title: Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs.
abstract: Exocrine pancreatic insufficiency (EPI) is a disease wherein pancreatic acinar cells fail to synthesize and secrete sufficient amounts of digestive enzymes for normal digestion of food. EPI affects many dog breeds, with a dramatically higher prevalence in the German shepherd dog (GSD) population. In this breed and perhaps others, EPI most often results from degeneration of the acinar cells of the pancreas, a hereditary disorder termed pancreatic acinar atrophy (PAA). Evidence of lymphocytic infiltration indicates that PAA is an autoimmune disease, but the genetic etiology remains unclear. Data from global gene expression and single nucleotide polymorphism profiles in the GSD suggest the involvement of the major histocompatibility complex [MHC; dog leukocyte antigen (DLA)]. To determine if alleles of the MHC influence development of EPI, genotyping of polymorphic class I (DLA-88) and II loci (DLA-DRB1, DLA-DQA1, and DLA-DQB1) was carried out for 70 affected and 63 control GSDs, and four-locus haplotypes were determined. One haplotype containing a novel allele of DLA-88 is very highly associated with EPI (OR > 17; P = 0.000125), while two haplotypes were found to confer protection from EPI (P = 0.00087 and 0.0115). Described herein is the genotyping of MHC class I and II loci in a GSD cohort, establishment of four-locus haplotypes, and association of alleles/haplotypes with EPI.
authors.affiliation: Department of Genetics and Biochemistry, College of Agriculture, Forestry and Life Sciences, Clemson University, 154 Poole Agricultural Center, 130 McGinty Ct, Clemson, SC 29634, USA.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Tsai
authors.forename: Alison N
authors.initials: AN
authors.lastname: Starr-Moss
authors.forename: Gopalakrishnan M
authors.initials: GM
authors.lastname: Venkataraman
authors.forename: Christopher
authors.initials: C
authors.lastname: Robinson
authors.forename: Lorna J
authors.initials: LJ
authors.lastname: Kennedy
authors.forename: Jörg M
authors.initials: JM
authors.lastname: Steiner
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Clark
mesh_terms: D061354:Acinar Cells / Q000276:immunology / Q000473:pathology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001284:Atrophy; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000662:veterinary*; D001483:Base Sequence; D001947:Breeding; D004283:Dog Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D004285:Dogs / Q000235:genetics* / Q000276:immunology; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000662:veterinary*; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D017385:Sequence Homology; D013045:Species Specificity
chemical_list: D015395:Histocompatibility Antigens Class I; C039692:histocompatibility antigen DLA