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

Kennerly, Erin; Idaghdour, Youssef; Olby, Natasha J.; Muñana, Karen R.; Gibson, Greg

doi:10.1097/fpc.0b013e3283307cba

Cited by 10 publications

(5 citation statements)

References 48 publications

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“…A recent genetic study screened 125 epileptic dogs representing 44 breeds for 384 SNP across 30 genes. 48 All of these genes were related to PB pharmacology. Five genes were suggested to have an association with PB response although they did not reach statistical significance (KCNQ3, SCN2A2, GABRA2, EPOX HYD, and ABC-B4).…”

Section: Discussionmentioning

confidence: 99%

“…In the ABCB1 gene, 18 SNP were found that were not further described but showed no statistically significant association with PB response. 48 The identification of the 4 bp deletion in the ABCB1 gene has been proven to be of clinical value to predict the response of an individual dog to a wide variety of xenobiotics and AEDs. Therefore, it would be valuable to identify polymorphisms in the ABCB1 gene that could be used as putative markers in order to make rational decisions concerning therapy.…”

Section: Discussionmentioning

confidence: 99%

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Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

Alves

Hülsmeyer

Jaggy

et al. 2011

Veterinary Internal Medicne

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Background: Variation in the ABCB1 gene is believed to play a role in drug resistance in epilepsy. Hypothesis/Objectives: Variation in the ABCB1 gene encoding the permeability-glycoprotein could have an influence on phenobarbital (PB) resistance, which occurs with high frequency in idiopathic epileptic Border Collies (BCs).Animals: Two hundred and thirty-six client-owned BCs from Switzerland and Germany including 25 with idiopathic epilepsy, of which 13 were resistant to PB treatment.Methods: Prospective and retrospective case-control study. Data were collected retrospectively regarding disease status, antiepileptic drug (AED) therapy, and drug responsiveness. The frequency of a known mutation in the ABCB1 gene (4 base-pair deletion in the ABCB1 gene [c.296_299del]) was determined in all BCs. Additionally, the ABCB1 coding exons and flanking sequences were completely sequenced to search for additional variation in 41 BCs. Association analyses were performed in 2 case-control studies: idiopathic epileptic and control BCs and PB-responsive and resistant idiopathic epileptic BCs.Results: One of 236 BCs (0.4%) was heterozygous for the mutation in the ABCB1 gene (c.296_299del). A total of 23 variations were identified in the ABCB1 gene: 4 in exons and 19 in introns. The G-allele of the c.-6-180T 4 G variation in intron 1 was significantly more frequent in epileptic BCs resistant to PB treatment than in epileptic BCs responsive to PB treatment (P raw 5 .0025).Conclusions and Clinical Importance: A variation in intron 1 of the ABCB1 gene is associated with drug responsiveness in BCs. This might indicate that regulatory mutations affecting the expression level of ABCB1 could exist, which may influence the reaction of a dog to AEDs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

Alves

Hülsmeyer

Jaggy

et al. 2011

Veterinary Internal Medicne

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“…Recent epilepsy research in dogs mainly focuses on the identification of epilepsy genes, but interest in mechanisms of pharmacoresistance and the characterization of the clinical course are increasing . It is generally stated that pharmacoresistance can develop in up to 30% of dogs with epilepsy .…”

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confidence: 99%

Disease Progression and Treatment Response of Idiopathic Epilepsy inAustralianShepherd Dogs

Weißl

Hülsmeyer

Brauer

et al. 2011

Veterinary Internal Medicne

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Background: Idiopathic epilepsy (IE) in Australian Shepherds (ASs) occurs worldwide but there is a lack of description of the epilepsy syndrome in this breed. The ABCB1-1D mutation is more prevalent in ASs than in many other dog breeds.Hypothesis: Australian Shepherds suffer from a poorly controlled IE syndrome with prevailing severe courses. Seizure control and ABCB1-1D mutation might be related in this breed.Animals: Fifty ASs diagnosed with IE and 50 unaffected ASs. Methods: Predominant study design is a longitudinal cohort study. Pedigrees, medical records, seizure, and treatment data of ASs with IE were analyzed descriptively. Sex, color, and the ABCB1-1D genotype were compared between case and control groups and ASs with poorly or well-controlled seizures. Differences in survival times were assessed by logrank tests and Cox regression analysis.Results: Idiopathic epilepsy in ASs is dominated by moderate and severe clinical courses with the occurrence of cluster seizures and status epilepticus and a high seizure frequency. Poor seizure control and a high initial seizure frequency ( ! 10 seizure days/first 6 months) are associated with shorter survival times (P < .05). Poor seizure control, unrelated to the ABCB1(MDR1) genotype, is evident in 56% of epileptic ASs. Pedigree analysis suggests a genetic basis.Conclusion and Clinical Importance: Frequent severe clinical courses, poor seizure control unrelated to the ABCB1 (MDR1) genotype, and a young age at death compromise animal welfare and warrant further genetic studies to unravel the underlaying molecular mechanisms of IE and seizure control in the breed.

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“…Five ABC transporters were found to be up-regulated in the studies included in this analysis: ABCA6, ABCA8, ABCC4, ABCA2 and ABCB6. Of these five transporters, only ABCC4 has previously been studied in pharmacoresistant epilepsy (26,27). The identification in this study of hitherto-overlooked MDTs suggests that the search for drug transporters relevant to epilepsy pharmacoresistance needs to be expanded beyond the selected few candidates which have been studied so far.…”

Section: Mdt Hypothesismentioning

confidence: 95%

Exploring the genomic basis of pharmacoresistance in epilepsy: an integrative analysis of large-scale gene expression profiling studies on brain tissue from epilepsy surgery

Mirza¹,

Vasieva

Marson³

et al. 2011

Human Molecular Genetics

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Some patients with pharmacoresistant epilepsy undergo therapeutic resection of the epileptic focus. At least 12 large-scale microarray studies on brain tissue from epilepsy surgery have been published over the last 10 years, but they have failed to make a significant impact upon our understanding of pharmacoresistance, because (1) doubts have been raised about their reproducibility, (2) only a small number of the gene expression changes found in each microarray study have been independently validated and (3) the results of different studies have not been integrated to give a coherent picture of the genetic changes involved in epilepsy pharmacoresistance. To overcome these limitations, we (1) assessed the reproducibility of the microarray studies by calculating the overlap between lists of differentially regulated genes from pairs of microarray studies and determining if this was greater than would be expected by chance alone, (2) used an inter-study cross-validation technique to simultaneously verify the expression changes of large numbers of genes and (3) used the combined results of the different microarray studies to perform an integrative analysis based on enriched gene ontology terms, networks and pathways. Using this approach, we respectively (1) demonstrate that there are statistically significant overlaps between the gene expression changes in different publications, (2) verify the differential expression of 233 genes and (3) identify the biological processes, networks and genes likely to be most important in the development of pharmacoresistant epilepsy. Our analysis provides novel biologically plausible candidate genes and pathways which warrant further investigation to assess their causal relevance.

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

Abstract: Further replication and assessment of breed specificity is required before these markers can be considered as predictive of responsiveness to phenobarbital in dogs.

Cited by 10 publications

References 48 publications

Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

Disease Progression and Treatment Response of Idiopathic Epilepsy inAustralianShepherd Dogs

Exploring the genomic basis of pharmacoresistance in epilepsy: an integrative analysis of large-scale gene expression profiling studies on brain tissue from epilepsy surgery

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