Publications (84)384.05 Total impact
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Article: Mitochondrial reactive oxygen species enhance AMPK activation in the endothelium of patients with coronary artery disease and diabetes.
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ABSTRACT: The aim of this study was to determine whether the endothelial dysfunction associated with coronary artery disease (CAD) and type 2 diabetes (T2D) is concomitant with elevated mitochondrial reactive oxygen species (mtROS) production in the endothelium and establish if this, in turn, regulates the activity of endothelial AMP-activated protein kinase (AMPK). We investigated endothelial function, mtROS production and AMPK activation in saphenous veins from patients with advanced CAD. Endothelium-dependent vasodilation was impaired in patients with CAD and T2D relative to those with CAD alone. Levels of mitochondrial hydrogen peroxide and activity of AMPK were significantly elevated in primary saphenous vein endothelial cells (HSVECs) from patients with CAD and T2D compared to those from patients with CAD alone. Incubation with the mitochondria-targeted antioxidant, MitoQ10 significantly reduced AMPK activity in HSVECs from patients with CAD and T2D but not in cells from patients with CAD alone. Elevated mtROS production in the endothelium of patients with CAD and T2D increases AMPK activation, supporting a role for the kinase in defence against oxidative stress. Pharmacological activators of AMPK may therefore have enhanced potential in prevention and treatment of endothelial dysfunction in these patients.Clinical Science 10/2012; · 4.61 Impact Factor -
Article: Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci.
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ABSTRACT: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor -
Article: Proteomics in hypertension and other cardiovascular diseases.
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ABSTRACT: Hypertension is a major cardiovascular risk factor with a multifactorial pathogenesis, including genetic and environmental factors. In addition to hypothesis-driven strategies, unbiased approaches such as genomics, proteomics, and metabolomics are useful tools to help unravel the pathophysiology of hypertension and associated organ damage. During development of cardiovascular disease the key organs and tissues undergo extensive functional and structural changes that are characterized by alterations in the amount and type of proteins that are expressed. Proteomic approaches study the expression of large numbers of proteins in organs, tissues, cells, and body fluids. A number of different proteomic platforms are available, many of which combine two methods to separate proteins and peptides after an initial digestion step. Identification of these peptides and changes in their expression in parallel with disease processes or medical treatment will help to identify as yet unknown pathophysiological pathways. There is also potential to use proteomic signatures as biomarkers of cardiovascular disease that will contribute to population screening, diagnosis of diseases and their severity, and monitoring of therapeutic interventions.Annals of medicine 06/2012; 44 Suppl 1:S55-64. · 3.52 Impact Factor -
Article: Genetics and hypertension: is it time to change my practice?
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ABSTRACT: Recent advances in genotyping technology and in particular a number of large-scale genome-wide association studies have helped to unravel the genetic basis of hypertension. Although our knowledge is still far from being complete it is important to ask how genetic findings could be translated to clinical practice. In a first step we summarize the strategies to dissect the genetics of hypertension from candidate gene studies to genome-wide association studies and recent sequencing experiments. The greatest hope in this context is the development of new drugs that are based on newly discovered pathophysiological principles. We describe examples where significant therapeutic effects are achieved with agents targeting pathways that contribute only small amounts to the genetic variability of a phenotype. There are good reasons to believe that new drugs will be developed based on genetic data in hypertension. We also highlight the potential for pharmacogenetics and risk stratification. The former is not currently supported by a larger body of evidence, but well designed studies are under way. The latter needs to follow the same principles for evaluation of other novel biomarkers of cardiovascular risk and is unlikely to influence clinical practice in the next few years.The Canadian journal of cardiology 04/2012; 28(3):296-304. · 3.36 Impact Factor -
Article: Reply.
Journal of hypertension 04/2012; 30(4):835. · 4.02 Impact Factor -
Article: Implementation of proteomic biomarkers: making it work.
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ABSTRACT: While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.European Journal of Clinical Investigation 03/2012; 42(9):1027-36. · 3.02 Impact Factor -
Article: Early pregnancy soluble E-selectin concentrations and risk of preeclampsia.
