title: Thorough investigation of a canine autoinflammatory disease (AID) confirms one main risk locus and suggests a modifier locus for amyloidosis.
abstract: Autoinflammatory disease (AID) manifests from the dysregulation of the innate immune system and is characterised by systemic and persistent inflammation. Clinical heterogeneity leads to patients presenting with one or a spectrum of phenotypic signs, leading to difficult diagnoses in the absence of a clear genetic cause. We used separate genome-wide SNP analyses to investigate five signs of AID (recurrent fever, arthritis, breed specific secondary dermatitis, otitis and systemic reactive amyloidosis) in a canine comparative model, the pure bred Chinese Shar-Pei. Analysis of 255 DNA samples revealed a shared locus on chromosome 13 spanning two peaks of association. A three-marker haplotype based on the most significant SNP (p<2.6×10(-8)) from each analysis showed that one haplotypic pair (H13-11) was present in the majority of AID individuals, implicating this as a shared risk factor for all phenotypes. We also noted that a genetic signature (F ST) distinguishing the phenotypic extremes of the breed specific Chinese Shar-Pei thick and wrinkled skin, flanked the chromosome 13 AID locus; suggesting that breed development and differentiation has played a parallel role in the genetics of breed fitness. Intriguingly, a potential modifier locus for amyloidosis was revealed on chromosome 14, and an investigation of candidate genes from both this and the chromosome 13 regions revealed significant (p<0.05) renal differential expression in four genes previously implicated in kidney or immune health (AOAH, ELMO1, HAS2 and IL6). These results illustrate that phenotypic heterogeneity need not be a reflection of genetic heterogeneity, and that genetic modifiers of disease could be masked if syndromes were not first considered as individual clinical signs and then as a sum of their component parts.
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Olsson
authors.forename: Linda
authors.initials: L
authors.lastname: Tintle
authors.forename: Marcin
authors.initials: M
authors.lastname: Kierczak
authors.forename: Michele
authors.initials: M
authors.lastname: Perloski
authors.forename: Noriko
authors.initials: N
authors.lastname: Tonomura
authors.forename: Andrew
authors.initials: A
authors.lastname: Lundquist
authors.forename: Eva
authors.initials: E
authors.lastname: Murén
authors.forename: Max
authors.initials: M
authors.lastname: Fels
authors.forename: Katarina
authors.initials: K
authors.lastname: Tengvall
authors.forename: Gerli
authors.initials: G
authors.lastname: Pielberg
authors.forename: Caroline
authors.initials: C
authors.lastname: Dufaure de Citres
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dorso
authors.forename: Jérôme
authors.initials: J
authors.lastname: Abadie
authors.forename: Jeanette
authors.initials: J
authors.lastname: Hanson
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.forename: Peter
authors.initials: P
authors.lastname: Leegwater
authors.forename: Åke
authors.initials: Å
authors.lastname: Hedhammar
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.forename: Jennifer R S
authors.initials: JR
authors.lastname: Meadows
mesh_terms: D000686:Amyloidosis / Q000235:genetics*; D000818:Animals; D004283:Dog Diseases; D004285:Dogs; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics