Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs

Joel Ås; Ilma Bertulyte; Nina Norgren; Anna Johansson; Niclas Eriksson; Henrik Green; Mia Wadelius; Pär Hallberg

doi:10.1371/journal.pone.0299075

Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs

PLoS One. 2024 Feb 29;19(2):e0299075. doi: 10.1371/journal.pone.0299075. eCollection 2024.

Authors

Joel Ås¹, Ilma Bertulyte¹, Nina Norgren², Anna Johansson³, Niclas Eriksson^{1

4}, Henrik Green^{5

6}, Mia Wadelius¹, Pär Hallberg¹

Affiliations

¹ Department of Medical Sciences, Clinical Pharmacogenomics and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
² Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Umeå, Sweden.
³ Dept of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁴ Uppsala Clinical Research Center, Uppsala, Sweden.
⁵ Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁶ Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.

Abstract

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.

Copyright: © 2024 Ås et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Anti-Bacterial Agents
Anti-Infective Agents* / toxicity
Antifungal Agents
Case-Control Studies
Central Nervous System
Membrane Transport Proteins

Substances

Anti-Infective Agents
Anti-Bacterial Agents
Antifungal Agents
Membrane Transport Proteins

Grants and funding

This study was granted by the Science for Life Laboratory’s Swedish Genomes Program 2017 that was supported by the Knut and Alice Wallenberg Foundation (application ID NP:00085). Furthermore, we received grants from the Swedish Research Council (Medicine 521-2011-2440, 521-2014-3370 and 2018-03307), and Clinical Research Support (Avtal om Läkarutbildning och Forskning, ALF) at Uppsala University. All grants mentioned were granted to MW and PH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.