| 1. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 2. |
- Zamora, Juan Carlos, et al.
(författare)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Tidskriftsartikel (refereegranskat)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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| 3. |
- Chen, X., et al.
(författare)
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A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:10, s. 1809-1818
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 x 10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.
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| 4. |
- Högberg, Jonas, 1976, et al.
(författare)
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Simulation Model of Microsphere Distribution for Selective Internal Radiation Therapy Agrees With Observations
- 2016
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Ingår i: International Journal of Radiation Oncology Biology Physics. - : Elsevier BV. - 0360-3016. ; 96:2, s. 414-421
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To perform a detailed analysis of microsphere distribution in biopsy material from a patient treated with 90 Y-labeled resin spheres and characterize microsphere distribution in the hepatic artery tree, and to construct a novel dichotomous bifurcation model for microsphere deposits and evaluate its accuracy in simulating the observed microsphere deposits. Methods and Materials: Our virtual model consisted of arteries that successively branched into 2 new generations of arteries at 20 nodes. The artery diameter exponentially decreased from the lowest generation to the highest generation. Three variable parameters were optimized to obtain concordance between simulations and measure microsphere distributions: an artery coefficient of variation (ACV) for the diameter of all artery generations and the microsphere flow distribution at the nodes; a hepatic tree distribution volume (HDV) for the artery tree; and an artery diameter reduction (ADR) parameter. The model was tested against previously measured activity concentrations in 84 biopsies from the liver of 1 patient. In 16 of 84 biopsies, the microsphere distribution regarding cluster size and localization in the artery tree was determined via light microscopy of 30-mm sections (mean concentration, 14 microspheres/mg; distributions divided into 3 groups with mean microsphere concentrations of 4.6, 14, and 28 microspheres/mg). Results: Single spheres and small clusters were observed in terminal arterioles, whereas large clusters, up to 450 microspheres, were observed in larger arterioles. For 14 microspheres/mg, the optimized parameter values were ACV = 0.35, HDV = 50 cm(3), and ADR = 6 mu m. For 4.6 microspheres/mg, ACV and ADR decreased to 0.26 and 0 mu m, respectively, whereas HDV increased to 130 cm(3). The opposite trend was observed for 28 microspheres/mg: ACV = 0.49, HDV = 20 cm(3), and ADR = 8 mu m. Conclusion: Simulations and measurements reveal that microsphere clusters are larger and more common in volumes with high microsphere concentrations and indicate that the spatial distribution of the artery tree must be considered in estimates of microsphere distributions.
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| 5. |
- Tercero, M., et al.
(författare)
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5G systems: The mmMAGIC project perspective on use cases and challenges between 6-100 GHz
- 2016
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Ingår i: IEEE Wireless Communications and Networking Conference, WCNC. - 1525-3511. ; 2016-September, s. 200-205
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Konferensbidrag (refereegranskat)abstract
- mmMAGIC (Millimetre-Wave Based Mobile Radio Access Network for Fifth Generation Integrated Communications) is an EU funded 5G-PPP project, whose overall objective is to design and pre-develop a mobile radio access technology (RAT) operating in the 6-100 GHz range, capable of impacting standards and other relevant fora. The focus of the project is on extreme Mobile Broadband, which is expected to drive the 5G requirements for massive increase in capacity and data-rates. This paper elaborates on some 5G key research areas such as: identification of the most compelling use-cases and Key Performance Indicators (KPIs) for future 5G systems, advantages and challenges of millimeter-wave (mmWave) technologies, channel measurements and channel modeling, network architecture; and the design of a new mobile radio interface including multi-node and multi-Antenna transceiver architecture.
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| 6. |
- Uhlén, Mathias, et al.
(författare)
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The human secretome
- 2019
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 12:609
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Tidskriftsartikel (refereegranskat)abstract
- The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood.
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| 7. |
- Cadrin-Tourigny, Julia, et al.
(författare)
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A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 40:23, s. 1850-1858
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).
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| 8. |
- Jung, Thomas, et al.
