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Selective IgA deficiency (IgAD) is the most common primary immunodeficiency disorder in Caucasians and is defined as serum IgA concentrations below or equal to 0.07 g/l, with normal serum concentrations of IgM and IgG, in individuals 4 years of age or older. The prevalence of IgAD is approximately 1:600 in the general population and recent results have shown that patients with IgAD have significantly poorer physical health and an increased risk of early death. The domestic dog is more than just a companion and working animal. The almost 400 distinct modern dog breeds represent great phenotypical diversity and there are more than 350 naturally occurring genetic diseases in dogs which clinically resemble the corresponding human diseases. As a result of domestication, the dog’s genome is characterised by long haplotype blocks and linkage disequilibrium (LD) making the dog an appealing model for genetic studies of human diseases. Low serum IgA concentrations in dogs have been reported to clinically resemble human IgAD. However, even though the literature on IgA concentrations in dogs is extensive, the normal range of serum IgA as well as a generally accepted cut-off value for IgAD deficiency has not yet been established. We performed an extensive screen of serum IgA concentrations in more than 1,500 dogs from 22 breeds. Dog breed-specific differences in the prevalence of IgAD indicate the involvement of genetic factors in the development of the disease. Furthermore, certain dog breeds were found to stand out as high-risk breeds. Genome-wide association studies (GWAS) in selected high-risk breeds show that IgAD is associated with genes involved in B cell development and haematopoiesis. Additionally, serum IgA concentrations were found to play an important role in the aetiology of canine atopic dermatitis (CAD), an autoimmune disease in dogs. Molecular identity allowed the quantification of IgA in serum samples from Canadian and Scandinavian wolves with the same antibodie

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.

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD., Correction in: PLoS Genetics, vol. 11(12):e1005740. doi:10.1371/journal.pgen.1005740