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ABSTRACT: Circulating biomarkers of endothelial dysfunction and inflammation are elevated in late pregnancy in women with preeclampsia. We examined plasma levels of inflammatory cytokines and adhesion molecules in early pregnancy, to assess their ability to predict preeclampsia. In a prospective longitudinal study, 2600 women with singleton pregnancies and no history of hypertension were recruited at their antenatal hospital (booking) visit at gestational week 12-16. Of these, 49 (1.9%) developed preeclampsia, whereas 74 women matched for age and BMI with uncomplicated pregnancies were selected as controls. A subset of women with risk factors for preeclampsia were sampled again at gestational weeks 16 and 28 (11 cases, 39 controls) and postnatally (six cases, 36 controls). From multiplex analysis, soluble E-selectin concentrations were higher at 12-16 weeks in women who subsequently developed preeclampsia (15.1 ± 4.9 versus 12.9 ± 4.5 ng/ml, P = 0.02). At gestational week 28, E-selectin concentrations were again higher in women who went on to develop preeclampsia compared with controls (14.4 ± 5.6 versus 10.7 ± 3.5 ng/ml, P = 0.010), whereas levels were not different between the two groups in postpartum samples. Changes in soluble E-selectin concentration in early pregnancy may reflect underlying pathophysiological processes, potentially providing mechanistic insights into preeclampsia.Journal of hypertension 03/2012; 30(5):954-9. · 4.02 Impact Factor -
Article: Role of microRNAs 99b, 181a, and 181b in the differentiation of human embryonic stem cells to vascular endothelial cells.
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ABSTRACT: MicroRNAs (miRNAs) are short noncoding RNAs, which post-transcriptionally regulate gene expression. miRNAs are transcribed as precursors and matured to active forms by a series of enzymes, including Dicer. miRNAs are important in governing cell differentiation, development, and disease. We have recently developed a feeder- and serum-free protocol for direct derivation of endothelial cells (ECs) from human embryonic stem cells (hESCs) and provided evidence of increases in angiogenesis-associated miRNAs (miR-126 and -210) during the process. However, the functional role of miRNAs in hESC differentiation to vascular EC remains to be fully interrogated. Here, we show that the reduction of miRNA maturation induced by Dicer knockdown suppressed hES-EC differentiation. A miRNA microarray was performed to quantify hES-EC miRNA profiles during defined stages of endothelial differentiation. miR-99b, -181a, and -181b were identified as increasing in a time- and differentiation-dependent manner to peak in mature hESC-ECs and adult ECs. Augmentation of miR-99b, -181a, and -181b levels by lentiviral-mediated transfer potentiated the mRNA and protein expression of EC-specific markers, Pecam1 and VE Cadherin, increased nitric oxide production, and improved hES-EC-induced therapeutic neovascularization in vivo. Conversely, knockdown did not impact endothelial differentiation. Our results suggest that miR-99b, -181a, and -181b comprise a component of an endothelial-miRNA signature and are capable of potentiating EC differentiation from pluripotent hESCs.Stem Cells 01/2012; 30(4):643-54. · 7.78 Impact Factor -
Article: Urinary proteomics to support diagnosis of stroke.
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ABSTRACT: Accurate diagnosis in suspected ischaemic stroke can be difficult. We explored the urinary proteome in patients with stroke (n = 69), compared to controls (n = 33), and developed a biomarker model for the diagnosis of stroke. We performed capillary electrophoresis online coupled to micro-time-of-flight mass spectrometry. Potentially disease-specific peptides were identified and a classifier based on these was generated using support vector machine-based software. Candidate biomarkers were sequenced by liquid chromatography-tandem mass spectrometry. We developed two biomarker-based classifiers, employing 14 biomarkers (nominal p-value <0.004) or 35 biomarkers (nominal p-value <0.01). When tested on a blinded test set of 47 independent samples, the classification factor was significantly different between groups; for the 35 biomarker model, median value of the classifier was 0.49 (-0.30 to 1.25) in cases compared to -1.04 (IQR -1.86 to -0.09) in controls, p<0.001. The 35 biomarker classifier gave sensitivity of 56%, specificity was 93% and the AUC on ROC analysis was 0.86. This study supports the potential for urinary proteomic biomarker models to assist with the diagnosis of acute stroke in those with mild symptoms. We now plan to refine further and explore the clinical utility of such a test in large prospective clinical trials.PLoS ONE 01/2012; 7(5):e35879. · 4.09 Impact Factor -
Article: Association of central and peripheral pulse pressure with intermediate cardiovascular phenotypes.
