation factor. The promoter region of HO-1 shows a polymorphism with different (GT) n repeats that has been reported to differently induce gene expression. The objective of this study was to examine the effect of this variation on the occurrence of restenosis after in-stent treatment in patients with coronary artery disease.

Methods: Candidates who underwent coronary stent implantation were genotyped for the HO-1 promoter polymorphism using polymerase chain reaction (PCR) and automated DNA capillary sequencer. Serum levels of IL-6 and C-reactive protein (CRP) were obtained at baseline, 24 hours and 48 hours after stenting. The primary end point for the study was angiographic evidence of in-stent restenosis at 6 months. All parameters for evaluation of restenosis were analysed by quantitative computer-assisted angiographic analysis (QCA).

Results: One hundred and eighty-seven patients who underwent coronary stent implantation were studied of whom 27.8% showed > or = 50% restenosis after 6 months. The distribution of (GT) n repeats of all patients in the promoter region of HO-1 genotype ranged from 22 to 42, with (GT) 25 and (GT) 32 being the two most common alleles. The allelic repeats were divided into the short class (S) with 29 (GT) n, the middle class (M) with 30-37 (GT) n and the long class (L) with 38 (GT) n. There was no significant difference in the restenosis between the genotype groups or between post operation levels of inflammation markers, but carriers of the S allele (n = 120) had 33.3% lower baseline IL-6 compared with non-S carriers (n = 67, P = 0.0008).

Conclusions: Although no association was observed between the HO-1 promoter polymorphism and coronary in-stent restenosis following the stent procedure, the association with plasma IL-6 levels suggests that HO-1 S allele might protect from the atherosclerotic inflammatory process.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2005

Inflammatory response to coronary artery bypass surgery: does the heme-oxygenase-1 gene microsatellite polymorphism play a role?

Chin Med J (Engl) 2005 Aug;118(15):1285-90

Cardiovascular Department, Second Affiliated Hospital of Jiangxi Medical College, Nanchang 330006, China.

Background: Heme-oxygenase 1 (HO-1) is a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide (CO) and may have significant anti-inflammatory function. The HO-1 gene promoter region shows microsatellite polymorphism with different (GT)n repeats, reported to differently induce gene expression, with the short allele associated with higher gene expression. We measured the acute inflammatory response using coronary artery bypass surgery (CABG) as a well-characterized and uniform stimulus and examined the correlation between levels of IL-6, C-reactive protein (CRP) and fibrinogen and their relationship to HO-1 genotype.

Methods: Two hundred and seventy-five consecutive patients undergoing CABG were genotyped for the HO-1 promoter polymorphism using PCR and automated DNA capillary sequencer. IL-6, CRP and fibrinogen were measured at baseline and 6, 24, 48, 72, 96 and 120 hours after CABG.

Results: Complete IL-6, CRP and fibrinogen measures were available in 220 patients. Before surgery IL-6 levels showed a strong correlation with CRP and fibrinogen (r = 0.48, P < 0.0001; r = 0.41, P < 0.0001 respectively), with a significant correlation between CRP and fibrinogen (r = 0.61, P < 0.0001). All three acute phase reactants showed a significant increase after CABG. After surgery, peak IL-6 was strongly correlated with peak CRP (r = 0.34, P = 0.0009) but not with peak fibrinogen (r = 0.15, P = 0.13), while peak CRP and peak fibrinogen were significantly correlated (r = 0.415, P < 0.0001). HO-1 allelic repeats ranged from 22-42, with (GT)25 and (GT)32 being the two most common alleles, and subsequently divided into three groups according to previous published work: <30 (GT)n were designated as S (short), 30-37 (GT)n as M (middle) and long repeats with >37 (GT)n as L (long); allele frequency 0.35, 0.58 and 0.07 respectively. Baseline CRP differed by genotype: those carrying at least one long allele having higher CRP than those with no long allele (3.76 +/- 0.79 vs. 2.07 +/- 0.17, P = 0.013). Conversely, those carrying at least one short allele had higher fibrinogen levels than those with no short allele (3.83 +/- 0.79 vs. 3.51 +/- 0.88, P = 0.006).

