Abstract
Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): The Innovation Fund Denmark
Background and aims
Stroke is a leading cause of mortality and disability, ...and atrial fibrillation (AF) is an important and potentially modifiable risk factor for stroke. AF screening can substantially increase the amount of patients diagnosed and treated, but randomized trials have yet to demonstrate a significant decrease in strokes following screening. N-terminal prohormone of brain natriuretic peptide (proBNP) is an established biomarker for AF and could potentially be used to select patients for screening.
We a used randomized trial of AF screening vs usual care to investigated the usefulness of proBNP as a tool to select patients for screening to prevent outcomes.
Methods
The LOOP Study randomized AF-naïve individuals aged >70 years with additional stroke risk factors in a 1:3 ratio to either continuous AF screening using implantable loop recorder (ILR) with initiation of anticoagulation upon detection of AF, or usual care. In this post-hoc analysis, study participants with a baseline measurement of proBNP were included, and the effect of screening vs usual care was compared in groups according to proBNP tertiles.
Results
Of 6004 participants randomized, 5819 (97%) had proBNP measured. The tertiles of proBNP were at <11, 11-22, and 22 pmol/L (Figure 1).
A total of 1014 participants (17.4%) were diagnosed with AF (ILR 32.1% vs Control 12.5%), and 310 (5.3%) endured a stroke or systemic arterial embolism (SAE) (ILR 4.5% vs Control 5.6%). In the lower two tertiles of proBNP, 13% were diagnosed with AF (ILR 26.6% vs Control 8.3%), and 4.6% endured a stroke or SAE (ILR 4.6% vs Control 4.6%), whereas in the highest tertile of proBNP, 25.9% were diagnosed with AF (ILR 42.9% vs 20.3%), and 6.73% endured a stroke or SAE (ILR 4.4% vs Control 7.5%).
In the lower two tertiles of proBNP, there was no protective effect from AF screening as compared with usual care (hazard ratio (HR) 1.00 (95% CI 0.71-1.41), p=0.999), whereas in the highest tertile of proBNP there was a significant effect of screening (HR 0.59 (95% CI 0.37-0.93), p=0.021) (Figure 2).
More details including proBNP cutoffs, and the impact on stroke subtypes, disability and mortality will be presented at the Congress.
Conclusions
In a population at increased risk of stroke, proBNP pose a useful biomarker to select individuals for AF screening to prevent stroke. In persons with increased proBNP, the effect of screening could be significant, whereas there is no signal towards effects from screening in people with normal proBNP levels.
Genome-Wide Association Analysis of High-Density Lipoprotein Cholesterol in the Population-Based KORA Study Sheds New Light on Intergenic Regions
Iris M. Heid, PhD ;
Eva Boes, MSc ;
Martina Müller, ...MSc ;
Barbara Kollerits, MSc ;
Claudia Lamina, MSc ;
Stefan Coassin, MSc ;
Christian Gieger, PhD ;
Angela Döring, MD ;
Norman Klopp, PhD ;
Ruth Frikke-Schmidt, MD, PhD ;
Anne Tybjærg-Hansen, MD ;
Anita Brandstätter, PhD ;
Andreas Luchner, MD ;
Thomas Meitinger, MD ;
H.-Erich Wichmann, MD, PhD and
Florian Kronenberg, MD
From the Institute of Epidemiology (I.M.H., M.M., C.L., C.G., A.D., N.K., H.-E.W.) and Institute of Human Genetics (T.M.), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Information Management, Biometry and Epidemiology (I.M.H., M.M., N.K., H.-E.W.), Ludwig Maximilians University of Munich, Munich, Germany; Division of Genetic Epidemiology (E.B., B.K., S.C., A.B., F.K.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria; Department of Clinical Biochemistry (R.F.-S., A.T.-H.), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen City Heart Study (A.T.-H.), Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Internal Medicine II (A.L.), University of Regensburg, Regensburg, Germany; and Institute of Human Genetics (T.M.), Technical University Munich, Munich, Germany.
Correspondence to Florian Kronenberg, MD, Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstraße 41, A-6020 Innsbruck, Austria. E-mail Florian.Kronenberg{at}i-med.ac.at
Received February 29, 2008; accepted June 13, 2008.
Background— High-density lipoprotein cholesterol (HDLC) is a strong risk factor for atherosclerosis and is assumed to be under considerable genetic control. We aimed to identify gene regions that influence HDLC levels by a genome-wide association analysis in the population-based KORA (Cooperative Health Research in the Region of Augsburg) study.
