Search

Background and Aims: Increased oxidative stress is associated with coronary heart disease (CHD). The mitochondrial uncoupling protein-2 (UCP2) negatively regulates reactive oxygen species generation. We have observed that a common variant (-866G>A) in the promoter region of UCP2 is associated with increased CHD risk in healthy men and increased oxidative stress in diabetic men with CHD. The aim of the current study was to test the hypothesis that this variant might interact with smoking (an environmental stress) to influence plasma markers of oxidative stress. Methods and Results: Amongst 453 Caucasian diabetic men there was a significant interaction (p=0.001) between genotype and smoking in determining plasma Total AntiOxidant Status (TAOS). Current smokers with the -866AA genotype had the lowest TAOS (indicating higher oxidative stress) of all subjects (AA vs. GG: 32.00+/-17.4% vs. 45.8+/-12.6%, p=0.04). In a sub-sample of 20 subjects (10 GG, 10 AA) matched for baseline characteristics, plasma markers of oxidative stress in current smokers were significantly higher in AA compared to GG subjects (TAOS 36.8+/-9.5% vs. 51.4+/-9.5%, p=0.04; F(2)-isoprostanes 1133.6+/-701.2 pg ml(-1) vs. 500.8+/-64.7 pg ml(-1), p=0.04). Conclusions: This study demonstrates an interaction between the UCP2 -866G>A variant and smoking to increase oxidative stress in vivo. [ABSTRACT FROM AUTHOR]

Meningococcal pericarditis is classically divided into three separate entities: isolated meningococcal pericarditis, disseminated meningococcal disease with pericarditis, and reactive (immunopathic) meningococcal pericarditis. We present the case of a 74-year-old woman with meningococcal septicaemia with meningococcal myopericarditis, which demonstrates crossover features., (© Royal College of Physicians 2018. All rights reserved.)

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role., (© 2016 The Authors. BioEssays published by WILEY Periodicals, Inc.)

Uncoupling proteins 2 and 3 (UCP2 and UCP3) may negatively regulate mitochondrial ATP synthesis and, through this, influence human physical performance. However, human data relating to both these issues remain sparse. Examining the association of common variants in the UCP3/2 locus with performance phenotypes offers one means of investigation. The efficiency of skeletal muscle contraction, delta efficiency (DE), was assessed by cycle ergometry in 85 young, healthy, sedentary adults both before and after a period of endurance training. Of these, 58 were successfully genotyped for the UCP3-55C>T (rs1800849) and 61 for the UCP2-866G>A (rs659366) variant. At baseline, UCP genotype was unrelated to any physical characteristic, including DE. However, the UCP2-866G>A variant was independently and strongly associated with the DE response to physical training, with UCP2-866A allele carriers exhibiting a greater increase in DE with training (absolute change in DE of -0.2 ± 3.6% vs. 1.7 ± 2.8% vs. 2.3 ± 3.7% for GG vs. GA vs. AA, respectively; P = 0.02 for A allele carriers vs. GG homozygotes). In multivariate analysis, there was a significant interaction between UCP2-866G>A and UCP3-55C>T genotypes in determining changes in DE (adjusted R(2) = 0.137; P value for interaction = 0.003), which was independent of the effect of either single polymorphism or baseline characteristics. In conclusion, common genetic variation at the UCP3/2 gene locus is associated with training-related improvements in DE, an index of skeletal muscle performance. Such effects may be mediated through differences in the coupling of mitochondrial energy transduction in human skeletal muscle, but further mechanistic studies are required to delineate this potential role.

Background: A variant in the promoter of the human uncoupling protein 2 (UCP2) gene, the G-866A polymorphism, has been associated with future risk of coronary heart disease events, in those devoid of traditional risk factors and in those suffering from diabetes. We thus examined the impact of the G-866A polymorphism on 5-year survival in a cohort of 901 post-myocardial infarction patients, and the impact of type-2 diabetes on this relationship. The association of UCP2 with baseline biochemical and hormonal measurements, including levels of the inflammatory marker myeloperoxidase, was also examined., Methods: UCP2 G-866A genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Myeloperoxidase levels were measured in plasma samples taken from 419 cohort patients 24-96 hours after admission., Results: Genotypes were obtained for 901 patients with genotype frequencies AA 15.5%, GA 45.5%, and GG 39.0%. Genotype was not associated with survival in the overall cohort (mortality: AA 15.6%, GA 16.8%, GG 19.4%, p = 0.541). However, amongst diabetics, AA and GA genotype groups had significantly worse survival than GG diabetic patients (p < 0.05) with an attributable risk of 23.3% and 18.7% for those of AA and GA genotype respectively. Multivariate analysis using a Cox proportional hazards model confirmed that the interaction of diabetes with genotype was significantly predictive of survival (p = 0.031). In the cohort's diabetic subgroup AA/GA patients had higher myeloperoxidase levels than their GG counterparts (GA/AA, n = 51, 63.9 +/- 5.23; GG, n = 34, 49.1 +/- 3.72 ng/ml, p = 0.041). Further analysis showed that this phenomenon was confined to male patients (GA/AA, n = 36, 64.3 +/- 6.23; GG, n = 29, 44.9 +/- 3.72 ng/ml, p = 0.015)., Conclusion: Diabetic patients in this post-myocardial infarction cohort with UCP2 -866 AA/GA genotype have poorer survival and higher myeloperoxidase levels than their GG counterparts.