(författare)
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ADVANCING POLAR PREDICTION CAPABILITIES ON DAILY TO SEASONAL TIME SCALES
- 2016
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 97:9, s. 1631-
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Tidskriftsartikel (refereegranskat)abstract
- The polar regions have been attracting more and more attention in recent years, fueled by the perceptible impacts of anthropogenic climate change. Polar climate change provides new opportunities, such as shorter shipping routes between Europe and East Asia, but also new risks such as the potential for industrial accidents or emergencies in ice-covered seas. Here, it is argued that environmental prediction systems for the polar regions are less developed than elsewhere. There are many reasons for this situation, including the polar regions being (historically) lower priority, with fewer in situ observations, and with numerous local physical processes that are less well represented by models. By contrasting the relative importance of different physical processes in polar and lower latitudes, the need for a dedicated polar prediction effort is illustrated. Research priorities are identified that will help to advance environmental polar prediction capabilities. Examples include an improvement of the polar observing system; the use of coupled atmosphere-sea ice-ocean models, even for short-term prediction; and insight into polar-lower latitude linkages and their role for forecasting. Given the enormity of some of the challenges ahead, in a harsh and remote environment such as the polar regions, it is argued that rapid progress will only be possible with a coordinated international effort. More specifically, it is proposed to hold a Year of Polar Prediction (YOPP) from mid-2017 to mid-2019 in which the international research and operational forecasting communites will work together with stakeholders in a period of intensive observing: modeling, prediction, verification, user engagement, and educational activities.
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| 9. |
- Raninen, J., et al.
(författare)
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One explanation to rule them all? : Identifying sub-groups of non-drinking Swedish ninth graders
- 2018
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Ingår i: Drug and Alcohol Review. - : Blackwell Publishing. - 0959-5236 .- 1465-3362. ; 37, s. S42-S48
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Tidskriftsartikel (refereegranskat)abstract
- Introduction and Aims: Researchers in a number of countries have recently identified major changes in adolescent alcohol consumption since the early 2000s, with the prevalence of teenage drinking more than halving in some countries. The major aims of the current study are to examine if there are sub-groups among non-drinking Swedish ninth graders and to describe how the prevalence of these groups has changed during the period 1999 to 2015. Design and Methods: Data from five waves of the Swedish European School Survey Project on Alcohol and other Drugs study was used. The data covered 16 years and the total sample comprised 14 976 students. Latent class analysis was used to identify sub-groups of non-drinkers (n = 4267) based on parental approval towards drinking, parental monitoring, leisure time activities, school performance and use of other substances. Results: Five latent classes were found: computer gamers (8.3%), strict parents (36.5%), liberal parents (27.0%), controlling but liberal parents (16.6%) and sports (11.6%). In the non-drinking sub-group the strict parents group increased most between 1999 and 2015. Discussion and Conclusions: The results imply that there is notable within-group diversity in non-drinking youth. Several mechanisms and explanations are thus likely to be behind the decline in drinking participation among Swedish adolescents.
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| 10. |
- Själander, Sara, et al.
(författare)
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Assessment of Use vs Discontinuation of Oral Anticoagulation After Pulmonary Vein Isolation in Patients With Atrial Fibrillation
- 2017
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Ingår i: JAMA cardiology. - : American Medical Association. - 2380-6583 .- 2380-6591. ; 2:2, s. 146-152
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Pulmonary vein isolation (PVI) is a recommended treatment for patients with atrial fibrillation, but it is unclear whether it results in a lower risk of stroke.OBJECTIVES: To investigate the proportion of patients discontinuing anticoagulation treatment after PVI in association with the CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age >= 75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65-74 years, sex category [female]) score, identify factors predicting stroke after PVI, and explore the risk of cardiovascular events after PVI in patients with and without guideline-recommended anticoagulation treatment.DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort studywas conducted using Swedish national health registries from January 1, 2006, to December 31, 2012, with a mean-follow up of 2.6 years. A total of 1585 patients with atrial fibrillation undergoing PVI from the Swedish Catheter Ablation Register were included, with information about exposure to warfarin in the national quality register Auricula. Data analysis was performed from January 1, 2015, to April 30, 2016.EXPOSURES: Warfarin treatment.MAIN OUTCOMES AND MEASURES: Ischemic stroke, intracranial hemorrhage, and death.RESULTS: In this cohort of 1585 patients, 73.0% were male, the mean (SD) age was 59.0 (9.4) years, and the mean (SD) CHA(2)DS(2)-VASc score was 1.5 (1.4). Of the 1585 patients, 1175 were followed up for more than 1 year after PVI. Of these, 360 (30.6%) discontinued warfarin treatment during the first year. In patients with a CHA(2)DS(2)-VASc score of 2 or more, patients discontinuing warfarin treatment had a higher rate of ischemic stroke (5 events in 312 years at risk [1.6% per year]) compared with those continuing warfarin treatment (4 events in 1192 years at risk [0.3% per year]) (P = .046). Patients with a CHA(2)DS(2)-VASc score of 2 or more or those who had previously experienced an ischemic stroke displayed a higher risk of stroke if warfarin treatment was discontinued (hazard ratio, 4.6; 95% CI, 1.2-17.2; P = .02 and hazard ratio, 13.7; 95% CI, 2.0-91.9; P = .007, respectively).CONCLUSIONS AND RELEVANCE: These findings indicate that discontinuation ofwarfarin treatment after PVI is not safe in high-risk patients, especially those who have previously experienced an ischemic stroke.
