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

Joel Ås1, Ilma Bertulyte1, Nina Norgren2

  • 1Department of Medical Sciences, Clinical Pharmacogenomics and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Plos One
|February 29, 2024
PubMed

Insights

Genetic variations in LCP1, RETSAT, and SFMBT2 are linked to central nervous system (CNS) toxicity from antimicrobial drugs. This study found no association with blood-brain barrier transporters but identified specific uncommon gene variants contributing to adverse drug reactions.

Area of Science:

  • Pharmacogenomics
  • Neuroscience
  • Genetics

Background:

  • A genetic predisposition to central nervous system (CNS) toxicity from antimicrobial drugs has been long suspected.
  • Understanding the genetic basis of drug-induced CNS toxicity is crucial for personalized medicine and patient safety.

Purpose of the Study:

  • To investigate the association between genetic variations and antimicrobial drug-induced CNS toxicity.
  • To specifically examine the role of blood-brain barrier efflux transporters in this toxicity.
  • To explore associations across the whole genome, including HLA and structural variations.

Main Methods:

  • Whole genome sequencing was performed on 66 cases with CNS toxicity and 833 controls.
  • Analysis focused initially on seventeen efflux transporters at the blood-brain barrier.
  • Secondary analyses included genome-wide association testing, HLA typing, and assessment of structural genetic variation using SKAT-O.

Main Results:

  • No significant association was found between CNS toxicity and variants in the studied efflux transporters.
  • Uncommon genetic variants in or near three genes—LCP1, RETSAT, and SFMBT2—were significantly associated with CNS toxicity.
  • Specific variants rs6561297 and rs10492451 in LCP1 were identified as key drivers of the observed association.

Conclusions:

  • Antimicrobial drug-induced CNS toxicity is associated with uncommon genetic variants in LCP1, RETSAT, and SFMBT2.
  • The findings suggest that genetic factors beyond blood-brain barrier transporters play a role in susceptibility to these adverse drug reactions.

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