Background: The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated., Methods: Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity., Results: Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia., Conclusions: High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.

The insertion (I) variant of the angiotensin-1 converting enzyme (ACE) I/D genetic polymorphism is associated with lower circulating and tissue ACE activity. Some studies have also suggested associations of ACE I/D genotype with endurance phenotypes. This study assessed the relationships between circulating ACE activity, ACE I/D genotype, mechanical efficiency and the maximal rate of oxygen uptake in sedentary individuals. Sixty-two untrained women were tested for mechanical efficiency during submaximal cycle ergometry (delta and gross efficiencies during exercise between 40 and 80 W) and the maximal rate of oxygen uptake during incremental treadmill running. Respiratory variables were measured using indirect calorimetry. Venous blood was obtained for direct assay of circulating ACE activity, allowing for the assessment of correlations between two continuous variables, rather than a categorical analysis of endurance phenotype by genotype alone. ACE I/D genotype was also determined, and was strongly associated with circulating ACE activity (P < 0.0005). Neither circulating ACE activity (27.4 +/- 8.4 nM His-Leu-ml(-1)) nor ACE genotype showed a statistically significant association with any of the endurance phenotypes measured. The weak correlations observed included r = -0.122 (P = 0.229) for the relationship between delta efficiency (23.9 +/- 2.5%) and circulating ACE activity and r = 0.134 (P > 0.6) for the relationship between maximal aerobic power (149.1 +/- 22.9 ml kg(-2/3) min(-1)) and circulating ACE activity. The data do not support a role for systemic ACE activity in the regulation of endurance performance in sedentary individuals, extending this observation to a large female cohort.

The strong association between the angiotensin I-converting enzyme (ACE) gene I/D polymorphism with serum ACE activity appears lacking in Nigerians and Kenyans, but has not previously been well assessed in others of African origin. This study addressed this issue in an ethnically well defined black South African population. A putative association for the A22982G ACE gene variant, a QTL likely to impact on serum ACE activity, was also sought. Subjects were 200 healthy male black South African volunteers from the Xhosa ethnic group. Venous blood was obtained from all subjects for DNA extraction. ACE I/D and A22982G genotypes were determined and serum ACE activity measured. Age and blood pressure were recorded. For the group as a whole (mean +/- SD age 38.5 +/- 9.8 years, SBP 119.6 +/- 14.1 mmHg, DBP 78.2 +/- 10.1 mmHg) serum ACE activity was 38.2 +/- 11.2 nmol ml(-1)min(-1). ACE I/D genotype was not significantly associated with serum ACE activity. In contrast, the A22982G variant was significantly associated with serum ACE activity, being 35.9 +/- 9.6, 38.1 +/- 10.6 and 42.4 +/- 15.3 nmol ml(-1)min(-1) for AA, AG and GG genotypes respectively; p = 0.03 by ANOVA and p = 0.01 by linear trend. In keeping with the findings in some other African populations, the ACE I/D polymorphism is not strongly associated with serum ACE activity in Xhosa South Africans. As such, it cannot be used as a marker of ACE activity in these subjects. In this regard the use of the A22982G gene variant may be more appropriate.

Aims: The D allele of the ACE I/D gene variant is associated with higher tissue and serum ACE activity. Previously, studies have suggested an association between the D allele with the microvascular complications of diabetes. The aim of this study was to explore the impact of this genotype in relation to clinically manifest peripheral neuropathy (PN) in a cohort of subjects with type 2 diabetes mellitus (type 2 DM)., Methods: Five hundred and seventy-two Caucasian subjects (230 females, 342 males) with type 2 DM were recruited from the diabetes clinic at University College London Hospitals NHS Trust. Clinically manifest PN was determined from a standardized clinical examination., Results: The ACE I/D genotype distribution was in Hardy-Weinberg equilibrium. In the whole group, no significant association was seen between genotype and PN; however, when stratified by sex, the D allele was associated with PN in females but not in males. The odds ratio (OR) for PN in the D allele carriers compared to those homozygous for the I allele was significantly higher in females [OR 2.93 (1.09-7.63), P=.027] but not in males [OR 1.2 (0.61-2.36), P=.60]., Conclusions: The presence of the D allele is associated with increased risk of peripheral neuropathy in females but not in male subjects with type 2 DM, suggesting a role for the renin-angiotensin system in the development of PN.