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| 11. |
- Ahmad, Abrar, et al.
(författare)
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Alpha 2-macroglobulin 5 bp insertion/deletion polymorphism increases the risk of recurrent venous thromboembolism
- 2018
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Ingår i: Gene Reports. - : Elsevier BV. - 2452-0144. ; 13, s. 104-109
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Tidskriftsartikel (refereegranskat)abstract
- Alpha 2-macroglobulin (A2M) is a protease inhibitor that has been reported to neutralize thrombin, which may decrease the risk of thrombosis. A 5-base pairs (bp) insertion/deletion polymorphism (rs3832852) at the splice acceptor site of exon 18 has been shown to affect the binding of A2M with proteases. However, the role of this important variant in A2M in recurrent VTE is unknown. We investigated the role of 5 bp insertion/deletion polymorphism in VTE recurrence in a follow up study. A2M 5 bp insertion/deletion polymorphism was genotyped in Malmö Thrombophilia Study (MATS, n = 1465, with follow up of ~10 years) by TaqMan Allelic Discrimination assay. Univariate Cox regression analysis showed that A2M polymorphism was significantly associated with higher risk of VTE recurrence (hazard ratio [HR] = 2.61, 95% confidence interval [CI] = 1.06–6.45, P = 0.037). This association remained significant (HR = 2.61, 95% CI = 1.06–6.47, P = 0.038) even after adjusting for sex, family history of VTE, thrombophilia and acquired risk factors for VTE. In conclusion, our results indicate that patients with A2M 5 bp insertion/deletion polymorphism are at significantly higher risk of VTE recurrence and this may predict VTE recurrence.
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| 12. |
- Ahmad, Abrar, et al.
(författare)
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Association between TLR9 rs5743836 polymorphism and risk of recurrent venous thromboembolism
- 2017
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 1573-742X .- 0929-5305. ; 44:1, s. 130-138
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Tidskriftsartikel (refereegranskat)abstract
- Recent gene knockout studies on mice have shown the role of toll-like receptor 9 (TLR9) in resolution of venous thromboembolism (VTE) through sterile inflammation. However, the role of a putative functional TLR9 polymorphism (rs5743836) in risk assessment of VTE recurrence remains unknown. The aim of our study was to investigate the TLR9 rs5743836 polymorphism in VTE patients and its association with the risk of VTE recurrence. We analyzed TLR9 rs5743836 polymorphism in Malmö thrombophilia study patients; a prospective follow-up study of 1465 VTE patients by Taqman PCR. From a total of 1465 VTE patients, those who had VTE before inclusion and those who died or had VTE recurrence during anticoagulant treatment were excluded (n = 415). Cox regression analyses were performed on the remaining 1050 VTE patients, including 126 (12.5%) patients that had recurrent VTE during follow-up period. TLR9 polymorphism was significantly associated with higher risk of VTE recurrence in female patients (HR 3.46, 95% CI 1.06-11.33) independent of acquired risk factors for VTE, family history, risk of thrombophilia and deep vein thrombosis (DVT) location. Similarly, in unprovoked VTE patients, TLR9 polymorphism was significantly associated with higher risk of VTE recurrence in female patients (HR 5.94, 95% CI 1.25-28.13) after adjusting for family history, risk of thrombophilia and DVT location. No association between TLR9 polymorphism and risk of VTE recurrence was found in male patients. Our results suggest that TLR9 rs5743836 polymorphism is an independent risk factor for VTE recurrence in female patients but not in males.
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| 13. |
- Ahmad, Abrar, et al.
