| 1. |
- Jood, Katarina, 1966, et al.
(författare)
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Fibrinolytic gene polymorphism and ischemic stroke
- 2005
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 36:10, s. 2077-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: The tissue-type plasminogen activator (tPA) -7351C>T and the plasminogen activator inhibitor type 1 (PAI-1) -675 4G>5G polymorphisms influence transcriptional activity. Both variants have been associated with myocardial infarction, with increased risk for the T and 4G allele, respectively. In this study we investigated the possible association between these polymorphisms, the respective plasma protein levels, and ischemic stroke. METHODS: In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 patients with acute ischemic stroke aged 18 to 69 years and 600 matched community controls were recruited. Stroke subtype was determined using Trial of Org 10172 in Acute Treatment criteria. RESULTS: There were no associations between individual genetic variants and ischemic stroke. The multivariate-adjusted odds ratio for overall ischemic stroke was 1.11 (95% CI 0.87 to 1.43) for tPA T allele carriers, and 0.84 (95% CI, 0.64 to 1.11) for subjects homozygous for the PAI-1 4G allele. When genotypes were combined, a protective effect for the tPA CC/PAI-1 4G4G genotype combination was observed (odds ratio 0.65, 95% CI 0.43 to 0.98; P<0.05). Plasma levels of tPA and PAI-1 antigen at follow-up were independently associated with overall ischemic stroke. tPA-antigen differed by stroke subtype and was highest among those with large-vessel disease and cardioembolic stroke. CONCLUSIONS: Neither the tPA -7351C>T nor the PAI-1 to 675 4G>5G polymorphism showed significant association with ischemic stroke. For the tPA CC/PAI-1 4G4G genotype combination, a protective effect was observed. Collectively, these results are consistent with a more complex role for tPA and PAI-1 in the brain as compared with the heart.
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| 2. |
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| 3. |
- Ladenvall, Claes, 1974, et al.
(författare)
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Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype
- 2006
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 37:8, s. 2018-23
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: C-reactive protein (CRP) has evolved as an inflammatory risk marker of cardiovascular disease. Several single-nucleotide polymorphisms at the CRP locus have been found to be associated with CRP levels. The aim of the present study was to investigate CRP levels and genetic variants in etiological subtypes of ischemic stroke. METHODS: The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 consecutive ischemic stroke cases (18 to 69 years) and 600 matched controls from western Sweden. Stroke subtypes were defined by the TOAST classification. Serum CRP levels were determined by a high-sensitivity immunometric assay. RESULTS: CRP levels were significantly higher for all ischemic stroke subtypes compared with controls, both in the acute phase and at the 3-month follow-up. After adjustment for traditional risk factors, CRP at follow-up was related to higher odds ratios (ORs) of overall ischemic stroke (OR, 1.25; 95% CI, 1.09 to 1.43) and large-vessel disease (OR, 1.48; 95% CI, 1.09 to 2.00). The CRP -286C>T>A, 1059G>C, and 1444C>T single-nucleotide polymorphisms showed significant associations with CRP levels. However, neither CRP genotypes nor haplotypes showed an association to overall ischemic stroke. CONCLUSIONS: This is the first large study on CRP in different TOAST subtypes in a young ischemic stroke population. CRP levels differed between etiological subtypes of ischemic stroke both in the acute phase and at the 3-month follow-up. CRP at follow-up was associated with overall ischemic stroke and the large-vessel disease subtype. Genetic variants at the CRP locus were associated with CRP levels, but no association was detected for overall ischemic stroke.
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| 4. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 5. |
- Abdulla, Maysaa, et al.
