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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

Two risk haplotypes at the German shepherd CFA5 locus results in lower IgA levels.(A) The genome wide significant locus on CFA5 consisted of 17 SNPs (grey circles) in LD (r2 >0.8) with the top SNP (white), with only the KIRREL3 gene within the associated region and six genes adjacent. (B) The 18 SNPs were phased into 12 different haplotypes, of which nine were rare (N <3). Haplotype 1 was the most common (N = 855) and the remaining two haplotypes; 12 and 3 were more similar to each other than to haplotype 1. (C) Dogs homozygous for haplotype 1 (1/1) represented all groups of IgA evenly, whereas dogs heterozygous 1/12 and 1/3 had significantly lower IgA levels compared to 1/1 (p = 0.04 and 0.0008, respectively).
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pone.0133844.g002: Two risk haplotypes at the German shepherd CFA5 locus results in lower IgA levels.(A) The genome wide significant locus on CFA5 consisted of 17 SNPs (grey circles) in LD (r2 >0.8) with the top SNP (white), with only the KIRREL3 gene within the associated region and six genes adjacent. (B) The 18 SNPs were phased into 12 different haplotypes, of which nine were rare (N <3). Haplotype 1 was the most common (N = 855) and the remaining two haplotypes; 12 and 3 were more similar to each other than to haplotype 1. (C) Dogs homozygous for haplotype 1 (1/1) represented all groups of IgA evenly, whereas dogs heterozygous 1/12 and 1/3 had significantly lower IgA levels compared to 1/1 (p = 0.04 and 0.0008, respectively).

Mentions: In GSD, a ~1 Mb long locus consisting of 14 SNPs on canine chromosome 5 (CFA5) 7,009,995–7,967,689 bp (CanFam3.1), with p-values ranging from 3.0 x 10−5 to 2.0 x 10−4, passed the threshold of genome-wide significant association. Based on SNPs in LD (r2 >0.8) with the top SNP, we phased a ~1.7 Mb long region (18 SNPs stretching from 6,392,996–8,122,621), which resulted in 12 different haplotypes. We defined two risk haplotypes; haplotype 3 and 12 (N = 28 and N = 95, respectively), one (haplotype 1) as the most common (N = 855) and present in all groups of dogs independent of IgA levels, and nine rare haplotypes (N ≤3). Heterozygous dogs carrying haplotypes 1 and 3, and haplotypes 1 and 12 had significantly lower IgA levels compared to dogs homozygous for haplotype 1 (p = 0.04 and p = 0.00008, respectively) (Fig 2). Despite the large size of the haplotype it harboured only one gene, KIRREL3 (alias NEPH1), a transmembrane protein implicated in development, both in synapse formation and as a regulator of hematopoiesis [22, 23].


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)

Two risk haplotypes at the German shepherd CFA5 locus results in lower IgA levels.(A) The genome wide significant locus on CFA5 consisted of 17 SNPs (grey circles) in LD (r2 >0.8) with the top SNP (white), with only the KIRREL3 gene within the associated region and six genes adjacent. (B) The 18 SNPs were phased into 12 different haplotypes, of which nine were rare (N <3). Haplotype 1 was the most common (N = 855) and the remaining two haplotypes; 12 and 3 were more similar to each other than to haplotype 1. (C) Dogs homozygous for haplotype 1 (1/1) represented all groups of IgA evenly, whereas dogs heterozygous 1/12 and 1/3 had significantly lower IgA levels compared to 1/1 (p = 0.04 and 0.0008, respectively).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133844.g002: Two risk haplotypes at the German shepherd CFA5 locus results in lower IgA levels.(A) The genome wide significant locus on CFA5 consisted of 17 SNPs (grey circles) in LD (r2 >0.8) with the top SNP (white), with only the KIRREL3 gene within the associated region and six genes adjacent. (B) The 18 SNPs were phased into 12 different haplotypes, of which nine were rare (N <3). Haplotype 1 was the most common (N = 855) and the remaining two haplotypes; 12 and 3 were more similar to each other than to haplotype 1. (C) Dogs homozygous for haplotype 1 (1/1) represented all groups of IgA evenly, whereas dogs heterozygous 1/12 and 1/3 had significantly lower IgA levels compared to 1/1 (p = 0.04 and 0.0008, respectively).
Mentions: In GSD, a ~1 Mb long locus consisting of 14 SNPs on canine chromosome 5 (CFA5) 7,009,995–7,967,689 bp (CanFam3.1), with p-values ranging from 3.0 x 10−5 to 2.0 x 10−4, passed the threshold of genome-wide significant association. Based on SNPs in LD (r2 >0.8) with the top SNP, we phased a ~1.7 Mb long region (18 SNPs stretching from 6,392,996–8,122,621), which resulted in 12 different haplotypes. We defined two risk haplotypes; haplotype 3 and 12 (N = 28 and N = 95, respectively), one (haplotype 1) as the most common (N = 855) and present in all groups of dogs independent of IgA levels, and nine rare haplotypes (N ≤3). Heterozygous dogs carrying haplotypes 1 and 3, and haplotypes 1 and 12 had significantly lower IgA levels compared to dogs homozygous for haplotype 1 (p = 0.04 and p = 0.00008, respectively) (Fig 2). Despite the large size of the haplotype it harboured only one gene, KIRREL3 (alias NEPH1), a transmembrane protein implicated in development, both in synapse formation and as a regulator of hematopoiesis [22, 23].

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