(författare)
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Evaluation of Expression Level of Apolipoprotein M as a Diagnostic Marker for Primary Venous Thromboembolism
- 2018
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Ingår i: Clinical and Applied Thrombosis/Hemostasis. - : SAGE Publications. - 1938-2723 .- 1076-0296. ; 24:3, s. 416-422
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Tidskriftsartikel (refereegranskat)abstract
- Recently, decreased levels of apolipoprotein M (ApoM) were shown to be associated with higher risk of recurrent venous thromboembolism (VTE) in male patients. However, the role of ApoM in primary VTE is unknown. We aimed in our study to analyze the plasma levels of ApoM in patients with VTE in order to evaluate the diagnostic importance of ApoM in primary VTE. A total of 357 patients with suspected first episode of VTE were recruited prospectively in the SCORE study. Plasma samples from 307 patients were available for quantifying the plasma levels of ApoM in patients with VTE using sandwich enzyme-linked immunosorbent assay method. Among the whole population, plasma levels (mean [standard deviation]) of ApoM were not significantly different between patients with VTE (0.72 [0.20]) and non-VTE patients (0.72 [0.16]), P = .99. Similarly, in regression analyses, no significant association of ApoM plasma levels with the risk of VTE was found on univariate (odds ratio [OR] =1.0, 95% confidence interval [CI] 0.21-4.84, P = .99) and multivariate analysis (OR = 1.25, 95% CI = 0.19-8.34, P = .819) after adjusting for age, body mass index, and smoking. Moreover, results did not differ significantly after stratification of data according to sex ( P > .05). In this study, our results do not suggest a diagnostic role for ApoM plasma levels in patients with primary VTE. Moreover, the current study suggests that role of ApoM as a risk factor may differ for primary VTE and recurrent VTE in male patients.
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| 14. |
- Ahmad, Abrar, et al.
(författare)
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Fat mass and obesity-associated gene rs9939609 polymorphism is a potential biomarker of recurrent venous thromboembolism in male but not in female patients
- 2018
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Ingår i: Gene. - : Elsevier BV. - 0378-1119. ; 647, s. 136-142
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Tidskriftsartikel (refereegranskat)abstract
- Multiple genetic variations have been identified in FTO (fat mass and obesity-associated) gene. Among them, FTO rs9939609 polymorphism is shown to be associated with the risk of primary venous thromboembolism (VTE). However, its role in recurrent VTE is not known. The aim of our study was to investigate the association between FTO rs9939609 polymorphism and the risk of VTE recurrence in a prospective follow-up study in both male and female patients. FTO rs9939609 polymorphism (T/A) was analyzed in the Malmö thrombophilia study (MATS, followed for ~10 years) by using TaqMan PCR. MATS patients (n = 1050) were followed from the discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of follow-up. A total of 126 patients (12%) had VTE recurrence during follow-up. Cox regression analyses showed that sex modified the potential effect of FTO rs9939609 polymorphism on VTE recurrence. Male patients with the AA genotype for the FTO rs9939609 polymorphism had significantly higher risk of VTE recurrence as compared to the TT or AT genotypes (univariate hazard ratio [HR] = 2.05, 95% confidence interval [CI] = 1.2-3.5, P = 0.009 and adjusted HR = 2.03, 95% CI 1.2-3.6, P = 0.013). There was no association between FTO rs9939609 polymorphism and VTE recurrence in female patients. In conclusion, our results show that FTO rs9939609 polymorphism in recurrent VTE may differ according to gender and FTO polymorphism may predict VTE recurrence in male patients.
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| 15. |
- Ahmad, Abrar, et al.
(författare)
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Identification of Genetic Aberrations in Thrombomodulin Gene in Patients with Recurrent Venous Thromboembolism
- 2017
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Ingår i: Clinical and Applied Thrombosis/Hemostasis. - : SAGE Publications. - 1076-0296 .- 1938-2723. ; 23:4, s. 319-328
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Tidskriftsartikel (refereegranskat)abstract
- Thrombomodulin (THBD) serves as a cofactor for thrombin-mediated activation of anticoagulant protein C pathway. Genetic aberrations in THBD have been studied in arterial and venous thrombosis. However, genetic changes in THBD and their role in the risk assessment of recurrent venous thromboembolism (VTE) are not well understood. The aim of the present study was to identify the genetic aberrations in THBD and their association with the risk of VTE recurrence in a prospective population-based study. We sequenced the entire THBD gene, first in selected patients with VTE (n = 95) by Sanger sequencing and later validated those polymorphisms with minor allele frequency (MAF) ≥5% in the whole study population (n = 1465 with the follow-up period of 1998-2008) by Taqman polymerase chain reaction. In total, we identified 8 polymorphisms in THBD, and 3 polymorphisms with MAF ≥5% were further validated. No significant association between THBD polymorphisms and risk of VTE recurrence on univariate or multivariate Cox regression analysis was found (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.62-1.28, HR = 1.27, 95% CI = 0.88-1.85, and HR = 1.15, 95% CI = 0.80-1.66 for THBD rs1962, rs1042580, and rs3176123 polymorphisms, respectively), adjusted for family history, acquired risk factors for VTE, location of deep vein thrombosis, and risk of thrombophilia. Subanalysis of patients with unprovoked first VTE also showed no significant association of identified THBD polymorphisms with the risk of VTE recurrence. Our results show that aberrations in the THBD gene may not be useful for the assessment of VTE recurrence; however, further studies with large sample size are needed to confirm these findings.