(författare)
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PD-L1 and IDO1 are potential targets for treatment in patients with primary diffuse large B-cell lymphoma of the CNS
- 2021
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 60:4, s. 531-538
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundProgrammed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, as well as Indoleamine 2,3-deoxygenase (IDO1) can be expressed both by tumor and microenvironmental cells and are crucial for tumor immune escape. We aimed to evaluate the role of PD-1, its ligands and IDO1 in a cohort of patients with primary diffuse large B-cell lymphoma of the CNS (PCNSL).Material and methodsTissue microarrays (TMAs) were constructed in 45 PCNSL cases. RNA extraction from whole tissue sections and RNA sequencing were successfully performed in 33 cases. Immunohistochemical stainings for PD-1, PD-L1/paired box protein 5 (PAX-5), PD-L2/PAX-5 and IDO1, and Epstein-Barr virus encoding RNA (EBER) in situ hybridization were analyzed.ResultsHigh proportions of PD-L1 and PD-L2 positive tumor cells were observed in 11% and 9% of cases, respectively. High proportions of PD-L1 and PD-L2 positive leukocytes were observed in 55% and 51% of cases, respectively. RNA sequencing revealed that gene expression of IDO1 was high in patients with high proportion of PD-L1 positive leukocytes (p = .01). Protein expression of IDO1 in leukocytes was detected in 14/45 cases, in 79% of these cases a high proportion of PD-L1 positive leukocytes was observed. Gene expression of IDO1 was high in EBER-positive cases (p = .0009) and protein expression of IDO1 was detected in five of six EBER-positive cases.ConclusionOur study shows a significant association between gene and protein expression of IDO1 and protein expression of PD-L1 in the tumor microenvironment of PCNSL, possibly of importance for prediction of response to immunotherapies.
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| 6. |
- Cumlin, Tomas, et al.
(författare)
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From SARS-CoV-2 to Global Preparedness : A Graphical Interface for Standardised High-Throughput Bioinformatics Analysis in Pandemic Scenarios and Surveillance of Drug Resistance
- 2024
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:12
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Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic highlighted the need for a rapid, convenient, and scalable diagnostic method for detecting a novel pathogen amidst a global pandemic. While command-line interface tools offer automation for SARS-CoV-2 Oxford Nanopore Technology sequencing data analysis, they are inapplicable to users with limited programming skills. A solution is to establish such automated workflows within a graphical user interface software. We developed two workflows in the software Geneious Prime 2022.1.1, adapted for data obtained from the Midnight and Artic's nCoV-2019 sequencing protocols. Both workflows perform trimming, read mapping, consensus generation, and annotation on SARS-CoV-2 Nanopore sequencing data. Additionally, one workflow includes phylogenetic assignment using the bioinformatic tools pangolin and Nextclade as plugins. The basic workflow was validated in 2020, adhering to the requirements of the European Centre for Disease Prevention and Control for SARS-CoV-2 sequencing and analysis. The enhanced workflow, providing phylogenetic assignment, underwent validation at Uppsala University Hospital by analysing 96 clinical samples. It provided accurate diagnoses matching the original results of the basic workflow while also reducing manual clicks and analysis time. These bioinformatic workflows streamline SARS-CoV-2 Nanopore data analysis in Geneious Prime, saving time and manual work for operators lacking programming knowledge.
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| 7. |
- Dahlberg, Johan, et al.
(författare)
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Arteria : An automation system for a sequencing core facility
- 2019
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Ingår i: GigaScience. - : Oxford University Press (OUP). - 2047-217X. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: In recent years, nucleotide sequencing has become increasingly instrumental in both research and clinical settings. This has led to an explosive growth in sequencing data produced worldwide. As the amount of data increases, so does the need for automated solutions for data processing and analysis. The concept of workflows has gained favour in the bioinformatics community, but there is little in the scientific literature describing end-to-end automation systems. Arteria is an automation system that aims at providing a solution to the data-related operational challenges that face sequencing core facilities.Findings: Arteria is built on existing open source technologies, with a modular design allowing for a community-driven effort to create plug-and-play micro-services. In this article we describe the system, elaborate on the underlying conceptual framework, and present an example implementation. Arteria can be reduced to 3 conceptual levels: orchestration (using an event-based model of automation), process (the steps involved in processing sequencing data, modelled as workflows), and execution (using a series of RESTful micro-services). This creates a system that is both flexible and scalable. Arteria-based systems have been successfully deployed at 3 sequencing core facilities. The Arteria Project code, written largely in Python, is available as open source software, and more information can be found at https://arteria-project.github.io/.Conclusions: We describe the Arteria system and the underlying conceptual framework, demonstrating how this model can be used to automate data handling and analysis in the context of a sequencing core facility.
