The Association of Atopy with a Gain-of-Function Mutation in the α Subunit of the Interleukin-4 Receptor

Hershey, Gurjit K. Khurana; Friedrich, Michal F.; Esswein, Laura A.; Thomas, Matthew L.; Chatila, Talal A.

doi:10.1056/nejm199712113372403

Cited by 693 publications

(465 citation statements)

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“…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. 19 However, in our study none of these combinations and indeed, no other haplotype, deviated from the expected Mendelian transmissions (see Table 6 for the five most common haplotypes).…”

Section: Resultscontrasting

confidence: 43%

“…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.…”

Section: Introductionmentioning

confidence: 95%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C4T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the À3223 C4T SNP showed evidence of negative association (P ¼ 0.014). There was some evidence for an interaction between À3233 C4T and the T1D locus IDDM2 in the insulin gene region (P ¼ 0.001 in the combined and P ¼ 0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.

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Section: Resultscontrasting

confidence: 43%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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“…This gene region is the location of the IL-4-receptor gene alpha, which is located at 16p11.2±12.1 (65). Initially, it was suspected that a mutation putatively leading to increased IL-4 receptor activity (Q576R) could be responsible for elevated IgE secretion (66). However, subsequent analyses have shown that polymorphisms affecting at least four different amino acids in the cytoplasmic domain of IL-4Ra may signi®cantly in¯uence the outcome of IL-4 receptor signaling and consequently IgE secretion (67).…”

Section: Atopic Dermatitismentioning

confidence: 99%

Atopic dermatitis: from the genes to skin lesions

Wollenberg

Bieber

2000

Allergy

118

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“…An international effort was made to define the markers spanning the 5q cytokine cluster by linkage analysis in a total of 11 retrospectively pooled data sets (1037 A Second-Generation Association Study of the 5q31 Cytokine Gene Cluster and the Interleukin-4 Receptor in Asthma IL4R, located on chromosome 16p12, is exceptionally polymorphic. Eight missense and six silent polymorphisms have been described [11][12][13]. Some of the polymorphisms have been reported to be associated with IgE-mediated disorders [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

A Second-Generation Association Study of the 5q31 Cytokine Gene Cluster and the Interleukin-4 Receptor in Asthma

et al. 2001

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We have analyzed a dense set of single-nucleotide polymorphisms (SNPs) and microsatellites spanning the T-helper cytokine gene cluster (interleukins 3, 4, 5, 9, and 13, interferon regulatory factor-1, colony-stimulating factor-2, and T-cell transcription factor-7) on 5q31 and the gene encoding the interleukin-4 receptor (IL4R) on 16p12 among Finnish families with asthma. As shown by haplotype pattern mining analysis, the number of disease-associated haplotype patterns differed from that expected for the 129Q allele polymorphism in IL13 for high serum total immunoglobulin (Ig) E levels, but not for asthma. The same SNP also yielded the best haplotype associations. For IL4R, asthma-associated haplotype patterns, most spanning the S411L polymorphism, showed suggestive association. However, these haplotypes consisted of the major alleles for the intracellular part of the receptor and were very common among both patients and controls. The minor alleles 503P and 576R have been reported to be associated with decreased serum IgE levels and changes in the biological activity of the protein, especially when inherited together. In the Finnish population, these two polymorphisms segregated in strong linkage disequilibrium. Our data support previous findings regarding IL4R, indicating that 503P and 576R may act as minor protecting alleles for IgE-mediated disorders.Key Words: asthma, atopy, haplotype pattern mining, polymorphism, association families). The study showed suggestive linkage for asthma (LOD = 2.6) but no evidence for atopy [8]. Although it is not known whether human genes in the 5q31 cytokine cluster are genetic regulators for atopic disorders, experimental models of asthma have shown the importance of both IL4 and IL13 signaling. Administration of either exogenous IL4 or IL13 induced the asthma phenotype in mice [9]. However, neither of these cytokines was able to induce the asthma phenotype in mice deficient in the IL4 receptor (IL4R) [9]. The IL4 receptor is a heterodimer consisting of a common ␥-chain that is shared by several other interleukin receptors (IL2, IL7, IL9, and IL13) and a ligand-specific ␣-chain encoded by IL4R. An IL4R␣-IL13R␣ heterodimer is also able to transduce IL13 signaling [10] and is an important signaling pathway in the asthma model. All this indicates the importance of IL4R␣ in IL4/IL13-mediated signaling.

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The Association of Atopy with a Gain-of-Function Mutation in the α Subunit of the Interleukin-4 Receptor

Abstract: The R576 allele of interleukin-4 receptor alpha is strongly associated with atopy. This mutation may predispose persons to allergic diseases by altering the signaling function of the receptor.

Cited by 693 publications

References 41 publications

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

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

Atopic dermatitis: from the genes to skin lesions

A Second-Generation Association Study of the 5q31 Cytokine Gene Cluster and the Interleukin-4 Receptor in Asthma

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