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AbstractHereditary periodic fever syndromes are characterized by recurrent episodes of feverand inflammation with no known pathogenic or autoimmune cause. In humans, severalgenes have been implicated in this group of diseases, but the majority of cases remainunexplained. A similar 1 periodic fever syndrome is relatively frequent in the ChineseShar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected fora distinctive thick and heavily folded skin. In this study, a mutation affecting both thesetraits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds,the strongest signal of a breed-specific selective sweep was located on chromosome13. The same region also harbored the strongest genome-wide association (GWA)signal for susceptibility to the periodic fever syndrome (praw=2.3x10-6, pgenome= 0.01).Dense targeted resequencing revealed two partially overlapping duplications, 14.3 kband 16.1 kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2(HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), amajor component of the skin. HA is up-regulated and accumulates in the folded skin ofShar-Pei. A high copy number of the 16.1 kb duplication was associated with anincreased expression of HAS2 as well as the periodic fever syndrome (p less than 0.0001).When fragmented, HA can act as a trigger of the innate immune system and stimulatesterile fever and inflammation. The strong selection for the skin phenotype thereforeappears to enrich for a pleiotropic mutation predisposing these dogs to a periodicfever syndrome. The identification of HA as a major risk factor for this canine diseaseraises the potential of this glycosaminoglycan as a risk factor for human periodicfevers and as an important driver of chronic inflammation. |