Genome-Wide Analyses Suggest Mechanisms Involving Early B-Cell Development in Canine IgA Deficiency

PLoS One. 2015 Jul 30;10(7):e0133844. doi: 10.1371/journal.pone.0133844. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Breeding / methods
  • Dog Diseases / genetics*
  • Dogs
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods
  • Haplotypes / genetics
  • IgA Deficiency / genetics*
  • Immunoglobulin A / genetics*
  • Lymphocyte Activation / genetics
  • Polymorphism, Single Nucleotide / genetics

Substances

  • Immunoglobulin A

Grants and funding

The study has been funded by grants to; KLT the Swedish Research Council, http://www.vr.se/, grant number 521-2012-2826, Swedish Research Council FORMAS, http://www.formas.se/, grant number: 221-2009-1689 and the European Research Council (ERC), http://erc.europa.eu/, starting grant agreement: 310203; LH the Swedish Research Council, http://www.vr.se/, grant number 521-2011-3515; TL the European Commission, http://www.eurolupa.eu/, FP7-LUPA, GA-201370. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.