Conclusions: There is a strong correlation between the measured acute phase reactants both at baseline and after the inflammatory response to CABG in patients with coronary disease. There was an association between the HO-1 microsatellite polymorphism and CRP and fibrinogen levels at baseline but there was no similar association following CABG. This may indicate that HO-1 is associated with chronic atherosclerotic inflammatory processes rather than acute.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2005

A common variant in the glutathione S transferase gene is associated with elevated markers of inflammation and lipid peroxidation in subjects with diabetes mellitus.

Atherosclerosis 2006 Feb 5;184(2):404-12. Epub 2005 Jul 5.

Lipid Research Unit, Rambam Medical Center, The Bruce Rappaport Faculty of Medicine, Haifa, Israel.

Introduction: Glutathione S transferases (GST) are enzymes responsible for the metabolism of numerous xenobiotics and play a major cellular antioxidant role. Our aim was firstly, to examine the association between the GST M1/GST mu-1 (GSTM1) and GST T1/GST theta-1 (GSTT1) gene variants with markers of oxidative stress and inflammation in diabetic patients, and secondly to examine the association and potential interaction between these variants and cigarette smoking.

Methods: Seven hundred and seventy-three Caucasian subjects with diabetes and 2592 Caucasian non-diabetic subjects were successfully genotyped. Plasma total antioxidant status, C-reactive protein (CRP), oxidized-LDL (Ox-LDL) and LDL-mean/peak particle diameter were recorded in the diabetes sample.

Results: No association was seen between genotype and cardiovascular disease (CVD) risk. In the diabetic subjects, GSTT1-1 compared to GSTT1-0 subjects had significantly higher CRP (p=0.001), Ox-LDL (p=0.004) and smaller LDL particles (p=0.01). In subjects without CVD, there was a significant interaction between the GSTT1-1 variant and smoking in determining Ox-LDL (p=0.04). Furthermore, CVD risk was higher in smokers compared to non-smokers with GSTT1-1. No significant associations were observed by GSTM1. Within the non-diabetic sample, no association was observed between genotype and prospective coronary heart disease (CHD) risk. Of note, the frequency of the GSTT1-1 variant was significantly lower in the diabetes subjects compared to the non-diabetic sample (p=0.01).

Conclusions: This study demonstrates an association between the GSTT1-1 variant and markers of inflammation and lipid peroxidation. Furthermore this variant interacts with smoking to increase lipid peroxidation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2005.05.017DOI Listing
February 2006

Influence of factor VII gene polymorphisms and environmental factors on plasma coagulation factor VII concentrations in middle-aged women with and without manifest coronary heart disease.

Thromb Haemost 2005 Feb;93(2):351-8

Cardiology Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

Plasma concentrations of coagulation factorVII (FVII) are determined by environmental and genetic factors. The influence of functional polymorphisms in the FVII gene (-670A>C, -402G>A, -401G>T and R353Q) and of established cardiovascular risk factors on plasma concentrations of FVII were investigated in a representative sample of middle-aged women with (n=238) and without (n=220) coronary heart disease (CHD). Specific and sensitive assays were used to measure FVII antigen (VIIag) and activated factorVII (VIIa). The effect of genotypes was markedly stronger on VIIa than on VIIag, with the percentage variation in FVII levels accounted for by genotypes being greater in controls than in patients. Of the four polymorphisms examined, only the R353Q contributed to the variation inVIIa (24.1% in patients and 30.3% in controls). The -401G>T and -670A>C promoter polymorphisms together accounted for 12.2% of the variation in VIIag amongst patients whereas the -401G>T polymorphism alone contributed 19.7% of the variation in VIIag in controls. Serum triglycerides exerted a major influence onVIIag in both patients (13.0%) and controls (7.2%). Three main haplotypes emerged from the four polymorphisms which accounted for 98% of all haplotypes. Large-scale prospective studies of CHD including FVII haplotypes and sensitive and specific FVII measurements are needed in women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH04-09-0616DOI Listing
February 2005

Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes.

Diabetes 2005 Feb;54(2):582-6

Centre for Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, London, UK.

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)alpha is a master regulator of fatty acid catabolism, and PPARalpha activators delay the onset of type 2 diabetes. We examined association between three PPARalpha gene polymorphisms (an A-->C variant in intron 1, the L162V variant, and the intron 7 G-->C variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPARalpha gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 A-->C (P < 0.001) and intron 7 G-->C (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPARalpha haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/diabetes.54.2.582DOI Listing
February 2005

Plasma fibrinogen concentration predicts the risk of myocardial infarction differently in various parts of Europe: effects of beta-fibrinogen genotype and environmental factors. The HIFMECH Study.

