Variation in the Interleukin 4–Receptor α Gene Confers Susceptibility to Asthma and Atopy in Ethnically Diverse Populations

Abstract

After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values.039-.0044 for atopy and. 029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

“…Ober et al 18 showed that certain haplotypes of exonic SNPs in IL4RA were associated with asthma in the Hutterites, most significantly the two-locus haplotype consisting of the +1124 A4C (E375A) and +1682 T4C (S478P) variants, and the six-locus haplotype consisting of +148 G and the wild-type alleles at all other sites. Some of the IL4RA haplotypes have been shown to increase phosphorylation of binding substrates, which might result from a change in the receptor's charge and conformation, leading to tighter substrate binding.…”

“…Some of these polymorphisms significantly upregulate receptor response to IL-4, with a resultant increased activation of STAT6, and thus increased cell proliferation and IgE production. 17,19 Ober et al 18 have also reported an apparent haplotype effect in outbred populations. S411L (+1232 C4T) and S761P (+2281 T4C) are further single nucleotide polymorphisms (SNPs) in exon 12, but have largely been excluded from previous analyses due to low minor allele frequencies and, therefore, low statistical power.…”

“…15,16 Polymorphisms in IL4RA have also been reported to be associated with atopic phenotypes: the I50V (+148 A4T), C406R (+1216 T4C), S478P (+1682 T4C, previously S503P), and Q551R (+1902 G4T, previously R576Q) variants have shown association with increased risk for asthma 17,18 and atopy. 18,19 All polymorphisms except for +148 A4T, which is in exon 5, are located in exon 12. Some of these polymorphisms significantly upregulate receptor response to IL-4, with a resultant increased activation of STAT6, and thus increased cell proliferation and IgE production.…”

“…18 The C-3223T (À3223 C4T) variant in the 5 0 promoter region of IL4RA, which disrupts the core sequences of at least two potential transcription factor-binding sites (cAMP response element-binding protein and TCF11/MafG heterodimers), was also investigated. Although it has never been tested for association with an atopic phenotype, it has been associated with reduced levels of a secreted form of IL4Ra, sIL4Ra.…”

Analysis of IL4R haplotypes in predisposition to multiple sclerosis

“…11 Changes to IL4R amino-acid residues, particularly the Ile50Val, Ser478Pro and Gln551Arg polymorphisms, are proposed to be functionally important and impact IL-4 receptor signaling (see Shirakawa et al 12 and citations therein). IL4R SNPs have been associated with susceptibility to immune-related diseases including asthma and atopy, [12][13][14] and, by constructing multi-SNP IL4R haplotypes, associations to type I diabetes (T1D) have been demonstrated. 15,16 The IL4R gene, at 16p11-p12, has been identified as a candidate gene for MS by linkage 5,17 and by the association of individual IL4R SNPs.…”