Aims/hypothesis: Plasma semicarbazide-sensitive amine oxidase (SSAO) is elevated in patients with type 1 and type 2 diabetes and has been implicated in the pathophysiology of diabetic late complications. The regulation of SSAO production remains unknown. We studied correlations between plasma SSAO activity and parameters associated with diabetic late complications., Methods: Plasma SSAO was measured in a well-characterised group of 287 patients with type 1 diabetes. Standard statistical methods were used to investigate correlations with clinical parameters and components of the renin-angiotensin system., Results: Overall, plasma SSAO was elevated, at 693+/-196 mU/l (mean+/-SD; normal controls 352+/-102 mU/l). Plasma SSAO was higher in the group with late complications or hypertension, and in patients treated with ACE-inhibitors. In univariate analysis a significant positive correlation (p<0.001, r=0.27) was found between plasma SSAO and serum ACE activity in patients untreated with ACE inhibitors or angiotensin II receptor antagonists (n=221), but plasma SSAO did not differ by ACE I/D genotype. Plasma SSAO correlated positively with duration of diabetes, HbA(1)c and plasma renin, and negatively with plasma angiotensinogen and body mass index. A multiple regression analysis including these variables resulted in serum ACE activity (p<0.001), ACE genotype (negatively, p<0.001) and HbA(1)c (p=0.023) as explaining variables., Conclusions/interpretation: Results suggest that a common factor is involved in the regulation of both plasma SSAO and serum ACE, which is different from the genetic determination of ACE activity.

The deletion D allele of the angiotensin-I converting enzyme (ACE) I/D gene variant is associated with higher ACE activity in Caucasians and previous studies in non-Caucasian samples have suggested an association between the D allele and type 2 diabetes (Type 2DM). The aim of this study was to compare the genotype distribution between Caucasian subjects with Type 2DM and non-diabetic Caucasian men. Genotype distribution was compared between 574 Caucasian subjects with Type 2DM, recruited from the UCL Diabetes and Cardiovascular Disease Study and 2413 non-diabetic Caucasian men, recruited from the second Northwick Park Heart Study. Within both samples, genotype distributions were in Hardy-Weinberg equilibrium. The genotype distributions in those with Type 2DM compared to the non-diabetic men (II/ID/DD) was 18%/50%/32% vs. 23%/49%/27%, p=0.004. In accordance with this, the frequency of the D allele was higher in those with Type 2DM (0.574 [0.55-0.60] vs. 0.519 [0.50-0.53], p=0.001). On combining the two samples, the odds ratio (OR) for Type 2DM was significantly higher in D allele carriers compared to II subjects (OR=1.55, p=0.02, after adjustment for age, sex, BMI, blood pressure, and lipids). In those with diabetes, there was a significant association between genotype and a family history of diabetes. The odds ratio for a family history of diabetes in DD compared to II subjects was 1.52 [0.89-2.60], p=0.03. This study clearly shows an association between the ACE I/D common gene variant and Type 2DM.

Introduction: The tissue renin-angiotensin system is implicated in the pathogenesis of coronary artery disease (CAD). As locally synthesised aldosterone is a potential mediator of CAD, we have sought an association of the -344T>C variant of the aldosterone synthase (CYP11B2) gene with CAD events., Methods: Subjects comprised of the Second Northwick Park Heart Study (NPHSII), a prospective study of unrelated, healthy middle-aged Caucasian males. CAD events were recorded in 2490 subjects, and defined as a sudden cardiac death, myocardial infarction or coronary artery revascularisation procedure. Mean follow-up was 10.8 years. Aldosterone synthase genotype was determined in 2490 subjects. Power calculation suggests that we have 80% power (at a significance level of 0.05) to detect a difference in hazard ratio (HR) between homozygote groups of 0.45., Results: One hundred and eighty-seven CAD events were recorded in 2490 subjects. In the group overall, CAD events were independent of genotype with adjusted hazard ratios being 1.00 versus 1.25 versus 0.80 for TT versus TC versus CC genotypes, respectively, P = 0.07. Genotype interactions with smoking and blood pressure were sought. Whilst CAD events were independent of genotype amongst non-smokers, CC genotype in smokers was associated with a reduced risk HR 2.02 versus 2.28 versus 0.82 for TT versus TC versus CC genotypes, P = 0.05 (HR for TT + TC versus CC were 1.77 versus 0.67, P = 0.02). This apparent interaction remained after adjustment for conventional risk factors. No such interaction was found with blood pressure., Conclusions: Aldosterone synthase genotype is unrelated to overall CAD events risk. A possible interaction with smoking requires confirmation.

