Department of Medical Sciences, Clinical Pharmacogenomics and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Umeå, Sweden.
PLoS One. 2024 Feb 29;19(2):e0299075. doi: 10.1371/journal.pone.0299075. eCollection 2024.
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.
人们怀疑抗菌药物（抗生素、抗病毒药、抗真菌药和抗寄生虫药）引起的中枢神经系统（CNS）毒性存在遗传易感性。对 66 例病例和 833 例对照进行了全基因组测序，以研究抗菌药物引起的 CNS 毒性是否与遗传变异有关。主要目的是测试抗菌药物引起的 CNS 毒性是否与血脑屏障上的十七种外排转运蛋白有关。在这项研究中，外排转运蛋白的变体或结构元件与 CNS 毒性没有显著关联。次要目的是测试抗菌药物引起的 CNS 毒性是否与整个基因组、HLA 或结构遗传变异有关。根据序列核关联测试与最优统一测试（SKAT-O）相结合，三个基因附近的罕见变异与 CNS 毒性显著相关（q = 0.013）。这些基因是 LCP1（q = 0.013）、RETSAT（q = 0.013）和 SFMBT2（q = 0.035）。两个变体驱动了 LCP1 的关联：rs6561297（p = 1.15x10-6，OR：4.60 [95% CI：2.51-8.46]）和调节变体 rs10492451（p = 1.15x10-6，OR：4.60 [95% CI：2.51-8.46]）。没有常见的遗传变异、HLA 型或结构变异与 CNS 毒性相关。总之，抗菌药物引起的 CNS 毒性与 LCP1、RETSAT 和 SFMBT2 的罕见变异有关。
