Limits...
Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus.

Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, Behrendt H, Heinrich J, Novak N, Bieber T, Krämer U, Berdel D, von Berg A, Bauer CP, Herbarth O, Koletzko S, Prokisch H, Mehta D, Meitinger T, Depner M, von Mutius E, Liang L, Moffatt M, Cookson W, Kabesch M, Wichmann HE, Illig T - PLoS Genet. (2008)

Bottom Line: The "top" SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2.Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 x 10(-7)-4.46 x 10(-8)) and increased the risk for atopic eczema and asthma.Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology and Allergy, Technische Universität München, München, Germany. weidinger@lrz.tum.de

ABSTRACT
High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85 x 10(-20) and 7.08 x 10(-19) in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78 x 10(-4) and P = 1.95 x 10(-3)). The "top" SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 x 10(-7)-4.46 x 10(-8)) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.

Show MeSH

Related in: MedlinePlus

Results of the KORA S3/F3 500 K analysis.a) Genome-wide association study of chromosomal loci for IgE levels: the analysis is based on a population-based sample of 1530 persons. The x-axis represents the genomic position of 353,569 SNPs, and the y-axis shows −log10 (P value). b) Quantile-quantile plot of P values: Each black dot represents an observed statistic (defined as the −log10( P value)) versus the corresponding expected statistic. The line corresponds to the  distribution.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2565692&req=5

pgen-1000166-g001: Results of the KORA S3/F3 500 K analysis.a) Genome-wide association study of chromosomal loci for IgE levels: the analysis is based on a population-based sample of 1530 persons. The x-axis represents the genomic position of 353,569 SNPs, and the y-axis shows −log10 (P value). b) Quantile-quantile plot of P values: Each black dot represents an observed statistic (defined as the −log10( P value)) versus the corresponding expected statistic. The line corresponds to the distribution.

Mentions: For the GWAS 1,530 individuals from the population-based KORA S3/F3 500 K study with available total IgE levels were typed with the Affymetrix 500 K Array Set. For statistical analysis, we selected SNPs by including only high-quality genotypes to reduce the number of false positive signals. A total of 353,569 SNPs passed all quality control measures and were tested for associations with IgE levels. Figure 1 summarizes the results of the KORA S3/F3 500 K analysis. No single SNPs reached genome-wide significance, but the scan pointed to the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1 (Figure 1A). Particularly the quantile-quantile-plot of the P values illustrates observed significant associations beyond those expected by chance (Figure 1B).


Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus.

Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, Behrendt H, Heinrich J, Novak N, Bieber T, Krämer U, Berdel D, von Berg A, Bauer CP, Herbarth O, Koletzko S, Prokisch H, Mehta D, Meitinger T, Depner M, von Mutius E, Liang L, Moffatt M, Cookson W, Kabesch M, Wichmann HE, Illig T - PLoS Genet. (2008)

Results of the KORA S3/F3 500 K analysis.a) Genome-wide association study of chromosomal loci for IgE levels: the analysis is based on a population-based sample of 1530 persons. The x-axis represents the genomic position of 353,569 SNPs, and the y-axis shows −log10 (P value). b) Quantile-quantile plot of P values: Each black dot represents an observed statistic (defined as the −log10( P value)) versus the corresponding expected statistic. The line corresponds to the  distribution.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2565692&req=5

pgen-1000166-g001: Results of the KORA S3/F3 500 K analysis.a) Genome-wide association study of chromosomal loci for IgE levels: the analysis is based on a population-based sample of 1530 persons. The x-axis represents the genomic position of 353,569 SNPs, and the y-axis shows −log10 (P value). b) Quantile-quantile plot of P values: Each black dot represents an observed statistic (defined as the −log10( P value)) versus the corresponding expected statistic. The line corresponds to the distribution.
Mentions: For the GWAS 1,530 individuals from the population-based KORA S3/F3 500 K study with available total IgE levels were typed with the Affymetrix 500 K Array Set. For statistical analysis, we selected SNPs by including only high-quality genotypes to reduce the number of false positive signals. A total of 353,569 SNPs passed all quality control measures and were tested for associations with IgE levels. Figure 1 summarizes the results of the KORA S3/F3 500 K analysis. No single SNPs reached genome-wide significance, but the scan pointed to the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1 (Figure 1A). Particularly the quantile-quantile-plot of the P values illustrates observed significant associations beyond those expected by chance (Figure 1B).

Bottom Line: The "top" SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2.Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 x 10(-7)-4.46 x 10(-8)) and increased the risk for atopic eczema and asthma.Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology and Allergy, Technische Universität München, München, Germany. weidinger@lrz.tum.de

ABSTRACT
High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85 x 10(-20) and 7.08 x 10(-19) in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78 x 10(-4) and P = 1.95 x 10(-3)). The "top" SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 x 10(-7)-4.46 x 10(-8)) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.

Show MeSH
Related in: MedlinePlus