Methods and Results— In KORA S3/F3 (n=1643), we analyzed 377 865 quality-checked single-nucleotide polymorphisms (SNPs; 500K, Affymetrix, Santa Clara, Calif), complemented by the publicly available genome-wide association results from the Diabetes Genetics Initiative (n=2631) and by replication data from KORA S4 (n=4037) and the Copenhagen City Heart Study (n=9205). Among the 13 SNPs selected from the KORA S3/F3 500K probability value list, 3 showed consistent associations in subsequent replications: 1 SNP 10 kb upstream of CETP (pooled probability value=8.5 x 10 –27 ), 1 SNP approximately 40 kb downstream of LIPG (probability value=4.67 x 10 –10 ), both independent of previously reported SNPs, and 1 from an already reported region of LPL (probability value=2.82 x 10 –11 ). Bioinformatical analyses indicate a potential functional relevance of the respective SNPs.
Conclusions— The present genome-wide association study identified 2 interesting HDLC-relevant regions upstream of CETP and downstream of LIPG . This draws attention to the importance of long-range effects of intergenic regions, which have been underestimated so far, and may impact future candidate-gene–association studies toward extending the region analyzed. Furthermore, the present study reinforced CETP and LPL as HDLC genes and thereby underscores the power of this type of genome-wide association approach to pinpoint associations of common polymorphisms with effects explaining as little as 0.5% of the HDLC variance in the general population.
Key Words: genome cholesterol genetics polymorphism, single nucleotide genotype genome-wide association study
CLINICAL PERSPECTIVE
The online-only Data Supplement is available with this article at http://circgenetics.ahajournals.org/cgi/content/full/1/1/10/DC1.
The authors wish to dedicate this work to Professor Gerd Utermann. We consider him one of the pioneers in the investigation of genetic variability in lipoprotein metabolism since he described the apolipoprotein E polymorphism as well as the kringle-IV repeat polymorphism of the apolipoprotein (a) gene.
Progressive multiple sclerosis (MS) will be a major area of research interest for years to come. No treatments exist and success in the field will generalise to other neurological conditions where ...neurodegeneration coexists with neuroinflammation. The issue is complex, and interdisciplinary approaches – uniting scientists with different competences (neurobiology, immunogenetics, etc.) and ‘mindsets’ (academia and industry) – will be decisive. The International Progressive MS Alliance is catalysing this process through various initiatives, the most recent of which was a meeting where scientists from academia (also outside the MS field) and from industry reviewed data and strategies to determine the next steps towards the translation of current knowledge into effective therapies.
Key findings are:
(i). Concerted efforts are essential to prioritise pathogenetic mechanisms according to impact on the disease and druggability.
(ii). Combination therapies will probably be needed, possibly early in the disease, along with new trial designs and treatment schedules.
(iii). Drug screenings are a pragmatic approach hopefully enriched by the use of neural and oligodendrocyte progenitors differentiated from induced pluripotent stem cells (iPSCs).
(iv). The field of network biology will increase our ability to predict therapeutic targets.
(v). Genome-wide association studies (GWAS) must try to identify variants associated with disease progression.
PurposeThe aim of Copenhagen Hospital Biobank-Cardiovascular Disease Cohort (CHB-CVDC) is to establish a cohort that can accelerate our understanding of CVD initiation and progression by jointly ...studying genetics, diagnoses, treatments and risk factors.ParticipantsThe CHB-CVDC is a large genomic cohort of patients with CVD. CHB-CVDC currently includes 96 308 patients. The cohort is part of CHB initiated in 2009 in the Capital Region of Denmark. CHB is continuously growing with ~40 000 samples/year. Patients in CHB were included in CHB-CVDC if they were above 18 years of age and assigned at least one cardiovascular diagnosis. Additionally, up-to 110 000 blood donors can be analysed jointly with CHB-CVDC. Linkage with the Danish National Health Registries, Electronic Patient Records, and Clinical Quality Databases allow up-to 41 years of medical history. All individuals are genotyped using the Infinium Global Screening Array from Illumina and imputed using a reference panel consisting of whole-genome sequence data from 8429 Danes along with 7146 samples from North-Western Europe. Currently, 39 539 of the patients are deceased.Findings to dateHere, we demonstrate the utility of the cohort by showing concordant effects between known variants and selected CVDs, that is, >93% concordance for coronary artery disease, atrial fibrillation, heart failure and cholesterol measurements and 85% concordance for hypertension. Furthermore, we evaluated multiple study designs and the validity of using Danish blood donors as part of CHB-CVDC. Lastly, CHB-CVDC has already made major contributions to studies of sick sinus syndrome and the role of phytosterols in development of atherosclerosis.Future plansIn addition to genetics, electronic patient records, national socioeconomic and health registries extensively characterise each patient in CHB-CVDC and provides a promising framework for improved understanding of risk and protective variants. We aim to include other measurable biomarkers for example, proteins in CHB-CVDC making it a platform for multiomics cardiovascular studies.
