Joel Ås, Ilma Bertulyte, Nina Norgren, Anna Johansson, Niclas Eriksson, Henrik Green, Mia Wadelius, Pär Hallberg
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).
Introduction
Antimicrobial drugs (antibiotics, antivirals, antifungals and antiparasitic drugs) are associated with central nervous system (CNS) toxicity in some patients [1–3]. Well-known examples are ototoxicity due to aminoglycosides, encephalopathy and seizures caused by beta-lactam antibiotics, benign intracranial hypertension due to tetracyclines, neuropsychiatric effects of trimethoprim-sulfamethoxazole, quinolones, antimalarials and antivirals, and cerebellar toxicity due to metronidazole. The risk of CNS toxicity is believed to be influenced by pharmacokinetic and genetic variation and by the penetration of drugs across the blood-brain barrier [4]. Efflux transporters play an important role for the exclusion of antimicrobial drugs from the brain. The efflux transporters P-gp (encoded by ABCB1) and BCRP (encoded by ABCG2) that are highly expressed in the blood-brain barrier are known to transport a number of antimicrobial drugs from the apical membrane or cytoplasm back into the bloodstream.
Materials and methods
This is case-control study of possible genetic variation underlying CNS toxicity to antimicrobial drug. All cases exhibited CNS-toxic adverse reactions to antimicrobial drug treatment. Table 2 provides a comprehensive list of the drugs and adverse reactions, while section 3.1 presents detailed patient characteristics. Genetic information was obtained through whole genome sequencing.
Ethics statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and the study was approved by the regional ethical review board in Uppsala, Sweden (2010/231 Uppsala). Written informed consent was obtained from all participants in the study.
Results
Patient characteristics
A total of 76 patients with suspected CNS toxicity due to antimicrobial drugs were available within the study cohort. Following adjudication, 10 patients were excluded as their symptoms were suspected to be due to peripheral neurotoxicity. Characteristics of the 66 included cases are shown in Table 2. There were more women than men (72% women). The parents’ country of birth was taken from standardized questionnaires, and was used as a proxy for genetic origin. For the majority of the cases, both parents were born in Sweden (n = 55). Nine cases had parents born in other Nordic or central European countries. The remaining two had parents born in the Middle East and North America. Among the 833 controls, 686 (~82%) had both parents born in Sweden, and 44 had one parent from Sweden. Among those with both parents born abroad,32 had at least one parent from another Nordic country. The remaining 46 parents’ place of birth was mainly in Europe, but other continents were represented as well.
Discussion
We investigated whether genetic variation in drug transporters expressed at the blood-brain barrier was associated with risk of CNS toxicity due to antimicrobial medications. No association was observed either with common genetic variation (frequency ≥ 0.123), uncommon variants (frequency < 0.123), or with structural variation in these genes. We further explored whether any genetic variation across the whole genome was associated with risk of CNS toxicity due to antimicrobial drugs. Three genes were significantly associated with risk of CNS toxicity when testing uncommon variants with SKAT-O; LCP1, RETSAT and SFMBT2. Two intronic variants in LCP1 were identified to be driving the association, rs6561297 and rs10492451.
Conclusions
While this study represents an important step towards understanding the genetic basis of antimicrobial-induced CNS toxicity, further research is necessary to elucidate the full spectrum of genetic risk factors and their contributions to diverse adverse drug reactions. In our study, CNS toxicity due to antimicrobial drugs was associated with uncommon variation in LCP1, RETSAT and SFMBT2. However, these findings need to be replicated in studies with larger cohorts and/or that are more homogeneous.
Acknowledgments
We are grateful to all physicians, research nurses, and supporting staff, who assisted in recruiting patients and controls or administering phenotype databases. In particular, we thank Associate Professor Marco Cavalli, Uppsala University, Sweden, for giving insights into functional genomics. Whole genome sequencing of the patient cohort was performed at the single nucleotide polymorphism and sequencing (SNP&SEQ) Technology Platform at Uppsala University (www.genotyping.se) that is part of the National Genomics Infrastructure, Sweden. Computations were done on resources provided by the Swedish National Infrastructure for Computing through the Uppsala Multidisciplinary Centre for Advanced Computational Science (UPPMAX).
Citation: Ås J, Bertulyte I, Norgren N, Johansson A, Eriksson N, Green H, et al. (2024) Whole genome case-control study of central nervous system toxicity due to antimicrobial drugs. PLoS ONE 19(2): e0299075. https://doi.org/10.1371/journal.pone.0299075
Editor: Nur Aizati Athirah Daud, Universiti Sains Malaysia, MALAYSIA
Received: April 4, 2023; Accepted: February 3, 2024; Published: February 29, 2024
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.
Data Availability: Full processing and analysis pipeline can be found at https://github.com/JoelAAs/WGS_pipeline, additional downstream analysis and plotting can be found at: https://github.com/JoelAAs/WGS_testing Genetic data will stored at the official Federated European Genome-phenome Archive (FEGA) at NBIS/Elixir (https://fega.nbis.se/). Data cannot be shared publicly because of patient agreement and GDPR. Data can be requested from the Swedegene data access committee: info@swedegene.se.
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.
Competing interests: The authors declare no conflict of interest. No funder took part in the study design, recruitment, analysis, interpretation of data, writing of the report or in the decision to submit the paper for publication. There are no other conflicts of interest. Genetic data will be available at the official Federated European Genome-phenome Archive (FEGA) at NBIS/Elixir (https://fega.nbis.se/). Data access can be requested if the recipient adheres to our ethics approval, and the request is in accordance with FAIR data management and the General Data Protection Regulation (GDPR) 2016/679.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299075#sec001
