The Genetics of Ivermectin Sensitivity in Breeds from the Working Collie Lineage
Project Status
- Completed
- Published as: Breed distribution and history of canine mdr1-1, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage.
This article is available for free download at Proc Natl Acad Sci U S A. 2004.
- A DNA test for the presence of the mdr1-1 mutation is now being commercially offered by Washington State University (WSU's DNA Test).
- Updated Results.
Collaborators
- Katrina Mealey, Washington State University
- Karl Broman, Johns Hopkins University
- Montgomery Slatkin, UC Berkeley
Background
In 2001, a group led by Dr. Katrina Mealey at Washington State University identified the mutation underlying adverse drug response in Collies (including so-called ivermectin sensitivity). Shortly thereafter, the researchers found the mutation in an Australian Shepherd, suggesting that other related breeds might be predisposed to multiple drug sensitivities. This prediction agreed with anecdotal observations that several other breeds also appeared to be supersensitive to the drug ivermectin
Project Goals
- To identify other breeds affected by the mutation that governs multi-drug sensitivity
- To characterize the frequency of the mutation, and thus the susceptibility to drug sensitivity, in each affected breed population
- To recount the history of the collie lineage by re-tracing the dispersal of the mdr1-1 mutation
Research Findings
- The mutation was found in nine breeds, including the Collie and Australian Shepherd
- The frequency of the mutation differed more than ten-fold among breeds, indicating that there is broad variation for drug sensitivity between affected breeds
- Two of the breeds were sighthounds, which were not previously expected to share ancestry with British sheepdogs
- DNA sequence surrounding mdr1-1 confirmed that the mutation arose only once; hence all dogs today that carry the mutation are descended from a single dog that probably lived in Great Britain in the 1800s
Future Direction
- Although it is clear that the mdr1-1 mutation predisposes animals to drug sensitivities, many questions remain to be answered. More than 20 drugs are expected to interact with the mutation to cause adverse reactions; the effects of these drugs in dogs with one or two copies of the mutation are currently be investigated by Katrina Mealey at Washington State University. Describing these drug sensitivities is complicated by variability of doses, and possibly by physiological and metabolic differences among breeds.
Related Links
Acknowledgments
- Research was supported by revenue from DNA tests offered by the Veterinary Genetics Laboratory of UC Davis
- Research was made possible by the participation of more than 4000 breeders and owners who submitted cheek swab samples from their private pets
References
- Mealey KL, Bentjen SA, Gay JM, Cantor GH.
Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. 2001 Nov;11(8):727-33.
- Mealey KL, Bentjen SA, Waiting DK.
Frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample population of collies from the northwestern United States. Am J Vet Res. 2002 Apr;63(4):479-81.
- Nelson OL, Carsten E, Bentjen SA, Mealey KL.
Ivermectin toxicity in an Australian Shepherd dog with the MDR1 mutation associated with ivermectin sensitivity in Collies. J Vet Intern Med. 2003 May-Jun;17(3):354-6.
- Mealey KL, Northrup NC, Bentjen SA.
Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. J Am Vet Med Assoc. 2003 Nov 15;223(10):1453-5, 1434.
- Sartor LL, Bentjen SA, Trepanier L, Mealey KL.
Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. J Vet Intern Med. 2004 Jan-Feb;18(1):117-8.
- Hugnet C, Bentjen SA, Mealey KL.
Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of collies from France. J Vet Pharmacol Ther. 2004 Aug;27(4):227-9.