Thromb Haemost 2004 Dec;92(6):1240-9

Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska University Hospital, S-171 76 Stockholm, Sweden.

The propensity to atherothrombotic disease differs in Europe, with high-risk regions located in the North of Europe and lowrisk regions in the South of Europe. The HIFMECH study (Hypercoagulability and Impaired Fibrinolytic function MECHanisms predisposing to myocardial infarction (MI) study) was undertaken to elucidate genetic and environmental mechanisms underlying MI based on investigations of postinfarction patients and healthy individuals recruited from Stockholm, Sweden, London, England (North of Europe), Marseille, France and San Giovanni Rotondo, Italy (South of Europe). In the present report, emphasis was placed on fibrinogen, a multifunctional protein, widely recognized as an independent predictor of atherothrombotic disease. The adjusted plasma fibrinogen concentration was an independent discriminator between cases and controls in London (SOR 3.58; 95% CI 1.31; 9.83), but not in the other centres. Genotyping for six beta-fibrinogen promoter single nucleotide polymorphisms was performed of which -249C/T, -455G/A and -854G/A were used in analysis as a consequence of the linkage disequilibrium pattern. Four haplotypes, with similar distribution across Europe, were detected: CGG (46.7%), CAG (20.3%), TGG (18.2%) and CGA (14.8%). A significant haplotype effect on plasma fibrinogen concentration was observed in patients (p < 0.001) but not in controls (p = 0.08). The -455G/A genotype related to plasma fibrinogen concentration amongst patients along with centre and IL-6 concentration (together explaining 11.5% of the variation), whereas predictors amongst controls included centre, body mass index, IL-6 and smoking habit (explaining 15.7%). Thus, plasma fibrinogen concentration contributes differently to MI across Europe, and a disease-related stimulus is required to evoke allele-specific regulation of fibrinogen synthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH04-06-0339DOI Listing
December 2004

R643G polymorphism in PECAM-1 influences transendothelial migration of monocytes and is associated with progression of CHD and CHD events.

Atherosclerosis 2004 Nov;177(1):127-35

Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Rayne Building, 5 University Street, UCL, London WC1E 6JF, UK.

The 643R allele of R643G polymorphism (also known as R670G in the premature protein) in PECAM-1 has been associated with risk of myocardial infarction (MI), while the 643G allele has been associated with risk of coronary artery stenosis (CAS). The aim of this study was to investigate this apparently conflicting association. The association of R643G with risk of MI was determined in the second Northwick Park Heart study (2037 men with 138 CHD events; mean age: 56 years). Smokers homozygous for the 643R allele showed increased risk of MI with a hazard ratio of 2.47 (95% CI: 1.23-4.97; P=0.01) compared to smokers homozygous for the 643G allele. Progression of disease was determined in the Lopid Coronary Angiography Trial (279 men; mean age: 58.9 years). The 643G homozygotes showed greater focal (-0.08 +/- 0.02 mm) and diffuse (-0.01 +/- 0.01 mm) progression of CAS compared to 643R homozygotes (-0.02 +/- 0.02 mm and 0.001 +/- 0.01 mm, respectively; P=0.04). While there was no genotype effect on platelet aggregation, PECAM-1 tyrosine phosphorylation in HUVECs of GG genotype was 2.4-fold greater (P <0.01) than cells of RR genotype, and the level of transendothelial migration of monocytes of GG genotype was greater than that of monocytes of RR genotype following stimulation with either IL-1beta (12% higher, P <0.01) or TNF-alpha (10% higher, P=0.05). These data confirm the association of the R643G polymorphism with MI and CAS and suggest that greater influx of monocytes in individuals homozygous for the 643G may explain the association with CAS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2004.06.009DOI Listing
November 2004

No APOEepsilon4 effect on coronary heart disease risk in a cohort with low smoking prevalence: the Whitehall II study.

Atherosclerosis 2004 Nov;177(1):105-12

British Heart Foundation Laboratories, Department of Medicine, Centre for Cardiovascular Genetics, Rayne Building, University College London, 5 University Street, London WC1E 6JF, UK.