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| 8. |
- Eriksson, Anna, 1977-, et al.
(författare)
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Somatic Exonic Deletions in RUNX1 Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia
- 2023
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 29:15, s. 2826-2834
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In acute myeloid leukemia (AML), somatic mutations (commonly missense, nonsense, and frameshift indels) in RUNX1 are associated with a dismal clinical outcome. Inherited RUNX1 mutations cause familial platelet disorder. As approximately 5%-10% of germline RUNX1 mutations are large exonic deletions, we hypothesized that such exonic RUNX1 aberrations may also be acquired during the development of AML.Experimental Design: Sixty patients with well-characterized AML were analyzed with multiplex ligation-dependent probe amplification (n = 60), microarray (n = 11), and/or whole-genome sequencing (n = 8).Results: In total, 25 (42% of the cohort) RUNX1-aberrant patients (defined by the presence of classical mutations and/or exonic deletions) were identified. Sixteen patients (27%) carried only exonic deletions, 5 (8%) carried classical mutations, and 4 (7%) carried both exonic deletions and mutations. No significant difference was observed between patients with classical RUNX1 mutations and RUNX1 exonic deletions in median overall survival (OS, 53.1 vs. 38.8 months, respectively, P = 0.63). When applying the European Leukemia Net (ELN) classification including the RUNX1-aberrant group, 20% of the patients initially stratified as intermediate-risk (5% of the whole cohort) were reassigned to the high-risk group, which improved the performance of ELN classification regarding OS between intermediate-and high-risk groups (18.9 vs. 9.6 months, P = 0.09).Conclusions: Somatic RUNX1 exonic deletions constitute a novel recurrent aberration in AML. Our findings have important clinical implications regarding AML classification, risk stratification, and treatment decision. Moreover, they argue in favor of further investigating such genomic aberrations not only in RUNX1 but also in other genes implicated in cancer biology and management.
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| 9. |
- Jood, Katarina, 1966, et al.
(författare)
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Family history in ischemic stroke before 70 years of age: the Sahlgrenska Academy Study on Ischemic Stroke
- 2005
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Ingår i: Stroke. - 1524-4628. ; 36:7, s. 1383-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Results from twin and family history studies of ischemic stroke suggest that future molecular genetic studies should focus on strictly defined stroke subtypes and younger cases. Accordingly, we investigated stroke subtypes, vascular risk factors, and family history in a large study of patients with ischemic stroke onset before age 70 years. METHODS: Six hundred consecutive white participants with ischemic stroke (18 to 69 years) and 600 age- and sex-matched controls were examined for vascular risk factors and family history of stroke and myocardial infarction (MI). Stroke subtype was defined using Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: Family history of stroke was associated with overall ischemic stroke (multivariate odds ratio [OR], 1.75; 95% confidence interval [CI], 1.26 to 2.43), large-vessel disease (LVD) (OR, 1.88; 95% CI, 1.02 to 3.44), small-vessel disease (SVD, OR, 1.79; 95% CI, 1.13 to 2.84), and cryptogenic stroke (OR, 1.70; 95% CI, 1.13 to 2.56), but not with cardioembolic stroke. Family history of MI was strongly associated with LVD (OR, 3.25; 95% CI, 1.74 to 6.07), whereas no significant association were observed for other subtypes. We also found an independent association between family history of stroke and a favorable outcome after 3 months. CONCLUSION: Family history of stroke is an independent risk factor for ischemic stroke with onset before age 70 years. For the first time to our knowledge, we report this association not only for LVD and SVD but also for cryptogenic stroke, implying that future studies of the genetics of ischemic stroke should target these 3 subtypes.
