The development of oligonucleotide microarray for simultaneous detection of two canine MDR1 genotypes and the association with chemotherapy side effects.

Canine MDR1 gene mutations produce the translated P-glycoprotein, an active drug efflux transporter, dysfunction or over-expression. The 4-base deletion of MDR1 gene at nucleotide position 230 (nt230[del4]) in exon 4 makes P-glycoprotein lose function, leading to drug accumulation and toxicity. The G-allele of the c.-6-180T>G variation in intron 1 of MDR1 gene (SNP 180) causes P-glycoprotein over-expression, making epileptic dogs resistant to phenobarbital treatment. Both of these mutations were reported to concentrate in collies. This study develops a more efficient method to detect these two mutations simultaneously, and clarifies the genotype association with the side effects of chemotherapy. The genotype distribution in Taiwan was also investigated. Oligonucleotide microarray was successfully developed for the detection of both genotypes and applied to clinical samples. No 4-base deletion mutant allele was found in dogs in Taiwan. However, the G allele variation of SNP 180 was spread across all species of dogs, not only in collies. The chemotherapy adverse effect percentages of SNP 180 T/T, T/G and G/G genotypes were 16.6%, 6.3% and 0%, respectively. This study presented an efficient way for MDR1 gene mutation detection, clarifying the genotype distribution and the association with chemotherapy.