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| 16. |
- Ahmad, Abrar, et al.
(författare)
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Identification of polymorphisms in Apolipoprotein M gene and their relationship with risk of recurrent venous thromboembolism
- 2016
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 116:3, s. 41-432
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein M (ApoM) plasma levels have been reported to be associated with risk of venous thromboembolism (VTE) recurrence. However, the role of genetic alterations in the ApoM gene in VTE recurrence remains unknown. The aim of this study was to identify genetic aberrations in ApoM gene in VTE recurrence and their role in prediction of VTE recurrence in a prospective follow-up study of 1465 VTE patients. During follow-up, 156 (10.6 %) patients had VTE recurrence. First screening of whole ApoM gene was performed by Sanger's sequencing in selected age and sex matched non-recurrent and recurrent patients (n=95). In total six polymorphisms were identified and two polymorphisms (rs805297 and rs9404941) with minor allele frequency (MAF) ≥5 % were further genotyped in the whole cohort by Taqman PCR. ApoM rs805297 polymorphism was significantly associated with higher risk of VTE recurrence in males but not in females on both univariate (p= 0.038, hazard ratio = 1.72, confidence interval = 1.03-2.88) and on multivariate analysis adjusted with mild and severe thrombophilia, family history, location and acquired risk factors for VTE. However, ApoM rs9404941 polymorphism showed no significant association with risk of VTE recurrence in all patients as well as in different gender groups. Moreover, ApoM rs805297 and rs9404941 polymorphisms were not associated with the ApoM plasma levels. In conclusion, for the first time we have sequenced whole ApoM gene in VTE and identified six polymorphisms. ApoM rs805297 was significantly associated with higher risk of VTE recurrence in male but not in female patients.
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| 17. |
- Ahmad, Abrar, et al.
(författare)
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Risk prediction of recurrent venous thromboembolism : a multiple genetic risk model
- 2019
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 47:2, s. 216-226
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Tidskriftsartikel (refereegranskat)abstract
- A single genetic biomarker is unable to accurately predict the risk for venous thromboembolism (VTE) recurrence. We aimed to: (a) develop a multiple single nucleotide polymorphisms (SNPs) model to predict the risk of VTE recurrence and (b) validate a previously described genetic risk score (GRS) and compare its performance with the model developed in this study. Twenty-two SNPs, including established and putative SNPs associated with VTE risk, were genotyped in the Malmö thrombophilia study cohort (MATS; n = 1465, follow-up ~ 10 years) by using TaqMan PCR. Out of 22-SNPs, 12 had an association with the risk of VTE recurrence and were included for calculating GRSs. The risk of VTE recurrence was calculated by stratifying patients according to number of risk alleles. In 12-SNP GRS, patients with ≥ 7 risk alleles were associated with higher risk of VTE recurrence compared to patients having ≤ 6 risk alleles. In a simplified model (8-SNP GRS), the discriminative power of 8-SNP GRS was similar to that of 12-SNP GRS based on post-test probabilities (PP). Furthermore, 8-SNP GRS further improved the risk prediction of VTE recurrence in unprovoked VTE and male patients (PP% = 15.4 vs 8.3, 17.1 vs 7.2 and 19.0 vs 7.1 for high risk groups vs low risk groups in whole population, males and unprovoked VTE patients respectively). In addition, we also validated previously described 5-SNP GRS in our cohort and found that the 8-SNP GRS performed better than the 5-SNP GRS in terms of higher PP. Our results show that a multiple SNP GRS consisting of 8-SNPs may be an effective model for prediction of VTE recurrence, particularly in unprovoked VTE and male patients.
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| 18. |
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| 19. |
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| 20. |
- Björck, Fredrik, et al.