Carriers of the APOEepsilon4 allele have consistently shown higher, and epsilon2 carriers have lower, plasma cholesterol and coronary heart disease (CHD) risk compared with epsilon3 homozygotes. An epsilon4:smoking interaction was observed in NPHSII, consistent with context dependency of the epsilon4 effect on CHD risk. In this study, APOE genotype was determined in 3787 male British civil servants followed for fatal and non-fatal myocardial infarction for median of 5.8 years, with 159 validated CHD events. APOE genotype was associated with expected effects on lipid traits (all P <0.0001). We tested the hypothesis that APOEepsilon4 was not a risk factor for CHD among non-smokers. In non-smokers, the odds ratio (OR) for epsilon2 and epsilon4 carriers were 0.51 (0.27, 0.97) and 0.70 (0.46, 1.08), respectively, compared with epsilon3 homozygotes. Thus epsilon2 carriers showed expected risk-protection, but despite 80% power to detect an OR in epsilon4 subjects of 1.71 (i.e. of magnitude increase reported in prospective studies), the epsilon4 non-smokers showed no increased risk compared with epsilon3 homozygotes. Smoking prevalence in this study was low (12.8%), but smokers had higher CHD risk which was of similar magnitude in risk in all genotypes [(OR 1.57 (1.03, 2.40)]. These data, therefore, provide strong corroborative evidence that there is no elevated risk of CHD in epsilon4 non-smokers, but failed to confirm the epsilon4:smoking interaction on risk. This supports the context dependency of the epsilon4 risk effect, but the low smoking incidence in the Whitehall men reduced our ability to examine a smoking:genotype interaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2004.06.008DOI Listing
November 2004

Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study.

Hypertension 2004 Nov 13;44(5):702-7. Epub 2004 Sep 13.

Genetics and Human Biology Laboratory, Department of Medicine at Universidad Autónoma de Bucaramanga, Colombia, Campus el Bosque, Calle 157 No. 19-55 Cañaveral Parque, Colombia.

Polymorphisms in the endothelial NO synthase (eNOS) gene have been evaluated as risk factors for preeclampsia. However, data from small studies are conflicting. We assessed whether eNOS genotypes alter the risk of preeclampsia in a population in which the incidence of this disorder is high. A total of 844 young pregnant women (322 preeclamptic and 522 controls) were recruited from 5 cities. Genotyping for the Glu298Asp, intron-4 and -786T-->C polymorphisms in the eNOS gene was conducted. Multivariate odds ratios (ORs) were obtained to estimate the association of individual polymorphisms and haplotypes with preeclampsia risk. No increase in the risk of preeclampsia for the intron-4 or -786T-->C polymorphisms was observed under any model of inheritance. In contrast, in women homozygous for the Asp298 allele, the adjusted OR for preeclampsia was 4.60 (95% confidence interval [CI], 1.73 to 12.22) compared with carriers of the Glu298 allele. After a multivariate analysis, carriage of the "Asp298-786C-4b" haplotype was also associated with increased risk of preeclampsia (OR, 2.11 [95% CI, 1.33 to 3.34]) compared with carriers of the "Glu298-786T-4b" haplotype. The eNOS Glu298Asp polymorphism and the Asp298-786C-4b haplotype are risk factors for preeclampsia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/01.HYP.0000143483.66701.ecDOI Listing
November 2004

Evidence of admixture from haplotyping in an epidemiological study of UK Caucasian males: implications for association analyses.

Hum Hered 2004 ;57(3):142-55

Human Genetics Division, School of Medicine, University of Southampton, Southampton General Hospital, England.

Objective: Cohort and case-control genetic association studies offer the greatest power to detect small genotypic influences on disease phenotypes, relative to family-based designs. However, genetic subdivisions could confound studies involving unrelated individuals, but the topic has been little investigated. We examined geographical and interallelic association of SNP and microsatellite haplotypes of the Y chromosome, of regions of chromosome 11, and of autosomal SNP genotypes relevant to cardiovascular risk traits in a UK-wide epidemiological survey.

