Polymyositis in Kooiker dogs is associated with a 39 kb deletion upstream of the canine IL21/IL2 gene pair

Recently we described an inflammatory myopathy (IM) in the Dutch Kooiker dog. The characteristics and the familial occurrence of the disease were suggestive of polymyositis with an inherited cause. Here we report the results of our molecular genetic investigation. A genome-wide association study of 33 cases and 106 controls indicated the involvement of a region on chromosome CFA19. Next Generation Sequencing of genomic DNA implicated a deletion of a 39 kb DNA fragment, located 10 kb upstream of the interleukin gene pair IL21/IL2. Genotyping of the locus showed that 66 of the available cases were homozygous for the deletion, 34 were heterozygous, and 2 cases were clear of the deletion. The frequency of the deletion allele was 0.81 in the cases and 0.25 in a random sample of the Kooiker dog breed. Leukocytes of affected, untreated dogs that were homozygous for the deletion overexpress IL21 and IL2 upon stimulation with mitogens. Postulating causality, the penetrance of the disease phenotype was estimated at 10-20% for homozygous dogs and 0.5-2% for dogs that were heterozygous for the deletion. We suggest that elements located 10-49 kb upstream of the IL21/IL2 gene pair play an important role in the regulation of the canine genes and that deletion of these elements is a risk factor for IM in Kooiker dogs. Our results imply that distant variants upstream of IL21 could also be important for human autoimmune diseases that were found to be associated with the IL21/IL2 chromosome region.