(författare)
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Outcomes in a Warfarin-Treated Population With Atrial Fibrillation
- 2016
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 1:2, s. 172-180
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Vitamin K antagonist (eg, warfarin) use is nowadays challenged by the non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). NOAC studies were based on comparisons with warfarin arms with times in therapeutic range (TTRs) of 55.2% to 64.9%, making the results less credible in health care systems with higher TTRs. OBJECTIVES To evaluate the efficacy and safety of well-managed warfarin therapy in patients with nonvalvular AF, the risk of complications, especially intracranial bleeding, in patients with concomitant use of aspirin, and the impact of international normalized ratio (INR) control. DESIGN, SETTING, AND PARTICIPANTS A retrospective, multicenter cohort study based on Swedish registries, especially AuriculA, a quality register for AF and oral anticoagulation, was conducted. The register contains nationwide data, including that from specialized anticoagulation clinics and primary health care centers. A total of 40 449 patients starting warfarin therapy owing to nonvalvular AF during the study period were monitored until treatment cessation, death, or the end of the study. The study was conducted from January 1, 2006, to December 31, 2011, and data were analyzed between February 1 and November 15, 2015. Associating complications with risk factors and individual INR control, we evaluated the efficacy and safety of warfarin treatment in patients with concomitant aspirin therapy and those with no additional antiplatelet medications. EXPOSURES Use of warfarin with and without concomitant therapy with aspirin. MAIN OUTCOMES AND MEASURES Annual incidence of complications in association with individual TTR (iTTR), INR variability, and aspirin use and identification of factors indicating the probability of intracranial bleeding. RESULTS Of the 40 449 patients included in the study, 16 201 (40.0%) were women; mean (SD) age of the cohort was 72.5 (10.1) years, and the mean CHA(2)DS(2)-VASc (cardiac failure or dysfunction, hypertension, age >= 75 years [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65-74 years, and sex category [female]) score was 3.3 at baseline. The annual incidence, reported as percentage (95% CI) of all-cause mortality was 2.19% (2.07-2.31) and, for intracranial bleeding, 0.44%(0.39-0.49). Patients receiving concomitant aspirin had annual rates of any major bleeding of 3.07%(2.70-3.44) and thromboembolism of 4.90% (4.43-5.37), and those with renal failure were at higher risk of intracranial bleeding (hazard ratio, 2.25; 95% CI, 1.32-3.82). Annual rates of any major bleeding and any thromboembolism in iTTR less than 70% were 3.81% (3.51-4.11) and 4.41% (4.09-4.73), respectively, and, in high INR variability, were 3.04%(2.85-3.24) and 3.48% (3.27-3.69), respectively. For patients with iTTR 70% or greater, the level of INR variability did not alter event rates. CONCLUSIONS AND RELEVANCE Well-managed warfarin therapy is associated with a low risk of complications and is still a valid alternative for prophylaxis of AF-associated stroke. Therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor INR control.
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| 21. |
- Björk, Anna, et al.
(författare)
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Type 1 diabetes mellitus and associated risk factors in patients with or without CHD: a case-control study
- 2017
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Ingår i: Cardiology in the Young. - : Cambridge University Press (CUP). - 1047-9511 .- 1467-1107. ; 27:9, s. 1670-1677
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Tidskriftsartikel (refereegranskat)abstract
- Background: Approximately 1% of children are born with CHD, and 90-95% reach adulthood. Increased exposure to infections and stress-strain can contribute to an increased risk of developing type 1 diabetes mellitus. CHD may increase the risk of more serious infections, stress-strain, and increased risk of developing type 1 diabetes mellitus. Methods: We analysed the onset of and the risk of mortality and morbidity associated with concurrent CHD in patients with type 1 diabetes mellitus compared with patients with type 1 diabetes mellitus without CHD. The study combined data from the National Diabetes Register and the National Patient Register. Results: A total of 104 patients with CHD and type 1 diabetes mellitus were matched with 520 controls. Patients with CHD and type 1 diabetes mellitus had an earlier onset of diabetes (13.9 versus 17.4 years, p < 0.001), longer duration of diabetes (22.4 versus 18.1 years, p < 0.001), higher prevalence of retinopathy (64.0 versus 43.0%, p = 0.003), higher creatinine levels (83.5 versus 74.1 mu mol/L, p = 0.03), higher mortality (16 versus 5%, p = 0.002), and after onset of type 1 diabetes mellitus higher rates of co-morbidity (5.28 versus 3.18, p <= 0.01), heart failure (9 versus 2%, p = 0.02), and stroke (6 versus 2%, p = 0.048) compared with controls. Conclusions: From a nationwide register of patients with type 1 diabetes mellitus, the coexistence of CHD and type 1 diabetes mellitus was associated with an earlier onset, a higher frequency of microvascular complications, co-morbidity, and mortality.
