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

TL;DR

This study found that rare genetic variants in three genes are linked to central nervous system toxicity caused by antimicrobial drugs.

Contribution

The study identifies uncommon genetic variants in LCP1, RETSAT, and SFMBT2 associated with CNS toxicity from antimicrobial drugs.

Findings

Uncommon variants in LCP1, RETSAT, and SFMBT2 were significantly associated with CNS toxicity.

Two specific variants in LCP1 (rs6561297 and rs10492451) were found to drive the association.

No common genetic variants, HLA types, or structural variations were linked to CNS toxicity.

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.

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