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

Recently we characterized polymyositis in the Dutch Kooiker dog. The familial occurrence of the disease were suggestive of 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 (p = 4.7*10⁻¹⁰). Haplotype analysis indicated that the cases shared a 2.9 Mb region in the homozygous or the heterozygous state. Next Generation Sequencing of genomic DNA implicated a deletion of a 39 kb DNA fragment, located 10 kb upstream of the neighbouring interleukin genes IL21 and IL2. The frequency of the deletion allele was 0.81 in the available 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. We suggest that elements located 10–49 kb upstream of the IL21/IL2 locus play an important role in the regulation of the canine genes and that deletion of these elements is a risk factor for polymyositis in Kooiker dogs. 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. Our results suggest that distant variants upstream of IL21 could also be important for human autoimmune diseases that have been found to be associated with the IL21/IL2 chromosome region. Author summary: Polymyositis in the breed of so-called Kooiker dogs is an autoimmune mediated inflammatory disease of skeletal muscles. The dogs are presented with swallowing and locomotion problems and in general the outcome is unfavorable. An inherited cause was suspected because affected dogs were often closely related. A genome-wide screen showed that the cases shared DNA variants in the region of the interleukin genes IL21 and IL2, wich are regulators of the cellular immune response. By analysis of the DNA sequence it became evident that a fragment of 39,000 base pairs had been deleted from the shared region. The deletion is located in front of the IL21 gene. All but two affected dogs had one or two copies of the deletion. Kooiker dogs with two copies have a risk of 10–20% to develop polymyositis in their lifetime; for dogs with one copy the risk is only 0.5–2%. We suggest that the deletion disturbs the normal regulation of IL21 and/or IL2 expression. Our results could be important for the research of human autoimmune diseases that have been associated with the same gene region. [ABSTRACT FROM AUTHOR]