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| 10. |
- Jood, Katarina, 1966, et al.
(författare)
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Fibrinogen gene variation and ischemic stroke.
- 2008
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Ingår i: Journal of thrombosis and haemostasis : JTH. - : Elsevier BV. - 1538-7836. ; 6:6, s. 897-904
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Plasma fibrinogen level and fibrin clot structure are heritable traits that may be of importance in the pathogenesis of ischemic stroke. OBJECTIVES: To investigate associations between variation in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes, fibrinogen level, and ischemic stroke. METHODS: The Sahlgrenska Academy Study on Ischemic Stroke comprises 600 cases and 600 matched population controls. Stroke subtypes were defined according to TOAST criteria. Plasma fibrinogen level was measured by an automated clot-rate assay. Eight tagging single nucleotide polymorphisms (SNPs) were selected to capture genetic variation in the FGA, FGG, and FGB genes. RESULTS: Plasma fibrinogen was independently associated with overall ischemic stroke and all subtypes, both in the acute stage (P < 0.001) and at three-month follow-up (P < 0.05). SNPs belonged to two haplotype blocks, one containing the FGB gene and the other the FGG and FGA genes. FGB haplotypes were associated with fibrinogen level (P < 0.01), but not with ischemic stroke. In contrast, FGG/FGA haplotypes showed independent association to ischemic stroke but not to fibrinogen level. In an additive model with the most common FGG/FGA haplotype (A1) as reference, the adjusted odds ratios of ischemic stroke were 1.4 [95% confidence interval (95% CI) 1.1-1.8], P < 0.01, 1.4 (95% CI 1.0-1.8), P < 0.05, and 1.5 (95% CI 1.0-2.1), P < 0.05 for the A2, A3, and A4 FGG/FGA haplotypes, respectively. CONCLUSION: FGG/FGA haplotypes show association to ischemic stroke. This association is independent of fibrinogen level, thus suggesting that the association between ischemic stroke and variation at the FGG/FGA genes is mediated by qualitative rather than quantitative effects on fibrin(ogen).
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| 11. |
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| 12. |
- Ladenvall, Claes, 1974, et al.
(författare)
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Association between factor XIII single nucleotide polymorphisms and aneurysmal subarachnoid hemorrhage Clinical article
- 2009
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Ingår i: JOURNAL OF NEUROSURGERY. - 0022-3085. ; 110:3, s. 475-481
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Tidskriftsartikel (refereegranskat)abstract
- Object Family studies have suggested a role of genetic factors in susceptibility to aneurysmal subarachnoid hemorrhage (aSAH), but the underlying genetic risk factors remain poorly defined. There is an activation of the fibrinolytic system in aSAH, and fibrinolytic markers may be useful in predicting outcome. The authors investigate associations between putative functional variants in genes of importance for fibrinolysis and aSAH and/or outcome following aSAH. Methods One hundred eighty-three patients presenting with aSAH at a neurointensive care unit were consecutively recruited. Two healthy controls per case, matched for age, sex, and geographic region, were randomly recruited. Outcome was assessed after 1 year according to the extended Glasgow Outcome Scale. Single nucleotide polymorphisms (SNPs) in the tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and factor XIII (FXIII) genes were investigated. Results Participants carrying the FXIII 34Leu allele showed an increased risk of aSAH. When adjusting for smoking and hypertension, 2 haplotypes, differing on either the FXIII Val34Leu or the Pro564Leu position, showed an association to aSAH. No significant association was observed for the tPA -7351 C > T, PAI-1 -675 4G > 5G, or TAFI Ala147Thr SNPs. No specific SNP or haplotype was associated with outcome after aSAH, whereas a weak association was observed for a tPA/PAI-1 genotype combination. Conclusions Polymorphisms in the FXIII gene showed association to aSAH. The finding of an increased risk of bleeding in FXIII 34Leu carriers is biologically plausible.