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ABSTRACT: We assessed the relationship between pulse pressure and intermediate cardiovascular phenotypes in a middle-aged cohort with high prevalence of hypertension. It has been suggested that central pulse pressure (cPP) is a better predictor of cardiovascular outcome than peripheral pulse pressure (pPP), particularly in the elderly. Yet, it is unclear if cPP provides additional prognostic information to pPP in younger individuals. In 535 individuals we assessed cPP and pPP as well as the intermediate cardiovascular phenotypes pulse wave velocity (PWV; SphygmoCor, Complior, PulsePen), carotid intima-media thickness (C-IMT; carotid ultrasound), left-ventricular mass index (LVMI; echocardiography) and urinary albumin : creatinine ratio (ACR). cPP was derived noninvasively from brachial blood pressure by pulse wave analysis (PWA; SphygmoCor) based on radial pulse wave tonometry and a validated transfer function. The cohort contained 331 hypertensive participants of whom 84% were treated. The average age was 46 ± 16 years. When compared to pPP, cPP had stronger associations with PWV (r = 0.471 vs. r = 0.372; P < 0.01), C-IMT (r = 0.426 vs. r = 0.235; P < 0.01) and LVMI (r = 0.385 vs. r = 0.189; P < 0.01), but equal association with ACR (r = 0.236 vs. r = 0.226; P = n.s.). In contrast, after adjustment for age, mean arterial pressure, heart rate and hypertension status there was no significant difference between cPP and pPP for prediction of PWV (adjusted R, 0.399 vs. 0.413; P = 0.066), C-IMT (adjusted R, 0.399 vs. 0.413; P = 0.487) and LVMI (adjusted R, 0.181 vs. 0.170; P = 0.094) in multivariate analysis. In our middle-aged cohort with high prevalence of hypertension cPP is more closely correlated with cardiovascular phenotypes than pPP. When adjusted for relevant cofactors, however, cPP does not provide additional information beyond pPP.Journal of hypertension 11/2011; 30(1):67-74. · 4.02 Impact Factor -
Article: Blood pressure loci identified with a gene-centric array.
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ABSTRACT: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.The American Journal of Human Genetics 11/2011; 89(6):688-700. · 10.60 Impact Factor -
Article: A pilot study on the effect of short-term consumption of a polyphenol rich drink on biomarkers of coronary artery disease defined by urinary proteomics.
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ABSTRACT: Polyphenol rich diets have been associated with a reduced risk of cardiovascular disease. We examined the effect of a polyphenol rich (P-R) drink on biomarkers assessed by urinary proteomics. Thirty nine middle aged and overweight subjects were randomized to P-R drink (n = 20) or placebo (n = 19) in addition to their normal diet. After two weeks urine samples were obtained for assessment of the urinary proteome using capillary electrophoresis coupled to a mass spectrometer. A total of 93 polypeptides were found to be candidates for differential distribution with a nominal p-value <0.05, though these differences did not reach significance when multiple testing was accounted for. Sequences were determined in 19 of these demonstrating that they originate from alpha-1 antitrypsin, collagens, fibrinogen alpha and IgG kappa. Levels of 27 polypeptides were greater than 4-fold different between the two groups. Of these, 7 were previously found to be part of a coronary artery disease (CAD) specific urinary biomarker pattern. Their direction of expression was closer to the healthy state in the P-R drink group and closer to CAD state in the placebo group. Our data suggest that the P-R drink may have beneficial effects on urinary biomarkers of CAD. The data encourage the planning of future prospective studies, aimed at investigating significant effects of polyphenol rich dietary products.Journal of Agricultural and Food Chemistry 11/2011; 59(24):12850-7. · 2.82 Impact Factor -
Article: Peripheral arterial tone: assessment of microcirculatory function in pregnancy.
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ABSTRACT: Endothelial dysfunction is known to play a key role in the pathogenesis of preeclampsia, but the majority of methods for its detection are too invasive to be used in pregnancy. In this study we report a novel method - peripheral arterial tonometry (PAT) - for examining microcirculatory function in pregnancy. One hundred and eighty women with at least two risk factors for preeclampsia were examined at gestational weeks 16 and 28; 80 women were examined at 6-9 months postnatally. Twenty-four women developed preeclampsia or pregnancy-induced hypertension (cases), 156 remained normotensive (controls). PAT was measured using fingertip pneumatic probes; after baseline recordings the study arm was occluded with a blood pressure cuff then released after 5 min, causing reactive hyperaemia. PAT recordings pre and post occlusion were used to generate the reactive hyperaemia index (RHI). RHI was significantly lower at gestational week 28 compared to week 16, both in cases and controls. Baseline pulse amplitude was significantly higher at week 28 compared to week 16. There was no difference in RHI at either week 16 or 28 between cases and controls. Postnatally, there was no difference in RHI between cases and controls, but baseline pulse amplitude was lower in affected women. PAT and other methods which rely on flow-mediated dilatation for detection of endothelial dysfunction are less likely to be reliable in later pregnancy, when women are more vasodilated. PAT did not predict the development of hypertensive pregnancy complications, but demonstrated a relative peripheral vasoconstriction in affected women postnatally.Journal of hypertension 11/2011; 30(1):117-23. · 4.02 Impact Factor -
Article: Urinary proteomics in the assessment of chronic kidney disease.
