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Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs
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: 0000-0001-8687-0629
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: 0000-0003-1623-9449
Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Umeå, Sweden.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.ORCID iD: 0000-0001-7752-269X
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2024 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 19, no 2, article id e0299075Article in journal (Refereed) Published
Abstract [en]

A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51–8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2024. Vol. 19, no 2, article id e0299075
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-526190DOI: 10.1371/journal.pone.0299075ISI: 001181714500084PubMedID: 38422004OAI: oai:DiVA.org:uu-526190DiVA, id: diva2:1849258
Part of project
Detection and use of pharmacogenomic biomarkers for personalised treatment, Swedish Research CouncilSwedegene: a national centre for pharmacogenomic studies of adverse drug reactions, Swedish Research CouncilStrategic initiative in pharmacogenetics: from discovery to implementation, Swedish Research Council
Funder
Knut and Alice Wallenberg Foundation, NP:00085Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2018-03307Science for Life Laboratory, SciLifeLabAvailable from: 2024-04-05 Created: 2024-04-05 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)
Opponent
Supervisors
Available from: 2024-05-21 Created: 2024-04-23 Last updated: 2024-05-21

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Ås, JoelBertulyte, IlmaJohansson, AnnaEriksson, NiclasWadelius, MiaHallberg, Pär

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