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.

Background: Oxidative stress reduces total antioxidant status (TAOS) and is implicated in atherogenesis. Mitochondrial uncoupling protein 2 (UCP2) negatively regulates reactive oxygen species generation. The UCP2 gene demonstrates a common functional promoter variant (-866G>A)., Methods and Results: Amongst 465 diabetic men (age 61.7 +/- 13.3 years), an association of the UCP2-866A allele with significantly lower TAOS in those without CHD was even more pronounced in those with CHD (TAOS 30.1 +/- 16.1% vs. 41.6 +/- 12.4% for AA vs. GG; P=0.016). In a sample of 20 diabetic men selected for homozygosity for the UCP2-866G>A variant, matched for baseline characteristics, plasma markers of oxidative stress in those with CHD were significantly higher in AA genotype men (TAOS 31.7 +/- 7.3% vs. 52.6 +/- 6.3%; P=0.001 and F2-isoprostanes 220.6 +/- 37.2 pg ml(-1) vs. 109.9 +/- 51.1 pg ml(-1); P=0.005 for AA vs. GG). Amongst 2695 healthy men (age 56.1 +/- 3.5 years) prospectively studied for a median 10.2 years, AA homozygotes had a highly significant doubling in CHD risk after adjustment for established risk factors (HR 1.99 [1.37-2.90]; P=0.002). Risk associated with this genotype was substantially increased by the presence of other risk factors (obesity, hypertension and diabetes)., Conclusions: This study provides the first in vivo evidence of a role for UCP2 in modifying oxidative stress and CHD risk in humans.

Renin-angiotensin systems may mediate cardiovascular disease pathogenesis through a balance of actions of angiotensin II on (potentially proatherogenic) constitutive type 1 (AT1R) and (potentially antiatherogenic) inducible type 2 (AT2R) receptors. We explored such potential roles in a prospective candidate gene association study. Cardiovascular end points (fatal, nonfatal, and silent myocardial infarction and coronary artery bypass surgery/angioplasty) were documented among 2579 healthy UK men (mean age, 56.1+/-3.5 years; median follow-up, 10.1 years) genotyped for the AT1R1166A>C and the X chromosome located AT2R1675A>G and 3123C>A polymorphisms. Baseline characteristics, including blood pressure, were independent of genotype. The AT1R1166CC genotype was associated with relative cardiovascular risk (hazard ratio, 1.65 [1.05 to 2.59]; P=0.03) independent of blood pressure. Systolic blood pressure was associated with risk (P=0.0005), but this association was restricted to AT2R1675A allele carriers (P<0.00001), with G allele carriers protected from the risk associated with blood pressure (P=0.18). Hypertensive carriers with the AT2R1675A/3123A haplotype were at most risk, with 37.5% having an event. This is the first study to demonstrate an association of AT2R genotype with coronary risk, an effect that was confined to hypertensive subjects and supports the concept that the inducible AT2R is protective. Conversely, the AT1R1166CC genotype was associated with cardiovascular risk irrespective of blood pressure. These data are important to our understanding of the divergent role of angiotensin II acting at its receptor subtypes and coronary disease pathogenesis and for the development of future cardiovascular therapies.

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.

The objective of this study was to examine the relationship between the interleukin-6 (IL-6) -174 G>C promoter polymorphism and exercise-induced femoral cortical bone resorption. Skeletal response to exercise was assessed in 130 male Caucasian army recruits. Five cross-sectional magnetic resonance images of the right femur were obtained before and after a 10-week period of basic physical training, and changes in cross-sectional cortical area were calculated. Recruits were genotyped for the -174 G>C IL-6 promoter polymorphism. Genotype frequencies (GG 36%, GC 47%, CC 22.17%) were in Hardy-Weinberg equilibrium. The mean percentage change in proximal femoral cross-sectional cortical area was strongly IL-6 genotype-dependent, with GG homozygotes losing 6.8 (3.82)% in cortical area, GC gaining+5.5 (4.88)% and CC gaining+17.3 (9.46)% (P=0.007 for linear trend). These changes persisted throughout the right femur and were significant in the femur as a whole (P=0.03). This study demonstrates an association between a functional polymorphism in the IL-6 gene and femoral cortical remodelling during strenuous physical exercise. Previous studies have suggested an important role for IL-6 in the regulation of bone mass in postmenopausal women, and in the invasion of bone by metastatic tumour deposits. These data extend these observations to the regulation of bone mass in healthy males, supporting a fundamental role for IL-6 in the regulation of bone mass and bone remodelling in humans.