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- 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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- Smeds, Patrik, et al.
(författare)
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Hydra-genetics, a modular framework for bioinformatics pipeline development
- 2024
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Ingår i: European Journal of Human Genetics. - : Nature Portfolio. - 1018-4813 .- 1476-5438. ; 32:Suppl. 1, s. 675-676
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Processing information from massively parallel sequencing/next-generation sequencing (NGS) data involves several steps that transform millions of rows of input data into more accessible genetic information. The combination of bioinformatics tools that extract all requested information for a particular clinical/research application, how they are tuned and the order in which they are executed constitute a bioinformatics pipeline. Software is often reused in several pipelines and regularly updated. For clinically validated NGS pipelines it may be challenging when individual components of several pipelines needs updating or when tools are replaced with new applications.Methods: The Hydra-genetics framework takes advantage of version controlled Snakemake modules. Pipeline steps are split into modules that can be configured and tested individually. The modules can be combined to build complete bioinformatics analyses, or be added to existing pipelines. All modules are subjected to extensive testing to ensure that new releases do not unexpectedly break existing pipelines or deviate from guidelines and best practices on how to write code.Results: Bioinformaticians from five Genomics Medicine Sweden centers used Hydra-genetics to develop the bioinformatics pipeline for the comprehensive solid tumor panel, GMS560. The pipeline analyses tumor DNA and/or RNA data and generates information on genetic variation including complex biomarkers such as tumor mutation burden and microsatellite instability. It is validated and in clinical use.Conclusions: The Hydra-genetics framework provides a platform for structured bioinformatics pipeline development and facilitates joint development projects involving multiple partners. It makes clinical pipeline development easier, faster and more structured.
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- Ström, Kristoffer, et al.
(författare)
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Genetic variation at RAB3GAP2 and its role in exercise-related adaptation and recovery
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Skeletal muscle fiber composition and capillary density influence physical performance and whole-body metabolic properties. ~45% of the variance in fiber type is heritable, which motivated us to perform a genome-wide association study of skeletal muscle histology from 656 Swedish men. Four independent variants were associated (p
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