title: Genome-Wide Analyses Suggest Mechanisms Involving Early B-Cell Development in Canine IgA Deficiency.
abstract: Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Olsson
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Tengvall
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Marcel
authors.initials: M
authors.lastname: Frankowiack
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kierczak
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bergvall
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Axelsson
authors.affiliation: Wurtsboro Veterinary Clinic, Wurtsboro, New York, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Tintle
authors.affiliation: Department of Clinical Veterinary Medicine, Division of Clinical Dermatology, Vetsuisse Faculty, University of Bern, Bern, Switzerland; Dermfocus, Vetsuisse Faculty, University of Bern, Bern Switzerland.
authors.forename: Eliane
authors.initials: E
authors.lastname: Marti
authors.affiliation: Dermfocus, Vetsuisse Faculty, University of Bern, Bern Switzerland; Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Roosje
authors.affiliation: Dermfocus, Vetsuisse Faculty, University of Bern, Bern Switzerland; Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Hedhammar
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001947:Breeding / Q000379:methods; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006239:Haplotypes / Q000235:genetics; D017098:IgA Deficiency / Q000235:genetics*; D007070:Immunoglobulin A / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D007070:Immunoglobulin A