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| 22. |
- Dellborg, Mikael, 1954, et al.
(författare)
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High mortality and morbidity among adults with congenital heart disease and type 2 diabetes
- 2015
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Ingår i: Scandinavian Cardiovascular Journal. - 1401-7431. ; 49:6, s. 344-350
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. With improving prognosis the prevalence of adult congenital heart disease (ACHD) is increasing. Patients with type 2 diabetes mellitus (T2DM) have a shorter life expectancy compared with the general population. We investigated, in a large national diabetes registry, the prevalence of ACHD in combination with T2DM to estimate the associated clinical risk, outcome and patient characteristics. Design. Data from the Swedish National Diabetes Register (NDR) were linked with the Swedish National Patient Register (NPR) and the Cause of Death Register. Results. 833 ACHD patients were matched with 5 controls each. ACHD patients had significantly lower body mass index or BMI, higher creatinine and were more sedentary as compared with patients with T2DM but without congenital heart disease. The overall mortality was 26.2% for ACHD patients as compared with 19.9% (P < 0.001) for the control group, and five-year mortality rates were 5.2 versus 3.4%, P = 0.014. Conclusions. Congenital heart disease and secondary risk factors for cardiovascular disease frequently coexist and the development of T2DM also in the ACHD population is not uncommon with an estimated prevalence of between 4 and 8%. Treatment of conventional cardiovascular risk factors in patients with congenital heart disease could be considered secondary prevention given the relatively high morbidity and high risk for mortality observed in patients with the combination of ACHD and T2DM. © 2015 Informa Healthcare.
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| 23. |
- Gottlieb, Assaf, et al.
(författare)
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Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans
- 2017
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects. Methods: Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals. Results: We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Conclusions: Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort.
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| 24. |
- Grzymala-Lubanski, Bartosz, 1980-
(författare)
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Anticoagulation treatment in patients with a mechanical heart valve
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundEvery year about 2,500 patients in Sweden undergo surgery for heart valve disease, primarily in the aortic valve. In contrast to the mitral valve, which can be repaired in 70% of the cases, the aortic valve is normally replaced by a mechanical or biological prosthesis. A mechanical heart valve (MHV) necessitates lifelong anticoagulation treatment with a vitamin K antagonist, most commonly warfarin, due to the high thrombogenicity of the prosthesis. The quality of the warfarin treatment is crucial in these patients. Compared to other countries, treatment quality in Sweden is very high; nonetheless, there is always room for improvement. One of the ways to achieve this improvement is to implement computerized dosing assistance. Treatment recommendations for anticoagulation intensity are based on few and old studies, making these recommendations uncertain. There is therefore a need for studies designed to establish the appropriate level of anticoagulation therapy.AimThe aim of these studies was to investigate the efficacy and safety of anticoagulation treatment among patients with mechanical heart valve prostheses in Sweden; to assess whether computerized dosing can increase the treatment quality; to investigate the influence of the treatment quality, measured by Time in Therapeutic Range (TTR) and INR variability, on the risk of complications and, finally, to establish the optimal intensity of anticoagulation treatment in this group of patients.MethodsData were obtained from AuriculA – a national quality registry established in 2006, which currently includes approximately 50% of all patients treated with oral anticoagulation in Sweden.Study II used only data from AuriculA. 769,933 warfarin-dosing suggestions proposed by the dosing algorithm in AuriculA were analysed. Accepted dose suggestions (590,939) were compared with 178,994 manually-changed doses in regard to the resultant INR value, measured as mean error (deviation from target INR) and hit rate (number of INR samples within the target range 2-3).In study III, AuriculA was used to identify patients in Sundsvall and Malmö in the period 2008 – 2011 who were receiving warfarin for a mechanical heart valve prosthesis, as well as to retrieve their INR data. Data on background characteristics and bleedings or thromboembolic complications were manually retrieved from medical records by two investigators. A total of 534 patients with mechanical heart valve prostheses were divided into quartiles based on TTR and were compared regarding