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.


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.


CONCLUSIONS
Further replication and assessment of breed specificity is required before these markers can be considered as predictive of responsiveness to phenobarbital in dogs.
Department of Genetics, Gardner Hall, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
Erin M
EM
Kennerly
Youssef
Y
Idaghdour
Natasha J
NJ
Olby
Karen R
KR
Munana
Greg
G
Gibson
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000627:therapeutic use*; D016022:Case-Control Studies; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy / Q000662:veterinary*; D010597:Pharmacogenetics; D010634:Phenobarbital / Q000378:metabolism* / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide
D000927:Anticonvulsants; D010634:Phenobarbital