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SWEDEGENE: a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-3465-3280
WHO Uppsala Monitoring Ctr, Uppsala, Sweden.
Karolinska Univ Hosp, Karolinska Inst, Dept Lab Med, Clin Pharmacol, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-6857-5973
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2020 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 20, no 4, p. 579-585Article in journal (Refereed) Published
Abstract [en]

SWEDEGENE is a Swedish nation-wide sample collection established to facilitate studies of clinical and genetic risk factors for adverse drug reactions (ADRs). Most cases are recruited among patients reported to the ADR registry at the Swedish Medical Products Agency by health-care professionals. Clinical data are collected both from medical and laboratory records and through interviews using standardized questionnaires. Genome-wide scans and whole-genome sequencing are done, and association studies are conducted using mainly controls from the Swedish TwinGene biobank with data on diagnoses and prescribed drugs. SWEDEGENE was established in 2008 and currently contains DNA and information from about 2550 adults who have experienced specific ADRs, and from 580 drug exposed controls. Results from genome-wide association studies have now been published, and data from whole-genome sequencing are being analyzed. SWEDEGENE has the potential to offer a new means of developing individualized and safe drug therapy through patient pre-treatment screening.

Place, publisher, year, edition, pages
2020. Vol. 20, no 4, p. 579-585
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-425656DOI: 10.1038/s41397-020-0148-3ISI: 000508151600001PubMedID: 31949290OAI: oai:DiVA.org:uu-425656DiVA, id: diva2:1502944
Funder
Swedish Research Council, 2017-00641Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2018-03307Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20170711Science for Life Laboratory - a national resource center for high-throughput molecular bioscience, NP00085Erik, Karin och Gösta Selanders FoundationThuréus stiftelse för främjande av geriatrisk forskningRegion StockholmKnut and Alice Wallenberg FoundationSwedish National Infrastructure for Computing (SNIC)Available from: 2020-11-23 Created: 2020-11-23 Last updated: 2024-04-23Bibliographically approved
In thesis
1. Genomic Analysis of Adverse Drug Reactions
Open this publication in new window or tab >>Genomic Analysis of Adverse Drug Reactions
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adverse drug reactions (ADRs) pose a significant global challenge, leading to substantial costs, suffering, and even loss of life. Genetic factors can play a role in determining a patient's response to the drug treatments and predicting ADRs. While many genetic associations with ADRs have been identified, there are still numerous ADRs suspected to have genetic components.

In Paper I, the collection and curation strategies for ADR cases in the Swedegene biobank are established, presenting a cohort of 2,550 ADR-cases. Paper II presents the association between genetic variations in human leukocyte antigen (HLA) genes and the development of pancreatitis as a response to azathioprine treatment in patients with Crohn's disease. Paper III reports on an international collaboration to investigate the genetic aetiology of atypical femur fractures (AFF) during bisphosphonate treatment. The study found that previously identified genetic variants did not replicate, and --- as the cohort is the largest of its kind --- provides valuable insights into common genetic factors of AFF. Paper IV examines the genetic associations with central nervous system (CNS) toxicity as an ADR to antimicrobial drugs, identifying correlations with three genes linked to suicide and schizophrenia, although the biological connection remains unclear. Finally, Paper V presents a methodology for the experimental design of ADR studies by analysing the known protein interactions of drugs and proteins associated with ADRs. This approach aims to mitigate the impact of competing genetic correlations by identifying common protein interactions to validate the inclusion of drugs and ADRs in the study. These interactions are then ranked based on importance to the selected drugs and ADRs and used to propose genetic targets of interest. 

Overall, the findings of these studies contribute to the understanding of genetic predispositions to ADRs and provide a novel approach for data-driven experimental design for phenotype and genetic target selection.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2055
Keywords
Adverse drug reactions, Genetic association, Network biology
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-527102 (URN)978-91-513-2139-4 (ISBN)
Public defence
2024-06-13, Rosénsalen, Akademiska sjukhuset, ing. 95/96, Uppsala, 13:00 (English)
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Supervisors
Available from: 2024-05-21 Created: 2024-04-23 Last updated: 2024-05-21

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Hallberg, PärMelhus, HåkanÅs, JoelWadelius, Mia

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