title: Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs.
abstract: Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher's exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12) and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared with the reference allele, DLA-79*001:01), resulting in F33L and N37D amino acid changes. These mutations occur in the peptide-binding pocket of the protein, and based upon our computational modeling studies, are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly and to determine the specific mechanism by which the identified variants alter canine immune system function.
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA. steven_friedenberg@ncsu.edu.|Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA. steven_friedenberg@ncsu.edu.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Friedenberg
authors.affiliation: Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Buhrman
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Lhoucine
authors.initials: L
authors.lastname: Chdid
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.|Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Natasha J
authors.initials: NJ
authors.lastname: Olby
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.|Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Olivry
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Guillaumin
authors.affiliation: Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, 01536, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: O'Toole
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Goggs
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK, M13 9PT.
authors.forename: Lorna J
authors.initials: LJ
authors.lastname: Kennedy
authors.affiliation: Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, 27695, USA.|Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Rose
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.|Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Meurs
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D001665:Binding Sites; D004283:Dog Diseases / Q000235:genetics* / Q000276:immunology*; D004285:Dogs; D005091:Exons; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D007154:Immune System Diseases / Q000662:veterinary*; D015201:Meta-Analysis as Topic; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
chemical_list: D015395:Histocompatibility Antigens Class I; D010455:Peptides; C039692:histocompatibility antigen DLA
keywords: Canine; Dog leukocyte antigen; Immune-mediated disease; Major histocompatibility complex class Ib