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      Mouse Chromosome 4 Is Associated with the Baseline and Allergic IgE Phenotypes

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          Abstract

          Regulation of IgE concentration in the blood is a complex trait, with high concentrations associated with parasitic infections as well as allergic diseases. A/J strain mice have significantly higher plasma concentrations of IgE, both at baseline and after ovalbumin antigen exposure, when compared to C57BL/6J strain mice. Our objective was to determine the genomic regions associated with this difference in phenotype. To achieve this, we used a panel of recombinant congenic strains (RCS) derived from A/J and C57BL/6J strains. We measured IgE in the RCS panel at baseline and following allergen exposure. Using marker by marker analysis of the RCS genotype and phenotype data, we identified multiple regions associated with the IgE phenotype. A single region was identified to be associated with baseline IgE level, while multiple regions wereassociated with the phenotype after allergen exposure. The most significant region was found on Chromosome 4, from 81.46 to 86.17 Mbp. Chromosome 4 substitution strain mice had significantly higher concentration of IgE than their background parental strain mice, C57BL/6J. Our data presents multiple candidate regions associated with plasma IgE concentration at baseline and following allergen exposure, with the most significant one located on Chromosome 4.

          Most cited references31

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          Association of asthma with serum IgE levels and skin-test reactivity to allergens.

          We investigated the association of self-reported asthma or allergic rhinitis with serum IgE levels and skin-test reactivity to allergens in 2657 subjects in a general-population study. Regardless of the subjects' status with respect to atopy or their age group, the prevalence of asthma was closely related to the serum IgE level standardized for age and sex (P less than 0.0001), and no asthma was present in the 177 subjects with the lowest IgE levels for their age and sex (greater than 1.46 SD below the mean). The log odds ratio increased linearly with the serum IgE level after we controlled for possible confounders and the degree of reactivity to skin tests. In contrast, allergic rhinitis appeared to be associated primarily with skin-test reactions to common aeroallergens, independently of the serum IgE level. We conclude that asthma is almost always associated with some type of IgE-related reaction and therefore has an allergic basis, although not all the allergic stimuli that cause asthma appear to have been included in the battery of common aeroallergens we used to assess atopic status. These findings challenge the concept that there are basic differences between so-called allergic ("extrinsic") and nonallergic ("intrinsic") forms of asthma.
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            Discovering susceptibility genes for asthma and allergy.

            Asthma and asthma-related traits are complex diseases with strong genetic and environmental components. Rapid progress in asthma genetics has led to the identification of several candidate genes that are associated with asthma-related traits. Typically the phenotypic impact of each of these genes, including the ones most often replicated in association studies, is mild, but larger effects may occur when multiple variants synergize within a permissive environmental context. Despite the achievements made in asthma genetics formidable challenges remain. The development of novel, powerful tools for gene discovery, and a closer integration of genetics and biology, should help to overcome these challenges.
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              Current concepts of IgE regulation and impact of genetic determinants.

              Immunoglobulin E (IgE) mediated immune responses seem to be directed against parasites and neoplasms, but are best known for their involvement in allergies. The IgE network is tightly controlled at different levels as outlined in this review. Genetic determinants were suspected to influence IgE regulation and IgE levels considerably for many years. Linkage and candidate gene studies suggested a number of loci and genes to correlate with total serum IgE levels, and recently genome-wide association studies (GWAS) provided the power to identify genetic determinants for total serum IgE levels: 1q23 (FCER1A), 5q31 (RAD50, IL13, IL4), 12q13 (STAT6), 6p21.3 (HLA-DRB1) and 16p12 (IL4R, IL21R). In this review, we analyse the potential role of these GWAS hits in the IgE network and suggest mechanisms of how genes and genetic variants in these loci may influence IgE regulation. © 2012 Blackwell Publishing Ltd.
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                Author and article information

                Journal
                G3 (Bethesda)
                Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes|Genomes|Genetics
                Genetics Society of America
                2160-1836
                10 July 2017
                August 2017
                : 7
                : 8
                : 2559-2564
                Affiliations
                [* ]Department of Human Genetics, McGill University, Montreal, Quebec, H3A 1B1, Canada
                []Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, H4A 3J1, Canada
                [§ ]Department of Microbiology and Immunology
                [** ]Institute of Parasitology, McGill University, Montreal, Quebec, H9X 3V9, Canada
                [†† ]Genome Quebec Innovation Centre, McGill University, Montreal, Quebec, H3A 0G1, Canada
                Author notes
                [1 ]Corresponding author: McGill University Health Center—Glen Site, 1001 Decarie Blvd., Room EM2.3242, Montreal, QC H4A 3J1, Canada. E-mail: danuta.radzioch@ 123456mcgill.ca
                Article
                GGG_042739
                10.1534/g3.117.042739
                5555462
                28696925
                c2e8a474-1baa-4e9e-bd78-0da4dbbdcc37
                Copyright © 2017 Kanagaratham et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 April 2017
                : 01 June 2017
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 34, Pages: 6
                Categories
                Investigations

                Genetics
                animal models,allergy,qtl mapping,complex traits,ige
                Genetics
                animal models, allergy, qtl mapping, complex traits, ige

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