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ABSTRACT: Urinary proteomics has emerged as an approach that could deliver relevant clinical information. In this review, we aim at highlighting the recent developments, especially with respect to clinical implementation. We review several of the recent publications reporting on larger cohorts, focusing on those that aim at qualification and/or validation of urinary proteomics biomarkers. Several components of the urinary proteome, especially its low molecular weight fraction (sometimes referred to as the 'peptidome'), have been significantly associated with chronic kidney disease (CKD). Independent studies, encompassing sometimes close to 1000 independent samples, indicate that specific peptides from extracellular matrix (ECM) proteins encompass a major component of the urinary proteome. Highly significant changes in the abundance of some of these peptides are associated with CKD indicating that alterations in ECM, reflected via the urinary proteome, may represent an early stage in CKD pathology. These peptides may serve as specific early biomarkers, and interference with pathological ECM accumulation may be a valuable new therapeutic approach in CKD. Urinary proteomic biomarkers have emerged as clinically relevant variables. First studies involving several hundred individuals indicate a potential added benefit of urinary proteomic biomarkers. First large clinical trials are being initiated to employ urinary proteomics in clinical decision making.Current opinion in nephrology and hypertension 08/2011; 20(6):654-61. · 3.96 Impact Factor -
Article: Urinary proteomics in cardiovascular disease: Achievements, limits and hopes.
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ABSTRACT: Cardiovascular disease (CVD) is the major cause of mortality and morbidity worldwide. Diagnosis of CVD and risk stratification of patients with CVD remains challenging despite the availability of a wealth of non-invasive and invasive tests. Clinical proteomics analyses a large number of peptides and proteins in biofluids. For clinical applications, the urinary proteome appears particularly attractive due to the relative low complexity compared with the plasma proteome and the noninvasive collection of urine. In this article, we review the results from pilot studies into urinary proteomics of coronary artery disease and discuss the potential of urinary proteomics in the context of pathogenesis of CVD.PROTEOMICS - CLINICAL APPLICATIONS 06/2011; 5(5-6):222-32. · 1.81 Impact Factor -
Article: Urinary proteomics for prediction of preeclampsia.
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ABSTRACT: Preeclampsia is a major determinant of fetal and maternal morbidity and mortality. We used a proteomic strategy to identify urinary biomarkers that predict preeclampsia before the onset of disease. We prospectively collected urine samples from women throughout pregnancy. Samples from gestational weeks 12 to 16 (n=45), 20 (n=50), and 28 (n=18) from women who subsequently had preeclampsia develop were matched to controls (n=86, n=49, and n=17, respectively). We performed capillary electrophoresis online coupled to micro-time-of-flight mass spectrometry. Disease-specific peptide patterns were generated using support vector machine-based software. Candidate biomarkers were sequenced by liquid chromatography-tandem mass spectrometry. From comparison with nonpregnant controls, we defined a panel of 284 pregnancy-specific proteomic biomarkers. Subsequently, we developed a model of 50 biomarkers from specimens obtained at week 28 that was associated with future preeclampsia (classification factor in cases, 1.032 ± 0.411 vs controls, -1.038 ± 0.432; P<0.001). Classification factor increased markedly from week 12 to 16 to 28 in women who subsequently had preeclampsia develop (n=16; from -0.392 ± 0.383 to 1.070 ± 0.383; P<0.001) and decreased slightly in controls (n=16; from -0.647 ± 0.437 to -1.024 ± 0.433; P=0.043). Among the biomarkers are fibrinogen alpha chain, collagen alpha chain, and uromodulin fragments. The markers appear to predict preeclampsia at gestational week 28 with good confidence but not reliably at earlier time points (weeks 12-16 and 20). After prospective validation in other cohorts, these markers may contribute to better prediction, monitoring, and accurate diagnosis of preeclampsia.Hypertension 03/2011; 57(3):561-9. · 6.21 Impact Factor -
Article: Association between proteinuria and left ventricular mass index: a cardiac MRI study in patients with chronic kidney disease.
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ABSTRACT: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. We hypothesized that the level of proteinuria would correlate with left ventricular mass, providing a potential link between elevated protein excretion, left ventricular hypertrophy (LVH) and the increased mortality seen in patients with CKD. In order to do this, we assessed the determinants of left ventricular mass, measured using cardiac magnetic resonance (CMR) imaging, in patients with CKD. Patients attending the renal clinic with CKD stages 2-4 and diabetic nephropathy (n = 26) and IgA nephropathy (n = 23) were recruited. They underwent detailed demographic, biochemical and vascular phenotyping and CMR imaging. Proteinuria was measured using spot protein:creatinine ratio (PCR). Left ventricular mass index (LVMI) was calculated from short-axis cine imaging using Argus software and adjusted for body surface area. Log-PCR correlated significantly with LVMI, as did waist circumference, pulse pressure and systolic blood pressure. LVMI was higher in men. When these variables were entered into a linear regression model, log-PCR (P = 0.006) and systolic blood pressure (P < 0.001) independently predicted LVMI. Renal function was not associated with LVMI. Using volume-independent CMR imaging, we have demonstrated that the level of urinary protein excretion is independently and significantly associated with left ventricular mass in patients with CKD. This relationship was independent of blood pressure. This finding provides a novel link between CKD and increased cardiovascular risk.Nephrology Dialysis Transplantation 03/2011; 26(3):933-8. · 3.40 Impact Factor -
Article: Reduction in basal nitric oxide activity causes albuminuria.
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ABSTRACT: The barrier function of the glomerular filter has been studied for decades. Albuminuria reflects a malfunction of this barrier, and in animals dysfunctional endothelial nitric-oxide (NO) synthase results in albuminuria. We aimed to analyze the importance of NO for the glomerular barrier function in humans. To assess the effect of endothelial dysfunction on albuminuria, we measured the urine albumin-to-creatinine ratio (UACR) both before and after the blockade of NO synthases (NOSs) with systemic infusion of N(G)-monomethyl-L-arginine (L-NMMA) in two distinct study populations. In population A, 62 hypertensive patients with type 2 diabetes and, in population B, 22 patients with hypercholesterolemia but without hypertension or type 2 diabetes were examined. All subjects had normal renal function. There was a significant increase in the UACR in response to NOS inhibition with L-NMMA in hypertensive patients with type 2 diabetes (study population A) and in patients with hypercholesterolemia (study population B). Linear regression analyses revealed that the change in mean arterial presssure in response to L-NMMA was not related to the increase in the UACR in response to L-NMMA in either population, even after adjusting for filtration fraction. NOS inhibition provokes albuminuria that is unrelated to changes in blood pressure. It is noteworthy that this finding was evident in patient groups prone to endothelial dysfunction and albuminuria. Thus, acute deterioration of endothelial function by reducing NO activity causes an increase in albuminuria.Diabetes 02/2011; 60(2):572-6. · 8.29 Impact Factor -
Article: Association of (pro)renin receptor gene polymorphism with blood pressure in Caucasian men.
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ABSTRACT: The renin-angiotensin system is a major regulatory system of cardiovascular and renal function. Recently, (pro)renin receptor [(P)RR] was identified as new component of the renin-angiotensin system. The IVS5+169C>T polymorphism of the (P)RR gene was shown to be associated with blood pressure (BP) in Japanese men, but no data are available for Caucasians. Hence, we genotyped the IVS5+169C>T polymorphism of the (P)RR gene in 266 Caucasian men with normal or mildly elevated BP and without any medication. Office BP was measured according to current guidelines. Office and resting systolic BP was lower in C-allele than in T-allele carriers (P<0.05) of the (P)RR gene, with no difference in diastolic BP and heart rate. Serum aldosterone was also lower in C-allele than in T-allele carriers (P<0.05). These findings indicate that C-allele carriers have lower systolic BP than T-allele carriers. Thus, our data suggest that (P)RR influences BP regulation in Caucasian men, potentially through altered aldosterone release.Pharmacogenetics and Genomics 02/2011; 21(6):347-9. · 3.48 Impact Factor -
Article: Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.
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ABSTRACT: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.The American Journal of Human Genetics 01/2011; 88(1):6-18. · 10.60 Impact Factor
Top co-authors
Top Journals
Institutions
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2002–2011
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Friedrich-Alexander Universität Erlangen-Nürnberg
- • Department of Ophthalmology
- • Department of Neurology
Erlangen, Bavaria, Germany
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2006–2010
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University of Glasgow
- Institute of Cardiovascular and Medical Sciences
Glasgow, SCT, United Kingdom
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2004–2005
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Universitätsklinikum Erlangen
Erlangen, Bavaria, Germany
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