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

Olsson M, Tengvall K, Frankowiack M, Kierczak M, Bergvall K, Axelsson E, Tintle L, Marti E, Roosje P, Leeb T, Hedhammar Å, Hammarström L, Lindblad-Toh K - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

The SLIT1 gene harbours an associated haplotype in Shar-Pei and fixed blocks in German shepherd.(A) In SP, four SNPs (grey circles) suggestively associated to IgA levels, were located within the first intron of SLIT1. (B) A distinct increase in the degree of genetic differentiation (FST) between dogs and wolves span a 75 kb region (windows with FST >0.67 are coloured in black) within the SLIT1 locus, with FST values of two consecutive 50 kb windows reaching 0.68 and 0.67, respectively (windows with FST >0.43 are coloured in grey). More extreme genetic differentiation was only seen in 7% of the whole dog genome, potentially indicating that IgA levels may have been affected in a pleiotropic manner by primary selection affecting another primary target (such as brain function) during dog domestication. Blocks of fixation were identified in GSD, spanning several regulatory sites including binding sites for the transcription factor CTCF. (C) The top SNPs in SP were in high LD (r2 >0.8) and phased into four haplotypes where two were common (1 and 4) and two were rare (2 and 3). Dogs homozygous for 1/1 had significantly higher IgA levels compared to dogs homozygous for 4 (4/4) and heterozygous 4/1 (p = 0.0005 and p = 0.03, respectively). Additionally, homozygous 4/4 had significantly lower IgA levels than heterozygous 4/1 (p = 0.006) indicating an additive effect of the risk and/or protective haplotype.
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pone.0133844.g003: The SLIT1 gene harbours an associated haplotype in Shar-Pei and fixed blocks in German shepherd.(A) In SP, four SNPs (grey circles) suggestively associated to IgA levels, were located within the first intron of SLIT1. (B) A distinct increase in the degree of genetic differentiation (FST) between dogs and wolves span a 75 kb region (windows with FST >0.67 are coloured in black) within the SLIT1 locus, with FST values of two consecutive 50 kb windows reaching 0.68 and 0.67, respectively (windows with FST >0.43 are coloured in grey). More extreme genetic differentiation was only seen in 7% of the whole dog genome, potentially indicating that IgA levels may have been affected in a pleiotropic manner by primary selection affecting another primary target (such as brain function) during dog domestication. Blocks of fixation were identified in GSD, spanning several regulatory sites including binding sites for the transcription factor CTCF. (C) The top SNPs in SP were in high LD (r2 >0.8) and phased into four haplotypes where two were common (1 and 4) and two were rare (2 and 3). Dogs homozygous for 1/1 had significantly higher IgA levels compared to dogs homozygous for 4 (4/4) and heterozygous 4/1 (p = 0.0005 and p = 0.03, respectively). Additionally, homozygous 4/4 had significantly lower IgA levels than heterozygous 4/1 (p = 0.006) indicating an additive effect of the risk and/or protective haplotype.

Mentions: The strongest signal of association to IgA levels in SP was a region on CFA28 with the top SNP at position 13,512,782 bp. At this locus, we identified a ~20 kb haplotype (CFA28: 10,496,764–10,517,160) based on 4 SNPs in high LD (r2 >0.8) with p-values ranging from 2.7 x 10−5 to 2.3 x 10−4. In total two rare (N ≤11) and two common haplotypes were identified. Haplotype 4 was defined as the risk (N = 108) and haplotype 1 as the protective haplotype (N = 68), as we discovered a significant difference (p = 0.0005) in IgA levels between dogs homozygous for the risk haplotype (4/4) vs. dogs homozygous for the control haplotype (1/1). Heterozygous dogs (1/4) had intermediate IgA levels, significantly different both compared to 1/1 (p = 0.03) and to 4/4 (p = 0.006) (Fig 3) suggesting an additive nature of the effect. This short haplotype spanned the first intron of the gene SLIT1, a large extracellular matrix-secreted glycoprotein that functions as a ligand to the repulsive guidance receptors (Robo) family [28].