Results: We show evidence (p = 0.00001) of the Danelaw history of the UK, marked by a two-fold excess of a Viking Y haplotype in central England. We also found evidence for a (different) single-centre geographical over-representation of one haplotype, both for APOC3-A4-A5 and for IGF2. The basis of this remains obscure but neither reflect genotyping error nor correlate with the phenotypic associations by centre of these markers. A panel of SNPs relevant to cardiovascular risks traits showed neither association with geographical location nor with Y haplotypes.

Conclusion: Combinations of Y haplotyping, autosomal haplotyping, and genome-wide SNP typing, taken together with phenotypic2 associations, should improve epidemiological recognition and interpretation of possible confounding by genetic subdivision.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000079245DOI Listing
February 2005

Angiotensin converting enzyme genotype and strength in chronic obstructive pulmonary disease.

Am J Respir Crit Care Med 2004 Aug 29;170(4):395-9. Epub 2004 Apr 29.

Respiratory Muscle Laboratory, Royal Brompton Hospital, Fulham Road, London, SW3 6NP, United Kingdom.

Quadriceps muscle weakness is an important contributor to exercise limitation in patients with chronic obstructive pulmonary disease. The deletion allele of the angiotensin converting enzyme gene polymorphism has previously been associated with a greater response to strength training in healthy subjects and might, therefore, protect against detraining in these patients. In 103 stable outpatients (mean [SD] FEV(1) 34.4 [16.5] % predicted), the angiotensin deletion allele was associated with greater isometric quadriceps strength; mean (SD) 31.4 (10.8) kg for insertion homozygotes, 34.1 (13.0) kg for heterozygotes, and 38.3 (11.6) kg for deletion homozygotes (p = 0.04 linear trend). Adjusted for fat-free mass, the relationship was stronger (linear trend p = 0.007). There was no correlation between strength and genotype in a group of 101 age-matched healthy control subjects. Twitch quadriceps force in response to magnetic femoral nerve stimulation, measured in 39 patients, was also genotype dependent; 8.3 (2.6) kg for insertion homozygotes, 10.1 (3.6) kg for heterozygotes, and 12.4 (3.5) kg for deletion homozygotes (p = 0.002 linear trend). Body mass index and fat-free mass did not differ significantly between genotypes in either group. There was no association in either patients or control subjects between genotype and inspiratory muscle strength. In chronic obstructive pulmonary disease the deletion allele is associated with greater quadriceps strength independent of confounding factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.200304-578OCDOI Listing
August 2004

Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits.

Hum Mol Genet 2004 Apr 28;13(7):715-25. Epub 2004 Jan 28.

Human Genetics Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK.

The IGF2-INS-TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD). Here we present detailed haplotype analysis of 2743 males 51-62 years old in relation to body weight and composition, blood pressure (BP) and plasma triglycerides (TG). Use of the total data set was complicated by the number of loci typed, missing data, multi-allelic markers and continuous trait phenotypes. Different algorithms and subsets of the data were analysed using the programmes haplotype trend regression, haplo.score, evolutionary-based haplotype analysis package and Phase, in conjunction with SPSS. Ten haplotypes designated in frequency order *1(20.0%) to *10(3.4%) represented 89% of all haplotypes. Haplotype *5 protected against obesity. Haplotype *4 carriers exhibited elevated BP and fat mass, haplotype *6 was associated with raised plasma TG levels. Haplotype *8 also showed similar magnitude effects as *4. These cohort trait analyses and detailed haplotypic analyses enable integration with published case data. Haplotypes *4, *6 and *8 are the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displays unique features in all three genes (with significant commonality with type 1 diabetes-predisposition haplotypes). We propose that long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, predisposes to the metabolic syndrome features of elevated BP, fat mass or TG level, therefore appearing more frequently in type 2 diabetic, polycystic ovary syndrome and CHD cases. The functional element(s) of *5 for weight-lowering could reside in any of the three genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddh070DOI Listing
April 2004

Early atherogenesis in senescence-accelerated mice.

Exp Gerontol 2004 Jan;39(1):115-22

The Cell Biology Group at the Centre for Cardiovascular Biology and Medicine, Department of Medicine, University College London, Rayne Building, 5 University Street, London WC1E 6JJ, UK.

