Holdaas H.,University of Oslo |
Holme I.,University of Oslo |
Schmieder R.E.,University Hospital |
Jardine A.G.,Glasgow Cardiovascular Research Center |
And 4 more authors.
Journal of the American Society of Nephrology | Year: 2011
A randomized, placebo-controlled trial in diabetic patients receiving hemodialysis showed no effect of atorvastatin on a composite cardiovascular endpoint, but analysis of the component cardiac endpoints suggested that atorvastatin may significantly reduce risk. Because the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial included patients with and without diabetes, we conducted a post hoc analysis to determine whether rosuvastatin might reduce the risk of cardiac events in diabetic patients receiving hemodialysis. Among the 731 participants with diabetes, traditional risk factors such as LDL-C, smoking, and BP did not associate with cardiac events (cardiac death and nonfatal myocardial infarction). At baseline, only age and high-sensitivity C-reactive protein were independent risk factors for cardiac events. Assignment to rosuvastatin associated with a nonsignificant 16.2% reduction in risk for the AURORA trial's composite primary endpoint of cardiac death, nonfatal MI, or fatal or nonfatal stroke (HR 0.84; 95% CI 0.65 to 1.07). There was no difference in overall stroke, but the rosuvastatin group had more hemorrhagic strokes than the placebo group (12 versus two strokes, respectively; HR, 5.21; 95% CI 1.17 to 23.27). Rosuvastatin treatment significantly reduced the rates of cardiac events by 32% among patients with diabetes (HR 0.68; 95% CI 0.51 to 0.90). In conclusion, among hemodialysis patients with diabetes mellitus, rosuvastatin might reduce the risk of fatal and nonfatal cardiac events. Copyright © 2011 by the American Society of Nephrology.
PubMed | University of Minnesota, University of Newcastle, University of Sfax, Cardiovascular Genetics and Genomics Group and 67 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including 120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
PubMed | University of Turku, Pennington Biomedical Research Center, Institute of Nutrition and Functional Foods, Glasgow Cardiovascular Research Center and 57 more.
Type: | Journal: Nature communications | Year: 2016
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium
PubMed | U.S. National Institute on Aging, Epidemiological Cardiology Research Center, University of Washington, Glasgow Cardiovascular Research Center and 15 more.
Type: | Journal: Journal of medical genetics | Year: 2016
Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45706; n=1417 TCA users), African (n=10235; n=296 TCA users) and Hispanic/Latino (n=13808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (=56.3, pAmong Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.
PubMed | Glasgow Cardiovascular Research Center, University of Groningen, Cleveland Clinic, University of Alberta and 6 more.
Type: Journal Article | Journal: European journal of heart failure | Year: 2016
We aimed to characterize abnormal liver function tests in patients with heart failure (HF), as they are commonly encountered yet poorly defined.We used data from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) to characterize associations with baseline liver function tests (LFTs). Each LFT was analysed as both a continuous and dichotomous variable [normal vs. abnormal; bilirubin >1.0mg/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >35mmol/L]. Logistic regression assessed the association of LFTs and 30-day all-cause mortality and HF rehospitalization, and Cox proportional hazards assessed the association with 180-day all-cause mortality among patients alive at a 30-day landmark. In ASCEND-HF, 4228 (59%) had complete admission LFT data. Of these, 42% had abnormal bilirubin, 22% had abnormal ALT, and 30% had abnormal AST. Patients with abnormal LFTs were younger, had lower body mass index, and lower left ventricular ejection fraction. In multivariable models, increased total bilirubin was associated with increased 30-day mortality or HF rehospitalization [hazard ratio (HR) 1.17 per 1mg/dL increase, 95% confidence interval (CI) 1.04, 1.32; P=0.012], but not with an increase in 180-day mortality (HR 1.10, 95% CI 0.97, 1.25; P=0.13) per 1mg/dl increase. Compared with normal bilirubin levels, abnormal bilirubin was associated with increased 30-day mortality or HF rehospitalization (HR 1.24, 95% CI 1.00, 1.54; P=0.048) and 180-day mortality (HR 1.32, 95% CI 1.08, 1.62; P=0.007). We found no association with AST or ALT and outcomes.Greater than 40% of patients hospitalized with acute HF had abnormal LFTs. After multivariable adjustment, only elevated bilirubin was independently associated with worse clinical outcomes and may represent an important prognostic variable.