Background:
Evidence is accumulating supporting a beneficial effect of vitamin D in multiple sclerosis (MS). Genome-wide association studies (GWAS) have shown significant associations between ...25-hydroxyvitamin D (25(OH)D) and single nucleotide polymorphisms (SNPs) in key genes in the vitamin D metabolism.
Objective:
To examine the association between 25(OH)D and six GWAS SNPs and environmental factors in 1497 MS patients.
Methods:
Blood samples and lifestyle questionnaires were collected between 2009 and 2012. Genotyping of GC-, CYP2R1- and NADSYN1-SNPs was performed by TaqMan allelic discrimination (Life Technologies).
Results:
We found significant associations between 25(OH)D and SNPs in GC (rs7041, p = 0.01 and rs2282679, p = 0.03) and CYP2R1 (rs10741657, p =1.8 × 10−4). Season of blood sampling (p = 2.8 × 10−31), sex (p = 1.9 × 10−5), BMI (p = 2.3 × 10−5), vitamin supplements (p = 7.0 × 10−22), and fish intake (p = 0.02) also had significant effects on 25(OH)D.
Conclusion:
In this cross-sectional study, we found significant effects of environmental factors and SNPs in GC and CYP2R1 on 25(OH)D in MS patients. Since 25(OH)D might have protective effects in MS, and vitamin D supply is a modifiable factor, it may be important to include this in the MS treatment regimen.
Background:
Cardiogenic shock complicating ST-elevation myocardial infarction is characterised by progressive left ventricular dysfunction causing inflammation and neurohormonal activation. Often, ...cardiogenic shock develops after hospital admission. Whether inflammation and a neurohormonal activation precede development of clinical cardiogenic shock is unknown.
Methods and results:
In 93% of 2247 consecutive patients with suspected ST-elevation myocardial infarction admitted at two tertiary heart centres, admission plasma levels of pro-atrial natriuretic peptide, copeptin, mid-regional pro-adrenomedullin and stimulation-2 were measured on hospital admission. Patients were stratified according to no cardiogenic shock development and cardiogenic shock developed before (early cardiogenic shock) or after (late cardiogenic shock) leaving the catheterization laboratory. In total, 225 (10%) patients developed cardiogenic shock, amongst these patients late cardiogenic shock occurred in 64 (2.9%). All four biomarkers were independently associated with the development of late cardiogenic shock (odds ratio per two-fold increase in risk: 1.19–3.13) even when adjusted for the recently developed Observatoire Régional Breton sur l’Infarctus risk score for prediction of late cardiogenic shock development. Furthermore, pro-atrial natriuretic peptide, copeptin and mid-regional pro-adrenomedullin, but not stimulation-2, added significant predictive information, when added to the Observatoire Régional Breton sur l’Infarctus risk score (area under the receiver-operating characteristic curve, pro-atrial natriuretic peptide: 0.87, p=0.0008; copeptin: 0.86, p<0.05; mid-regional pro-adrenomedullin: 0.88, p=0.006).
Conclusions:
Pro-atrial natriuretic peptide, copeptin, mid-regional pro-adrenomedullin and stimulation-2 admission plasma concentration were associated with late cardiogenic shock development in patients admitted with suspected ST-elevation myocardial infarction. Pro-atrial natriuretic peptide, mid-regional pro-adrenomedullin and copeptin had independent predictive value for late cardiogenic shock development.
Background Meta-analysis of individual participant time-to-event data from multiple prospective epidemiological studies enables detailed investigation of exposure–risk relationships, but involves a ...number of analytical challenges. Methods This article describes statistical approaches adopted in the Emerging Risk Factors Collaboration, in which primary data from more than 1 million participants in more than 100 prospective studies have been collated to enable detailed analyses of various risk markers in relation to incident cardiovascular disease outcomes. Results Analyses have been principally based on Cox proportional hazards regression models stratified by sex, undertaken in each study separately. Estimates of exposure–risk relationships, initially unadjusted and then adjusted for several confounders, have been combined over studies using meta-analysis. Methods for assessing the shape of exposure–risk associations and the proportional hazards assumption have been developed. Estimates of interactions have also been combined using meta-analysis, keeping separate within- and between-study information. Regression dilution bias caused by measurement error and within-person variation in exposures and confounders has been addressed through the analysis of repeat measurements to estimate corrected regression coefficients. These methods are exemplified by analysis of plasma fibrinogen and risk of coronary heart disease, and Stata code is made available. Conclusion Increasing numbers of meta-analyses of individual participant data from observational data are being conducted to enhance the statistical power and detail of epidemiological studies. The statistical methods developed here can be used to address the needs of such analyses.
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