We studied atheromatous lesion formation in an animal model of accelerated ageing. The senescence-accelerated prone mouse (SAM-P) has a reduced life-span and exhibits clinical features characteristic of human ageing. Our aim was to establish whether these mice are more susceptible to atherosclerosis than a related strain, senescence-accelerated resistant mice (SAM-R), which age normally. We fed a Western-type diet to 14 SAM-P/8 and 14 SAM-R/1 mice for 17 weeks, starting at 28 weeks of age, measuring their serum lipid profiles before and after this diet. We stained aortic root cryostat cross-sections with Oil red O, and assessed lipid deposition morphometrically. We used immunohistochemistry to detect macrophages in the aortic roots. We found that despite showing similar alterations in lipid profile, SAM-P/8 mice developed more prevalent and extensive fatty lesions than SAM-R/1 mice. Furthermore, the lipid lesions in SAM-P/8 mice showed a greater frequency of invasion by macrophages. We conclude that mice, which age at an accelerated rate, are more prone to early atherogenesis than mice which age normally. We suggest that this increased susceptibility may result from abnormalities in the oxidative status and cellular replicative capacity of these mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exger.2003.10.004DOI Listing
January 2004

Human paraoxonase gene cluster polymorphisms as predictors of coronary heart disease risk in the prospective Northwick Park Heart Study II.

Biochim Biophys Acta 2003 Nov;1639(3):203-12

Division of Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University St., London WC1E 6JF, UK.

The anti-atherogenic effect of HDL has been suggested to be partly due to the action of HDL-associated paraoxonase (PON). Three distinct enzymes have been identified, encoded by PON1, PON2 and PON3, clustered on chromosome 7q21-q22. Two cSNPs in PON1 (L55M and Q192R) and one in PON2 (S311C) have been implicated as independent risk factors for coronary heart disease (CHD) in some, but not all, studies. A PON3 SNP (A99A) was identified and the effect of these four PON SNPs on HDL levels and CHD risk was examined in the prospective Northwick Park Heart Study II (NPHSII). Genotype frequencies did not differ between cases and controls but the CHD risk associated with smoking was significantly modified by PON1 L55M genotype. Compared to LL non-smokers, LL smokers had a hazard ratio (HR) of 1.30 (95% CI 0.81-2.06) while M-allele carriers had a HR of 1.76 (1.17-2.67). When genotypes were analysed in combination, men with the genotype PON1 55 LM/MM+PON2 311 CC, had HR of 3.54 (1.81-6.93) compared to PON1 LL+PON2 SS/SC men (interaction P=0.004). These effects were independent of classical risk factors. These data demonstrate the importance of stratifying by environmental factors and the use of multiple SNPs for genetic analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2003.09.008DOI Listing
November 2003

Bradykinin receptor gene variant and human physical performance.

J Appl Physiol (1985) 2004 Mar 7;96(3):938-42. Epub 2003 Nov 7.

Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, UK.

Accumulating evidence suggests that athletic performance is strongly influenced by genetic variation. One such locus of influence is the gene for angiotensin-I converting enzyme (ACE), which exhibits a common variant [ACE insertion (I)/deletion (D)]. ACE can drive formation of vasoconstrictor ANG II but preferentially degrades vasodilator bradykinin. The ACE I allele is associated with higher kinin activity. A common gene variant in the kinin beta(2) receptor (B(2)R) exists: the -9 as opposed to +9 allele is associated with higher receptor mRNA expression. We tested whether this variant was associated with the efficiency of muscular contraction [delta efficiency (DE)] in 115 healthy men and women, or with running distance among 81 Olympic standard track athletes. We further sought evidence of biological interaction with ACE I/D genotype. DE was highly significantly associated with B(2)R genotype (23.84 +/- 2.41 vs. 24.25 +/- 2.81 vs. 26.05 +/- 2.26% for those of +9/+9 vs. +9/-9 vs. -9/-9 genotype; n = 25, 61, and 29, respectively; P = 0.0008 for ANOVA adjusted for sex). There was evidence for interaction with ACE I/D genotype, with individuals who were ACE II, with B(2)R -9/-9 having the highest DE at baseline. The ACE I/B(2)R -9 "high kinin receptor activity" haplotype was significantly associated with endurance (predominantly aerobic) event among elite athletes (P = 0.003). These data suggest that common genetic variation in the B(2)R is associated with efficiency of skeletal muscle contraction and with distance event of elite track athletes and that at least part of the associations of ACE and fitness phenotypes is through elevation of kinin activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.00865.2003DOI Listing
March 2004

The serum angiotensin-converting enzyme and angiotensin II response to altered posture and acute exercise, and the influence of ACE genotype.