the risk of complications.For Studies I and IV, data from AuriculA were merged with the Swedish National Patient Register, SWEDEHEART/ Heart surgery, and the Swedish Cause of Death Register, comprising in total 77,423 patients on warfarin with 217,804 treatment years. Every treatment period registered in AuriculA was given an individual identification number. During the study period a patient could have any number of treatment periods. The number of complications in total and in different patient groups within the study population was investigated. Complications were defined by ICD-10 codes. Major bleeding was defined as an event necessitating hospital treatment and given a discharge diagnosis with one of the ICD-10 codes reflecting bleeding, as listed in the Appendix. Bleeding events were divided into intracranial, gastrointestinal and other bleedings. Thromboembolic complications consist of venous events (deep vein thrombosis, pulmonary embolism, venous stroke) or arterial events (stroke, TIA, acute myocardial infarction, peripheral arterial embolism).Data were analysed using both simple, descriptive statistical methods and various tests such as Mann-Whitney (or two sample Wilcoxon), T-test, Chi 2 test, ANOVA, multivariate analysis with logistic regression and survival analysis with Cox Regression with proportional hazard assumption.ResultsTreatment quality Mean TTR among all patients in Study I was 76.5% whereas patients with mechanical heart valve prostheses had a TTR of 74.5%. The annual incidence of major bleeding or thromboembolic events among all patients was 2.24% and 2.65%, respectively. The incidence of intracranial bleeding was 0.37% per year in the general population and 0.51% among patients with mechanical heart valve prostheses, who also had a higher bleeding rate in total (3.37% per year).Both the mean and median errors were smaller (0.44 vs. 0.48 and 0.3 vs. 0.4, respectively) and the hit rate was higher (0.72 vs. 0.67) when the dose suggested by the algorithm was accepted, compared to when it was manually changed.TTR In Study III there was no significant difference in the risk of thromboembolism regardless of TTR level. Risk of bleeding in quartiles I and II was more than two times higher than in the quartile with TTR >82.9.In Study IV, lower TTR (≤70%) was associated with a significantly higher rate of complications when compared with TTR >70%. Bleeding risk was higher in the group with lower TTR (HR=2.43, CI 2.02-2.89, p<0.001). After dividing patients into TTR quartiles, the rate of complications in total was significantly higher in quartiles I to III compared with quartile IV, which had the highest TTR. Risk of thromboembolism, major bleeding and death was higher in the first and second quartile compared to the quartile with the highest TTR.INR variability Higher INR variability above mean (≥0.40) was related to a higher rate of complications compared with lower INR variability (<0.40) as shown in Study IV. Bleeding risk was higher in the group with INR variability ≥0.40 (HR = 2.15, CI 1.75-2.61, p<0.001).Comparison of quartile IV, which had the lowest INR variability, with the other three revealed that quartiles I and II, which had the highest INR variability, had significantly worse outcomes for all complications except for thromboembolic events, plus also death in quartile II.TTR and INR variability combined High variability and low TTR combined was associated with a higher risk of bleedings (HR 2.50, CI 1.99-3.15), death (3.34, CI 2.62-4-27) and thrombosis (1.55, CI 1.21-1.99) compared to the best group.Level of anticoagulation Higher warfarin treatment intensity (mean INR 2.8-3.2 vs. 2.2-2.7) was associated with a higher rate of bleedings (HR 1.29, CI 1.06-1.58), death (1.73, CI 1.38-2.16) and complications in total (1.24, CI 1.06-1.41) after adjustment for MHV position, age and comorbidity.ConclusionWarfarin treatment quality is crucial for patients with mechanical heart valve prostheses. Computerized dosing assistance could help maintain high warfarin treatment quality.Well-managed treatment with TTR ≥70% and INR variability below mean <0.40 is associated with a lower risk of serious complications compared with a lower TTR and higher INR variability.No benefit of higher warfarin treatment intensity was found for any valve type or position.
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| 25. |
- Grzymala-Lubanski, Bartosz, et al.
(författare)
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Warfarin treatment quality and prognosis in patients with mechanical heart valve prosthesis.
- 2017
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Ingår i: Heart (British Cardiac Society). - : BMJ. - 1468-201X .- 1355-6037. ; 103:3
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Tidskriftsartikel (refereegranskat)abstract
- To study the impact of time in therapeutic range (TTR) and international normalised ratio (INR) variability on the risk of thromboembolic events, major bleeding complications and death after mechanical heart valve (MHV) implantation. Additionally, the importance of different target INR levels was elucidated.
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