Gene-Gene Interaction in Asthma: IL4RA and IL13 in a Dutch Population with Asthma

Abstract

Asthma is a common respiratory disease that is characterized by variable airways obstruction caused by acute and chronic bronchial inflammation; associated phenotypes include bronchial hyperresponsiveness (BHR), elevated total serum immunoglobulin E (IgE) levels, and skin tests positive to common allergens. Binding of interleukin-13 (IL13) or interleukin-4 (IL4) to the IL4 receptor (IL4R) induces the initial response for Th2 lymphocyte polarization. Both IL13 and IL4 are produced by Th2 cells and are capable of inducing isotype class-switching of B-cells to produce IgE after allergen exposure. These cytokines also share a common receptor component, IL4R alpha. We have investigated five IL4RA single-nucleotide polymorphisms in a population of Dutch families ascertained through a proband with asthma. By considering the probands and their spouses as an unrelated sample, we observed significant associations of atopy and asthma-related phenotypes with several IL4RA polymorphisms, including S478P and total serum IgE levels (P=.0007). A significant gene-gene interaction between S478P in IL4RA and the -1111 promoter variation in IL13, previously shown to be associated with BHR (P=.003), was detected. Individuals with the risk genotype for both genes were at almost five times greater risk for the development of asthma compared to individuals with both non-risk genotypes (P=.0004). These data suggest that variations in IL4RA contribute to elevated total serum IgE levels, and interaction between IL4RA and IL13 markedly increases an individual's susceptibility to asthma.

Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region

“…Although, the results of these linkage mappings varied across studies and across racial and ethnic groups, regions 5q and 13q are two of the few most frequently reproduced regions in these studies Ober et al 1998;Ober et al 2000;Wiltshire et al 1998;Xu et al 2000). It is interesting to note that these regions contain the asthma candidate genes IL4, IL13, and TGFβ, which have been studied extensively (Bartram and Speer 2004;Basehore et al 2004;Battle 2007;CamorettiMercado and Solway 2005;Howard et al 2002;Li et al 2007;Marsh et al 1994). In addition, these regions contain several new potential asthma candidate genes including IL3, IL5, IL9, SMAD5, IRF1, FBN2 and SMAD9 that warrant further investigation.…”

Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus

“…4 The IL13 gene encompasses 2938 bp and includes four exons, 56 bp of 5 0 UTR and 828 bp of 3 0 UTR ( Figure 1). Previous studies [6][7][8][9][10][11] and single-nucleotide polymorphism (SNP) discovery initiatives such as the University of Washington-Fred Hutchinson Cancer Research Center Variation Discovery Resource (http://pga.gs.washington.edu/) and SNP500Cancer (http://snp500cancer.nci.-nih.gov/) have identified 32 SNPs in the IL13 gene and its promoter region in European, European-American, Chinese, Japanese, African American and African samples. These include two SNPs in the promoter region and a single nonsynonymous substitution (2043G4A, Arg130Gln), located in exon 4.…”

“…These include two SNPs in the promoter region and a single nonsynonymous substitution (2043G4A, Arg130Gln), located in exon 4. Epidemiological studies in different populations have shown an association of the À1111T allele in the promoter region, 8,9,12 or of the Gln130 allele, 6,7,12 with different asthma-related disorders and proximal risk phenotypes, such as serum IL-13 and IgE levels. Moreover, Hoerauf et al 13 have identified an association between the Gln130 allele and sowda, an immunological hyper-reactive form of onchocerciasis.…”

Associação dos polimorfismos dos genes TGF-beta1, CD14, IL-4, IL-4R e ADAM33 com a gravidade da asma em crianças e adolescentes

“…26 50 analyzed IL-4R gene polymorphisms in families in Germany and did not find evidence that the ILe50VaL is the main responsible for susceptibility to allergy, suggesting that other IL-4R polymorphisms are associated with asthma and atopy.…”