Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy
Tracy A Glauser1,2, Katherine Holland1,2, Valerie P O'Brien1,2
1Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Insights
Genetic variations in T-type calcium channels and ABCB1 influence drug response in childhood absence epilepsy (CAE). This study confirms the impact of a CACNA1H variant on ethosuximide effectiveness, highlighting genetics in CAE treatment.
Area of Science:
- Neurogenetics
- Pharmacogenomics
- Epilepsy Research
Background:
- Childhood absence epilepsy (CAE) treatment response varies significantly among individuals.
- Genetic factors are increasingly recognized as potential contributors to this variability.
- Specific genes encoding T-type calcium channels and drug transporters are plausible candidates for influencing antiepileptic drug efficacy.
Purpose of the Study:
- To investigate the association between common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 genes and short-term seizure outcomes in children with CAE.
- To explore the functional impact of a specific CACNA1H variant on T-type calcium channel activity and response to ethosuximide.
Main Methods:
- A cohort of 446 children with CAE participated in a randomized trial of ethosuximide, lamotrigine, or valproate.
- Genotyping was performed for common polymorphisms (minor allele frequency ≥15%) in the four target genes.
- Seizure outcomes were assessed, and associations with genetic variants were analyzed.
- In vitro electrophysiology was used to study the effect of a CACNA1H variant on channel function and drug response.
Main Results:
- Eighty percent of participants had informative seizure status data.
- Two CACNA1H polymorphisms (rs61734410/P640L, rs3747178) and one CACNA1I polymorphism (rs3747178) were associated with poorer outcomes in the ethosuximide group.
- An ABCB1 polymorphism (rs2032582/S893A) was linked to unfavorable outcomes with lamotrigine, while two CACNA1H polymorphisms (rs2753326, rs2753325) were associated with better outcomes.
- No significant associations were found in the valproate group.
- In vitro studies confirmed that the P640L variant reduced ethosuximide's effect on CaV 3.2 channel activity.
Conclusions:
- Several T-type calcium channel variants and an ABCB1 transporter variant are associated with differential responses to antiepileptic drugs in CAE.
- The P640L variant in CACNA1H demonstrably affects ethosuximide efficacy, as confirmed by in vitro electrophysiology.
- Genetic variations play a significant role in determining individual drug responses in CAE, suggesting potential for personalized treatment strategies.
Objective:
To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in childhood absence epilepsy (CAE).
Methods:
Four hundred forty-six CAE children in a randomized double-blind trial of ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency ≥ 15%) in 4 genes and seizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of 1 variant on T-type calcium channel responsiveness to ethosuximide.
Results:
Eighty percent (357 of 446) of subjects had informative short-term seizure status (242 seizure free, 115 not seizure free). In ethosuximide subjects, 2 polymorphisms (CACNA1H rs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not-seizure-free participants (p = 0.011, odds ratio [OR] = 2.63, 95% confidence limits [CL] = 1.25-5.56; p = 0.026, OR = 2.38, 95% CL = 1.11-5.00). In lamotrigine subjects, 1 ABCB1 missense polymorphism (rs2032582/S893A; p = 0.015, OR = 2.22, 95% CL = 1.16-4.17) was more common in not-seizure-free participants, and 2 CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure-free participants (p = 0.038, OR = 0.52, 95% CL = 0.28-0.96). In valproate subjects, no common polymorphisms were associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in the absence of ethosuximide. Ethosuximide's effect on rate of decay of CaV 3.2 was significantly less for P640L channel compared to wild-type channel.
Interpretation:
Four T-type calcium channel variants and 1 ABCB1 transporter variant were associated with differential drug response in CAE. The in vivo P640L variant's ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests that genetic variation plays a role in differential CAE drug response. Ann Neurol 2017;81:444-453.
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