PubMed | Leiden University, University College Cork, University of Glasgow, Copenhagen University and Glasgow Cardiovascular Research Center
Type: Journal Article | Journal: European journal of clinical pharmacology | Year: 2016
In pharmacogenetic research, genetic variation in non-responders and high responders is compared with the aim to identify the genetic loci responsible for this variation in response. However, an important question is whether the non-responders are truly biologically non-responsive or actually non-adherent? Therefore, the aim of this study was to describe, within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), characteristics of both non-responders and high responders of statin treatment in order to possibly discriminate non-responders from non-adherers.Baseline characteristics of non-responders to statin therapy (10 % LDL-C reduction) were compared with those of high responders (>40 % LDL-C reduction) through a linear regression analysis. In addition, pharmacogenetic candidate gene analysis was performed to show the effect of excluding non-responders from the analysis.Non-responders to statin therapy were younger (p = 0.001), more often smoked (p < 0.001), had a higher alcohol consumption (p < 0.001), had lower LDL cholesterol levels (p < 0.001), had a lower prevalence of hypertension (p < 0.001), and had lower cognitive function (p = 0.035) compared to subjects who highly responded to pravastatin treatment. Moreover, excluding non-responders from pharmacogenetic studies yielded more robust results, as standard errors decreased.Our results suggest that non-responders to statin therapy are more likely to actually be non-adherers, since they have more characteristics that are viewed as indicators of high self-perceived health and low disease awareness, possibly making the subjects less adherent to study medication. We suggest that in pharmacogenetic research, extreme non-responders should be excluded to overcome the problem that non-adherence is investigated instead of non-responsiveness.
PubMed | University of Minnesota, U.S. National Institute on Aging, University of Washington, Fred Hutchinson Cancer Research Center and 16 more.
Type: | Journal: The pharmacogenomics journal | Year: 2016
Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 10
Calvin C.M.,University of Edinburgh |
Batty G.D.,University of Edinburgh |
Batty G.D.,University College London |
Batty G.D.,MRC Social and Public Health science Unit |
And 3 more authors.
Health Psychology | Year: 2011
Objective: In a prospective cohort study the authors examined associations between childhood intelligence at age 11 and inflammatory and hemostatic biomarkers in middle age. Method: Participants were 9,377 men and women born in the United Kingdom in March 1958, and whose blood plasma samples at age 45 years were analyzed for levels of C-reactive protein (CRP), D-dimer, fibrinogen, tissue plasminogen activator (t-PA) antigen, and von Willebrand factor (VWF). Sex-adjusted linear regression models tested cognition-blood biomarker associations, with and without adjustment for potential confounding by parental socioeconomic status and potential mediation by cardiovascular disease (CVD) risk factors at midlife. Cognitive tests taken at age 50 enabled the inflammation-cognition association to be tested for reverse causation, by adjusting for age 11 intelligence. Results: Higher childhood intelligence test scores were significantly associated (p < .001) with lower adult levels of CRP (beta coefficient = -0.068), t-PA antigen (β = -0.014), D-dimer (β = -0.011), fibrinogen (β = -0.011), and VWF antigen (β = -0.008). Early life factors including parental socioeconomic status accounted for 24%-44% of these associations, whereas further adjustment for adult CVD risk factors largely attenuated the effects (82%-100%). The significant inverse associations between age 45 biomarker levels and age 50 cognition could be accounted for to a substantial degree by childhood intelligence (50%-100% attenuation). Conclusions: Childhood intelligence is predictive of inflammatory and hemostatic biomarker status at middle age, which may be largely explained by health behaviors. This highlights the need to consider possible bidirectional associations between cognition and inflammation (and hemostasis) in lifecourse models of CVD-related health. © 2011 American Psychological Association.