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| 13. |
- Ladenvall, Claes, 1974
(författare)
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Genetic association studies in stroke
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stroke is the third most common cause of death and the most common cause of disability in adults in developed countries. It is a complex disease in which genetic and environmental factors make about equal contributions. A significant proportion of the environmental component remains to be elucidated and little is known about which genes that are involved. There are two main stroke types; ischemic and hemorrhagic. Both these types have several different etiological subtypes. The specific aim of the present work was to perform clinical association studies to test the hypothesis that hemostatic and inflammatory gene polymorphisms, and/or plasma levels of the respective proteins, are associated with stroke, and to investigate whether associations differ between stroke subtypes. The studies on ischemic stroke were based on the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), in which great emphasize has been put on phenotyping by physical examination and neuroimaging. The study comprises 600 consecutive ischemic stroke patients presenting with ischemic stroke before the age of 70 years and 600 matched population-based controls. Stroke patients were classified according to the main etiological subtypes of ischemic stroke, i.e. large-vessel disease (LVD), small-vessel disease (SVD), cardioembolic stroke (CE stroke) and cryptogenic stroke. The study on aneurysmal subarachnoid hemorrhage (aSAH) was based on patients admitted to the Neurointensive Care Unit, Sahlgrenska. A total of 183 patients with a confirmed aneurysmal origin of the SAH were included. Two matched population-based controls were recruited for each case. Genotyping was performed using 5´nuclease assays (TaqMan) and plasma levels of proteins were determined by immunological methods. Family history of stroke showed independent association to all ischemic stroke subtypes, except CE stroke. In our first genetic association study, the fibrinolytic pathway was studied. A reduced risk of ischemic stroke was observed for a genotype combination indicating a high gene expression level of both tissue-type plasminogen activator and plasminogen activator inhibitor type 1. This association was not detected in aSAH. However, an increased risk of aSAH was found for subjects carrying the coagulation factor XIII 34Leu allele. This variant has been shown to influence fibrinolysis by affecting the fibrin network. Family history of myocardial infarction (MI) only showed association to one ischemic stroke subtype, i.e. LVD. The explanation for this may be that atherosclerosis is a common denominator for MI and LVD. In support for this hypothesis, increased plasma levels of the inflammatory marker C-reactive protein was only found in the LVD group. This is in contrast to the fibrinolytic pathway. Plasma levels of tPA, PAI-1 and the fibrinolytic inhibitor TAFI were increased in all ischemic stroke subtypes. In conclusion, the results support a genetic contribution in stroke. This genetic contribution seems to differ between subtypes, which highlights the importance of subtype classification in stroke research. Furthermore, the findings suggest that inflammatory factors may be of more importance for developing LVD, while the fibrinolytic pathway seems to be involved in all ischemic stroke subtypes.
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| 14. |
- Ladenvall, Claes, 1974, et al.
(författare)
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Thrombin activatable fibrinolysis inhibitor activation peptide shows association with all major subtypes of ischemic stroke and with TAFI gene variation
- 2007
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Ingår i: Arterioscler Thromb Vasc Biol. - 1079-5642. ; 27:4, s. 955-62
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Thrombin activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis. The aim of the present study was to investigate the possible association between TAFI and overall ischemic stroke and ischemic stroke subtypes. METHODS AND RESULTS: The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 cases (18 to 69 years) and 600 matched population controls. Stroke subtype was defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. TAFI was investigated at the protein level, by analyzing plasma levels of intact TAFI and released activation peptide [AP], and at the genetic level, by genotyping a selection of eleven single nucleotide polymorphisms. After adjustment for traditional risk factors, both TAFI measurements showed association with overall ischemic stroke (AP: odds ratio, 2.22; 95% confidence interval, 1.89 to 2.61; intact TAFI: odds ratio, 1.21; 95% confidence interval, 1.06 to 1.38; for 1-SD increase in AP and intact TAFI, respectively). AP showed associations with all 4 major subtypes of ischemic stroke and intact TAFI to large vessel disease and cryptogenic stroke. TAFI genotypes and haplotypes showed significant associations with both TAFI measurements. In contrast, no association was observed between genetic variants and overall ischemic stroke. CONCLUSION: TAFI levels show independent association with overall ischemic stroke. This association is stronger for released AP than for intact TAFI, and for released AP, it is present in all ischemic stroke subtypes.
