Genetics and Canine Kidney Disease: A Risk Locus in Boxers with Renal Dysplasia Identified by Genome-Wide Association
Andrew L. Lundquist1; Noriko Tonomura1,2; Ross Swofford1; Michele Perloski1; Katarina Tengvall3; Åke A. Hedhammar4; Kerstin Lindblad-Toh1,3
Kidney disease is common in dogs, and many breeds are affected. Dogs can be affected early in life by various forms of inherited kidney disease, or chronic kidney disease can manifest later in life from a variety of causes. Previous studies have shown that renal failure is among the top five causes of death in dogs, and up to 30% of geriatric dogs have chronic kidney disease. Historically, certain breeds have been affected with a specific type of kidney disease, suggesting a genetic cause. Current canine genetic tests available include testing for hereditary nephritis in Samoyed and Cocker spaniel (vetGen), cystinuria in Newfoundland (vetGen), and primary hyperparathyroidism in Keeshonden (Cornell University). Our group is focused on identifying the genetic cause of various forms of inherited canine nephropathy through genetic association studies. We are looking for collaborations with owners, breed clubs, and veterinarians to identify cases of canine kidney disease including: breed-specific inherited nephropathies, isolated or litter-specific cases of spontaneous kidney disease, and cases of adult dogs with chronic kidney disease. Previously, we helped identify the risk alleles for renal amyloidosis in Shar Peis and primary hyperparathyroidism in Keeshonden. Here we will discuss our efforts to identify risk alleles for renal dysplasia in Boxers.
Identification of genetic risk factors for renal dysplasia in dogs is essential, as there is no treatment and affected dogs progress to renal failure and death at a young age. A genetic test for renal dysplasia is available; however, its validity across species has come into question, and the scientific community has called for additional validation of the test. We previously conducted a genome-wide association study using the Canine HD BeadChip comparing 17 U.S. Boxers with renal dysplasia (age < 5) to 40 older Boxers (age > 10) with no known kidney disease. No association was detected at the locus defined by the currently available genetic test. Association analyses suggest a risk allele adjacent to a gene previously implicated in human hypodysplasia, a common cause of pediatric kidney disease. Sequencing the coding region of our candidate gene did not reveal a causative mutation, though variants nearby suggest a haplotype associated with disease. We are currently analyzing a 4-MB region surrounding the risk locus with targeted sequence capture to identify the causative variant(s), and we are working to acquire additional cases of renal dysplasia in Boxers and other breeds, as these are essential to help validate our findings. These studies will help us dissect the genetics of canine renal dysplasia, improve our understanding of renal development in dogs and humans, and determine the appropriate genetic testing strategies for prevention.