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

Erin M. Kennerly, Youssef Idaghdour, Natasha J. Olby, Karen R. Munana, Greg Gibson

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)911-922
Number of pages12
JournalPharmacogenetics and Genomics
Volume19
Issue number12
DOIs
StatePublished - Dec 2009

Keywords

  • Canine epilepsy
  • Drug response
  • Epoxide hydrolase
  • GABRA2
  • KCNQ3
  • Pharmacogenetics
  • Phenobarbital
  • SCN2A2

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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