Correspondence

Atopy and a Mutation in the Interleukin-4 Receptor Gene

N Engl J Med 2000; 343:69-70July 6, 2000

Article

To the Editor:

In 1997, Hershey et al. reported finding a mutation in the interleukin-4 receptor α allele in 13 of 20 patients with atopy, as compared with 5 of 30 control subjects.1 This mutation (termed Q576R) increases the signaling function of the interleukin-4 receptor, thereby favoring the expression of IgE receptors on immune cells.

We studied 75 patients with atopic dermatitis or asthma and 150 control subjects for the presence of the Q576R mutation. Wild-type and mutant alleles were amplified by the polymerase chain reaction with modified primers and segregated after enzymatic digestion with AvaI and electrophoretic migration. We found the mutant gene in 18 percent of the 75 patients with atopy and in 16 percent of the 150 control subjects (P=0.59).

We believe that our results do not confirm those of Hershey et al. for two main reasons. First, Hershey et al. studied 50 patients, 20 of whom were identified as having atopy on the basis of elevated serum IgE levels. Our patients with atopy were identified on the basis of clinical and family histories, typical clinical findings, and the IgE level. Second, since atopy is a heterogeneous disease, our results may differ because we studied a different population.

Dominique Dupre, M.D.
Marie-Pierre Audrezet, Ph.D.
Claude Ferec, M.D.
University Hospital of Brest, 29609 Brest CEDEX, France

1 References

1. 1

   Hershey GKK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. The association of atopy with a gain-of-function mutation in the α subunit of the interleukin-4 receptor. N Engl J Med 1997;337:1720-1725
   Full Text | Web of Science | Medline

Author/Editor Response

Dr. Chatila replies:

To the Editor: Since my colleagues and I reported on the association of atopy with an intracellular polymorphism (Q576R) in the α chain of the interleukin-4 receptor, a total of eight such amino acid substitutions have been described. One substitution (Ile50V) is in the extracellular domain, whereas the remaining seven, including Q576R, are in the intracellular domain. The frequency of these substitutions differs among racial and ethnic groups, and many of the intracellular-domain substitutions are in linkage disequilibrium.1 These attributes have complicated studies scrutinizing the association of single polymorphic residues of the interleukin-4 receptor α with atopy and atopic diseases and may have contributed to the finding of Dupre et al. that there was no association between Q576R and atopy in their cohort.

Nevertheless, a strong relation between mutations in interleukin-4 receptor α alleles and atopy and asthma has emerged in recent studies.1,2 Particularly informative has been the study by Ober et al., which confirmed the presence of a strong association between interleukin-4 receptor α alleles and atopy and asthma in several populations including the Hutterites, a founder population of European origin, and outbred white, black, and Hispanic groups. An important finding in this study is that no single polymorphism analyzed in isolation was associated with atopy or asthma in all populations studied. Moreover, when such an association was found, it was frequently modest. In contrast, combinations of different polymorphic residues were found to be strongly associated with both phenotypes, suggesting that the small disease-modifying effect of any one polymorphism is compounded by other, coexisting substitutions. It thus appears that future studies will be most informative if they are preceded by a complete analysis of the haplotype of interleukin-4 receptor α.

Talal Chatila, M.D.
Washington University School of Medicine, St. Louis, MO 63110

2 References

1. 1

   Ober C, Leavitt SA, Tsalenko A, et al. Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet 2000;66:517-526
   CrossRef | Web of Science | Medline

2. 2

   Rosa-Rosa L, Zimmermann N, Bernstein JA, Rothenberg ME, Khurana Hershey GK. The R576 IL-4 receptor alpha allele correlates with asthma severity. J Allergy Clin Immunol 1999;104:1008-1014
   CrossRef | Web of Science | Medline

Citing Articles (5)

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   Michihiro Hide, Yuhki Yanase, Malcolm W. Greaves. (2007) Cutaneous Mast Cell Receptors. Dermatologic Clinics 25:4, 563-575
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   Izolda Franjkovic, Andre Gessner, Inke Knig, Karin Kissel, Anette Bohnert, Anne Hartung, Astrid Ohly, Andreas Ziegler, Holger Hackstein, Gregor Bein. (2005) Effects of common atopy-associated amino acid substitutions in the IL-4 receptor alpha chain on IL-4 induced phenotypes. Immunogenetics 56:11, 808-817
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   T. Jung, R. Moessner, C. Neumann. (2003) Naive CD4+ T cells from patients with atopic dermatitis show an aberrant maturation towards IL-4-producing skin-homing CLA+ cells. Experimental Dermatology 12:5, 555-562
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   K. I. Mujica-Lopez, S. E. Flores-Martinez, R. Ramos-Zepeda, S. A. Castaneda-Ramos, A. Gazca-Aguilar, J. Garcia-Perez, J. Sanchez-Corona. (2002) Association analysis of polymorphisms in the interleukin-4 receptor (alpha) gene with atopic asthma in patients from western Mexico. European Journal of Immunogenetics 29:5, 375-378
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   Hakon Hakonarson, Eva Halapi. (2002) Genetic Analyses in Asthma. American Journal of PharmacoGenomics 2:3, 155-166
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