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| 15. |
- Malinski, Bartosz, et al.
(författare)
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Novel pathological variants of NHP2 affect N-terminal domain flexibility, protein stability, H/ACA Ribonucleoprotein (RNP) complex formation and telomerase activity
- 2023
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 32:19, s. 2901-2912
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Tidskriftsartikel (refereegranskat)abstract
- Telomere biology disorders (TBDs) are characterized by short telomeres, premature aging, bone marrow failure and cancer predisposition. Germline mutations in NHP2, encoding for one component of the telomerase cofactor H/ACA RNA binding complex together with Dyskerin, NOP10 and GAR1, have been previously reported in rare cases of TBDs. Here, we report two novel NHP2 variants (NHP2-A39T and NHP2-T44M) identified in a compound heterozygous patient affected by premature aging, bone marrow failure/myelodysplastic syndrome and gastric cancer. Although still able to support cell viability, both variants reduce the levels of hTR, the telomerase RNA component, and telomerase activity, expanding the panel of NHP2 pathological variants. Furthermore, both variants fail to be incorporated in the H/ACA RNA binding complex when in competition with wild-type endogenous NHP2, and the lack of incorporation causes their drastic proteasomal degradation. By RoseTTAFold prediction followed by molecular dynamics simulations, we reveal a dramatic distortion of residues 33-41, which normally position on top of the NHP2 core, as the main defect of NHP2-A39T, and high flexibility and the misplacement of the N-terminal region (residues 1-24) in NHP2-T44M and, to a lower degree, in NHP2-A39T. Because deletion of amino acids 2-24 causes a reduction in NHP2 levels only in the presence of wild-type NHP2, while deletion of amino acids 2-38 completely disrupts NHP2 stability, we propose that the two variants are mis-incorporated into the H/ACA binding complex due to the altered dynamics of the first 23 amino acids and/or the distortion of the residues 25-41 loop.
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| 16. |
- Pandzic, Tatjana, et al.
(författare)
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Five Percent Variant Allele Frequency Is a Reliable Reporting Threshold for TP53 Variants Detected by Next Generation Sequencing in Chronic Lymphocytic Leukemia in the Clinical Setting
- 2022
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Ingår i: HemaSphere. - : Lippincott Williams & Wilkins. - 2572-9241. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- The clinical significance of small TP53 clones detected with next generation sequencing (NGS) in chronic lymphocytic leukemia is an issue of active debate. According to the official guidelines, treatment decisions should be guided only by variants with variant allele frequency (VAF) >= 10%. We present data on 325 consecutive patients with chronic lymphocytic leukemia analyzed with NGS. In total 47 pathogenic/likely pathogenic (P/LP), TP53 variants were detected in 26 patients (8%). Eleven of these (23%) were in the 5% to 10% VAF range and reported according to our institutional policy. All TP53 variants in the 5% to 10% VAF range were confirmed (100% concordance) with a second NGS panel. Our results where further validated with the performance of Sanger sequencing and digital droplet PCR (ddPCR). In 12 patients with available fluorescence in situ hybridization data and TP53 mutations within 5% to 10% VAF, deletion of chromosome 17p (del(17p)) was detectable in only 1 patient. We propose a robust diagnostic algorithm, which allows the safe detection and reporting of TP53 variants with VAF down to 5% in the clinical setting. Our study provides evidence that NGS is equally potent to detect variants with VAF 5% to 10% compared to those with VAF 10% to 15%, highlighting the urgent need for harmonization of NGS methodologies across diagnostic laboratories.
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