Eur J Appl Physiol 2004 Mar 1;91(2-3):342-8. Epub 2003 Nov 1.

Department of Diabetes and Endocrinology, Freeman Hospital, Newcastle upon Tyne, UK.

The deletion (D) rather than insertion (I) allele of the angiotensin-converting enzyme (ACE) gene is associated with greater ACE activity. We examined: (1) the influence of posture change (recumbent to seated) and acute exercise on serum ACE and angiotensin II (Ang II) activity; (2) the relationship between ACE and Ang II levels; and (3) the influence of ACE genotype on changes in ACE and Ang II levels with posture and exercise. Recreationally active young male Caucasians (10 each of II, ID and DD genotypes) rested for 35 min supine then 15 min upright, took 20 min bicycle ergometric exercise at 70% maximum oxygen uptake, then rested for 40 min. Samples were taken throughout for ACE activity and Ang II levels. Supine ACE levels were dependent upon ACE genotype [24.8 (5.7), 26.9 (4.5), 45.5 (6.4) nmol His-Leu ml(-1) min(-1); II, ID, DD, respectively; P<0.00005] and thereafter. ACE activity rose with assumption of a seated posture [from 32.4 (10.9) nmol His-Leu ml(-1) min(-1) to 35.0 (11.5) nmol His-Leu ml(-1) min(-1), P<0.00001], the absolute rise being independent of genotype [3.22 (1.92), 1.6 (1.6), 2.4 (2.3) nmol His-Leu ml(-1) min(-1); II, ID, DD; P=0.22], unlike percentage change [12.8 (6.8), 5.6 (5.5), 5.3 (5.0)%; II, ID, DD; P<0.01, and P=0.004 for II vs presence of the D allele]. A further genotype-independent rise occurred with exercise [+2.9 (3.7) units, P<0.0003]. An associated rise in Ang II levels [30.3 (15.9), or 2587.9 (489.76)%, P<0.00001] was independent of ACE genotype or activity. Upright posture increases ACE activity, and this may be influenced by ACE genotype. ACE activity and Ang II levels rise independently with exercise in a non-genotype-dependent fashion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00421-003-0993-1DOI Listing
March 2004

Variation in bradykinin receptor genes increases the cardiovascular risk associated with hypertension.

Eur Heart J 2003 Sep;24(18):1672-80

Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free & University College London Medical School, Rayne Building, London, UK.

Aims: The contribution of kinins to the beneficial effects of angiotensin I converting enzyme (ACE) inhibition in cardiovascular risk reduction remains unclear. The genes for the kinin inducible B1 receptor (B(1)R) and constitutive B2 receptor (B(2)R) contain functional variants: the B(1)R-699C (rather than G) and the B(2)R(-9) (rather than +9) alleles are associated with greater mRNA expression and the B(2)R(-9) allele with reduced left ventricular hypertrophic responses. We tested whether these gene variants influenced hypertensive coronary risk in a large prospective study.

Methods And Results: Two thousand, seven hundred and six previously healthy UK men (mean age at recruitment 56 years; median follow-up 10.8 years) were genotyped for the kinin receptor variants. The coronary risk attributable to systolic hypertension (SBP>/=160 mmHg) was significantly higher only in B(1)R-699GG homozygotes (HR 2.14 [1.42-3.22]; P<0.0001) and B(2)R(+9,+9) individuals (HR 3.51 [1.69-7.28]; P=0.001) but not in B(1)R-699C allele carriers (HR 0.82 [0.28-2.42]; P=0.76) or in B(2)R(-9,-9) homozygotes (HR 1.25 [0.51-3.04]; P=0.63).

Conclusions: Common variation in the genes for the kinin B(1)and B(2)receptors influences prospective hypertensive coronary risk. These are the first reported human data to suggest a role for the B(1)R in human coronary vascular disease, and the first prospective study to demonstrate a similar role for the B(2)R.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0195-668x(03)00441-xDOI Listing
September 2003
-->