Pharmacogenetic association study of 30 genes with phenobarbital drug response in epileptic dogs

BACKGROUND: Epilepsy, with a prevalence as high as 6%, is the most common neurological disorder in dogs. Although several antiepileptic drugs are in common use, in one-third of all epileptic dogs, adequate seizure control is not achieved with a single medication, and hence a combinatorial drug treatment must be adopted. Exploration of the genetic mechanisms involved in drug response may provide better treatment options for epileptic patients. METHODS AND RESULTS: A custom Illumina BeadChip was designed for high throughput genotyping of 384 single nucleotide polymorphisms in 30 genes involved in drug metabolism, drug targeting, and drug transport. A case-control association study of 125 epileptic dogs identified five genes with suggestive association to phenobarbital drug response: KCNQ3, P=0.0003; SNC2A2, P=0.0008; EPOX HYD, P=0.0005; ABCC4, P=0.0091; and GABRA2, P=0.0130. These associations are not significant after adjustment for multiple comparisons, but on functional grounds may tag strong candidate genes. The study was powered to detect alleles with at least 3.5-fold additive increases in responsiveness. A combined area under the curve value of 0.74 from receiver operating curve analysis also provides suggestive support for their consideration as canine pharmacogenetic markers. CONCLUSION: Further replication and assessment of breed specificity is required before these markers can be considered as predictive of responsiveness to phenobarbital in dogs.