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

Olsson M, Tengvall K, Frankowiack M, Kierczak M, Bergvall K, Axelsson E, Tintle L, Marti E, Roosje P, Leeb T, Hedhammar Å, Hammarström L, Lindblad-Toh K - PLoS ONE (2015)

The SLIT1 gene harbours an associated haplotype in Shar-Pei and fixed blocks in German shepherd.(A) In SP, four SNPs (grey circles) suggestively associated to IgA levels, were located within the first intron of SLIT1. (B) A distinct increase in the degree of genetic differentiation (FST) between dogs and wolves span a 75 kb region (windows with FST >0.67 are coloured in black) within the SLIT1 locus, with FST values of two consecutive 50 kb windows reaching 0.68 and 0.67, respectively (windows with FST >0.43 are coloured in grey). More extreme genetic differentiation was only seen in 7% of the whole dog genome, potentially indicating that IgA levels may have been affected in a pleiotropic manner by primary selection affecting another primary target (such as brain function) during dog domestication. Blocks of fixation were identified in GSD, spanning several regulatory sites including binding sites for the transcription factor CTCF. (C) The top SNPs in SP were in high LD (r2 >0.8) and phased into four haplotypes where two were common (1 and 4) and two were rare (2 and 3). Dogs homozygous for 1/1 had significantly higher IgA levels compared to dogs homozygous for 4 (4/4) and heterozygous 4/1 (p = 0.0005 and p = 0.03, respectively). Additionally, homozygous 4/4 had significantly lower IgA levels than heterozygous 4/1 (p = 0.006) indicating an additive effect of the risk and/or protective haplotype.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4520476&req=5

pone.0133844.g003: The SLIT1 gene harbours an associated haplotype in Shar-Pei and fixed blocks in German shepherd.(A) In SP, four SNPs (grey circles) suggestively associated to IgA levels, were located within the first intron of SLIT1. (B) A distinct increase in the degree of genetic differentiation (FST) between dogs and wolves span a 75 kb region (windows with FST >0.67 are coloured in black) within the SLIT1 locus, with FST values of two consecutive 50 kb windows reaching 0.68 and 0.67, respectively (windows with FST >0.43 are coloured in grey). More extreme genetic differentiation was only seen in 7% of the whole dog genome, potentially indicating that IgA levels may have been affected in a pleiotropic manner by primary selection affecting another primary target (such as brain function) during dog domestication. Blocks of fixation were identified in GSD, spanning several regulatory sites including binding sites for the transcription factor CTCF. (C) The top SNPs in SP were in high LD (r2 >0.8) and phased into four haplotypes where two were common (1 and 4) and two were rare (2 and 3). Dogs homozygous for 1/1 had significantly higher IgA levels compared to dogs homozygous for 4 (4/4) and heterozygous 4/1 (p = 0.0005 and p = 0.03, respectively). Additionally, homozygous 4/4 had significantly lower IgA levels than heterozygous 4/1 (p = 0.006) indicating an additive effect of the risk and/or protective haplotype.
Mentions: The strongest signal of association to IgA levels in SP was a region on CFA28 with the top SNP at position 13,512,782 bp. At this locus, we identified a ~20 kb haplotype (CFA28: 10,496,764–10,517,160) based on 4 SNPs in high LD (r2 >0.8) with p-values ranging from 2.7 x 10−5 to 2.3 x 10−4. In total two rare (N ≤11) and two common haplotypes were identified. Haplotype 4 was defined as the risk (N = 108) and haplotype 1 as the protective haplotype (N = 68), as we discovered a significant difference (p = 0.0005) in IgA levels between dogs homozygous for the risk haplotype (4/4) vs. dogs homozygous for the control haplotype (1/1). Heterozygous dogs (1/4) had intermediate IgA levels, significantly different both compared to 1/1 (p = 0.03) and to 4/4 (p = 0.006) (Fig 3) suggesting an additive nature of the effect. This short haplotype spanned the first intron of the gene SLIT1, a large extracellular matrix-secreted glycoprotein that functions as a ligand to the repulsive guidance receptors (Robo) family [28].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus