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

Erin M. Kennerly, Youssef Idaghdhour, 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 1 2009

    Fingerprint

    Phenobarbital
    Dogs
    Pharmaceutical Preparations
    Genes
    Pharmacogenetics
    Drug Delivery Systems
    Nervous System Diseases
    Anticonvulsants
    Area Under Curve
    Single Nucleotide Polymorphism
    Canidae
    Case-Control Studies
    Epilepsy
    Seizures
    Alleles
    Pharmacogenomic Testing
    Therapeutics

    Keywords

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

    ASJC Scopus subject areas

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

    Cite this

    Pharmacogenetic association study of 30 genes with phenobarbital drug response in epileptic dogs. / Kennerly, Erin M.; Idaghdhour, Youssef; Olby, Natasha J.; Munana, Karen R.; Gibson, Greg.

    In: Pharmacogenetics and Genomics, Vol. 19, No. 12, 01.12.2009, p. 911-922.

    Research output: Contribution to journalArticle

    Kennerly, Erin M. ; Idaghdhour, Youssef ; Olby, Natasha J. ; Munana, Karen R. ; Gibson, Greg. / Pharmacogenetic association study of 30 genes with phenobarbital drug response in epileptic dogs. In: Pharmacogenetics and Genomics. 2009 ; Vol. 19, No. 12. pp. 911-922.
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