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Two loci on chromosome 5 are associated with serum IgE levels in Labrador retrievers.

Owczarek-Lipska M, Lauber B, Molitor V, Meury S, Kierczak M, Tengvall K, Webster MT, Jagannathan V, Schlotter Y, Willemse T, Hendricks A, Bergvall K, Hedhammar A, Andersson G, Lindblad-Toh K, Favrot C, Roosje P, Marti E, Leeb T - PLoS ONE (2012)

Bottom Line: We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro.We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5.No obvious candidate gene for the regulation of IgE levels is located under the two association signals.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

ABSTRACT
Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response.

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A genome-wide association study of the IgE-responsiveness to A. siro in Labrador Retrievers performed using a mix-model approach efficiently corrected for the population stratification.The red line indicates the Bonferroni-corrected significance level (p<3.9×10−7). The Quantile-quantile (QQ) plot shows the observed versus expected log p-values (on the top-right). The straight line on the QQ plot indicates the distribution of SNP markers under the  hypothesis and the skew at the right edge indicates that these markers are stronger associated with the A. siro IgE response than it would be expected by chance.
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pone-0039176-g001: A genome-wide association study of the IgE-responsiveness to A. siro in Labrador Retrievers performed using a mix-model approach efficiently corrected for the population stratification.The red line indicates the Bonferroni-corrected significance level (p<3.9×10−7). The Quantile-quantile (QQ) plot shows the observed versus expected log p-values (on the top-right). The straight line on the QQ plot indicates the distribution of SNP markers under the hypothesis and the skew at the right edge indicates that these markers are stronger associated with the A. siro IgE response than it would be expected by chance.

Mentions: For the selection of dogs we had minimized the use of first-degree relatives in order to reduce the stratification of our samples. Nonetheless, in purebred dogs there is always a certain amount of cryptic relatedness present. A preliminary analysis without correction for cryptic relatedness gave a genomic inflation factor of 1.09 indicating a relatively low level of stratification. For the GWAS we used a mixed model approach using the marker-derived kinship matrix as a co-variable to correct for both stratification and cryptic relatedness. After this correction the genomic inflation factor was 1.00. We performed an allelic association analysis and detected one region on chromosome 5 (CFA 5) that was significantly associated with the IgE response to A. siro. The best-associated SNPs within the interval, BICF2S2297212 (CFA5:g.79,522,993A>G), showed a raw p-value of 2.14×10−9. This is below the Bonferroni-corrected significance threshold of 4.4×10−7. We also determined the empirical significance threshold by performing 100,000 permutations with randomly assigned phenotypes, which yielded a genome-wide corrected p-value of 0.001 (Figure 1, Table 1). A second marker at the same locus (BICF2P1022237; CFA5:g.80,037,053C>T) was also significantly associated with the A. siro-specific IgE response with a raw p-value of 1.07×10−7. Apart from these two SNPs, no other SNP on any chromosome reached genome-wide significance.


Two loci on chromosome 5 are associated with serum IgE levels in Labrador retrievers.

Owczarek-Lipska M, Lauber B, Molitor V, Meury S, Kierczak M, Tengvall K, Webster MT, Jagannathan V, Schlotter Y, Willemse T, Hendricks A, Bergvall K, Hedhammar A, Andersson G, Lindblad-Toh K, Favrot C, Roosje P, Marti E, Leeb T - PLoS ONE (2012)

A genome-wide association study of the IgE-responsiveness to A. siro in Labrador Retrievers performed using a mix-model approach efficiently corrected for the population stratification.The red line indicates the Bonferroni-corrected significance level (p<3.9×10−7). The Quantile-quantile (QQ) plot shows the observed versus expected log p-values (on the top-right). The straight line on the QQ plot indicates the distribution of SNP markers under the  hypothesis and the skew at the right edge indicates that these markers are stronger associated with the A. siro IgE response than it would be expected by chance.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376118&req=5

pone-0039176-g001: A genome-wide association study of the IgE-responsiveness to A. siro in Labrador Retrievers performed using a mix-model approach efficiently corrected for the population stratification.The red line indicates the Bonferroni-corrected significance level (p<3.9×10−7). The Quantile-quantile (QQ) plot shows the observed versus expected log p-values (on the top-right). The straight line on the QQ plot indicates the distribution of SNP markers under the hypothesis and the skew at the right edge indicates that these markers are stronger associated with the A. siro IgE response than it would be expected by chance.
Mentions: For the selection of dogs we had minimized the use of first-degree relatives in order to reduce the stratification of our samples. Nonetheless, in purebred dogs there is always a certain amount of cryptic relatedness present. A preliminary analysis without correction for cryptic relatedness gave a genomic inflation factor of 1.09 indicating a relatively low level of stratification. For the GWAS we used a mixed model approach using the marker-derived kinship matrix as a co-variable to correct for both stratification and cryptic relatedness. After this correction the genomic inflation factor was 1.00. We performed an allelic association analysis and detected one region on chromosome 5 (CFA 5) that was significantly associated with the IgE response to A. siro. The best-associated SNPs within the interval, BICF2S2297212 (CFA5:g.79,522,993A>G), showed a raw p-value of 2.14×10−9. This is below the Bonferroni-corrected significance threshold of 4.4×10−7. We also determined the empirical significance threshold by performing 100,000 permutations with randomly assigned phenotypes, which yielded a genome-wide corrected p-value of 0.001 (Figure 1, Table 1). A second marker at the same locus (BICF2P1022237; CFA5:g.80,037,053C>T) was also significantly associated with the A. siro-specific IgE response with a raw p-value of 1.07×10−7. Apart from these two SNPs, no other SNP on any chromosome reached genome-wide significance.

Bottom Line: We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro.We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5.No obvious candidate gene for the regulation of IgE levels is located under the two association signals.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

ABSTRACT
Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response.

Show MeSH
Related in: MedlinePlus