Polymyositis in Kooiker dogs is associated with a 39 kb deletion upstream the IL21/IL2 genes

An inflammatory myopathy with characteristics of polymyositis is prevalent in the
‘Nederlandse Kooikerhondje’ dog breed. A genome wide association study of 33
cases and 106 controls indicated the involvement of a region on chromosome 19
containing the cytokine gene pair IL21 and IL2 (praw = 2.1*10-14). Next generation
DNA sequencing revealed that 8 cases shared a 39 kb deletion, situated 10 kb
upstream of IL21. Of the 102 cases with available DNA, 66 were homozygous, 34
were heterozygous and only 2 cases were clear of the deletion. The frequency of
the deletion allele in a random sample of the Kooiker dog breed was 0.25. Postulating
causality, the penetrance of the disease phenotype was estimated at 5-15%
for homozygous dogs and 0.5-2% for dogs that are heterozygous for the deletion.
Leukocytes of affected, untreated dogs that were homozygous for the deletion overexpress
IL21 and IL2 after stimulation with mitogens. 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
inflammatory myopathy 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.