Testing association of rare genetic variants with resistance to three common antiseizure medications

Abstract

Objective: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene-and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. Significance: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

“…The results align with our previous studies that found no common genetic variants in association to VPA, LTG, and LEV response in genetic generalized epilepsy ( Wolking et al, 2020b ) or for the response to lacosamide in focal epilepsy ( Heavin et al, 2019 ). One previous study suggests that rare genetic variants in genes related to drug targets and pharmacokinetics might be involved ( Wolking et al, 2020b ). Given that many individuals with epilepsy exhibit a broad pharmacoresistance, regardless of the drugs’ mechanism of action, other factors are probably at play ( Löscher et al, 2020 ).…”

“…We performed GWAS for drug response for specific ASMs and groups of ASMs (as shown in Table 1) for focal epilepsy and all epilepsies. Results for GGE alone have been published previously (Wolking et al, 2020b). We found no evidence for a relevant GWAS p-value inflation (lambda-range between 0.99 and 1.06).…”

Assessing the role of rare genetic variants in drug‐resistant, non‐lesional focal epilepsy

“…This finding is in accordance with previous studies that showed the association of rare variants with drug‐resistance to specific ASMs: levetiracetam and valproic acid. 15 The enrichment of rare variants in NAFE genes could not be shown in a direct comparison of non‐responders and responders. This was probably due to a lack of sufficient power owed to the much smaller sample size.…”

“…There is some evidence that rare variants are associated with drug resistance to specific ASMs. 15 These effects are likely to remain undetected in a cohort with broad drug resistance. By design, this study did not assess the role of intergenic and non‐exonic regions.…”

“…Few studies have addressed this issue, and those have shown no or only marginal association of genetic markers with response to specific ASMs or broad pharmacoresistance. 13 , 14 , 15 , 16 Various theories have been proposed to explain drug resistance in epilepsy. The drug transporter hypothesis purports that genetic variation of transporter genes could influence the pharmacokinetics of ASMs.…”