Andersen S.,Steno Diabetes Center |
Mischak H.,Glasgow Cardiovascular Research Center |
Mischak H.,Mosaiques Diagnostics GmbH |
Zurbig P.,Mosaiques Diagnostics GmbH |
And 3 more authors.
BMC Nephrology | Year: 2010
Background. Previously the angiotensin II receptor blocker Irbesartan has been demonstrated to reduce the risk for progression from microalbuminuria to macroalbuminuria in type 2 diabetic patients. The purpose of this study was to evaluate the effect of treatment with Irbesartan in type 2 diabetic patients with microalbuminuria on the urinary proteome. Methods. High-resolution capillary-electrophoresis coupled to mass-spectrometry (CE-MS) was used to profile the low-molecular-weight proteome in urine of a subgroup of patients from a two year randomized irbesartan versus placebo therapy trial, which included hypertensive type 2 diabetic patients with microalbuminuria on ongoing antihypertensive medication (IRMA2-substudy). Results. We demonstrate that the therapy with 300 mg Irbesartan daily over a period of two years results in significant changes of the urinary proteome. Both, a classifier developed previously that consists of urinary peptides indicative of chronic kidney disease, as well as several individual peptides changed significantly after treatment. These changes were not observed in the placebo-treated individuals. Most prominent are changes of urinary collagen fragments associated with progression of diabetic nephropathy, indicating normalization in urinary peptides. Conclusion. CE-MS analysis of urine enabled identification of peptides as potential surrogate markers for renoprotection in microalbuminuric type 2 diabetic patients, which show persistent improvement after longterm treatment with Irbesartan. The results suggest that a major benefit of treatment by Irbesartan may be improvement of collagen turnover, reduction of fibrosis. They further suggest that urinary proteome analysis could be utilized to assess potential benefit of therapeutic intervention, providing statistically significant results even on a small population. © 2010 Andersen et al; licensee BioMed Central Ltd.
Schiffer E.,Mosaiques diagnostics GmbH |
Schiffer E.,Glasgow Cardiovascular Research Center |
Bick C.,Urological Office |
Grizelj B.,Urological Office |
And 2 more authors.
International Journal of Urology | Year: 2012
Objectives: Capillary electrophoresis mass spectrometry urinary proteome analysis for prostate cancer has been shown to be highly accurate in the detection of prostate cancer. The aim of the present study was to report our experience with routine application of this test in clinical practice and its cost-effectiveness. Methods: The urinary proteome analysis for prostate cancer test was carried out in 211 patients in outpatient centers. In 184 of them, data about their follow up and the test results were available for analysis. Prostate cancer was detected in 49 cases. Results: The test correctly recognized 42 out of 49 tumor patients, showing a sensitivity of 86% (95% confidence interval 73-94). Of 135 prostate cancer-negative patients, 79 had a negative urinary proteome analysis for prostate cancer test (specificity 59% [79/135 95% confidence interval 50-66]). Negative and positive predictive values were 92% (95% confidence interval 84-96) and 43% (95% confidence interval 33-53), respectively. A statistically significant (P<0.0005) improvement in terms of diagnostic accuracy was observed in comparison with serum prostate-specific antigen and percent-free prostate-specific antigen. Whereas the urinary proteome analysis for prostate cancer test results agreed in 65.7% with follow-up reference results, prostate-specific antigen achieved 33.3% and percent-free prostate-specific antigen achieved 42.7%. Cost-effectiveness analysis showed that the urinary proteome analysis for prostate cancer strategy outperformed the biopsy approach as well as prostate-specific antigen tests. Conclusions: The non-invasive urinary proteome analysis for prostate cancer test appears to be a helpful addition to prostate cancer diagnostics for patients with suspicious prostate-specific antigen and/or digital-rectal examination. © 2011 The Japanese Urological Association.