The glutamine 27 β2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families,☆☆,,★★

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Abstract

Background: The β2-adrenoceptor polymorphisms occurring at amino acid positions 16 (arginine to glycine) and 27 (glutamine to glutamate) are known to be functionally relevant and also disease-modifying in subjects with asthma. However, the contribution of these polymorphisms to the development of the asthmatic phenotype or other markers for allergic disease remains to be established. Objective: This large family study examines the contributions of these polymorphisms in determining the heritable component of markers for allergic disease in asthmatic families. Methods: Three hundred twenty-four individuals from 60 families multiplex for asthma selected by means of an asthmatic proband were characterized for the following markers of allergic disease: asthma, atopy, and serum IgE. The polymerase chain reaction was used to generate a 234 base pair fragment spanning the region of interest, and the β2-adrenoceptor polymorphism was then defined by allele-specific oligonucleotide hybridization. Segregation analysis was then performed. Results: We found a significant association (p = 0.009) between the glutamine 27 β2-adrenoceptor polymorphism and elevated levels of IgE, which was supported by the observation of linkage between IgE and β2-adrenoceptor polymorphisms at locus 27 (p = 0.037). However, there was no association between either the arginine-glycine 16 or the glutamine-glutamate 27 β2-adrenoceptor polymorphism and an increased risk of asthma or atopy per se. Conclusion: The glutamine 27 β2-adrenoceptor polymorphism appears to contribute to IgE variability in families with asthma. However, it seems that although both amino acid 16 and 27 β2-adrenoceptor polymorphisms are disease-modifying in subjects with asthma, they do not contribute markedly to the development of the asthmatic phenotype. (J Allergy Clin Immunol 1997;100:261-5.)

Section snippets

Subjects

Three hundred twenty-four individuals from 60 unrelated families selected by means of an asthmatic proband were studied. Of these 60 families, 44 were nuclear in structure. The families were outbred, and all subjects were Caucasian. The probands were recruited from hospital clinics in the Wessex area of Southern England, and all had a physician's diagnosis of asthma. The study was approved by the Southampton University Hospitals Joint Ethical Committee. Informed written consent was obtained

Results

We used ASO hybridization7, 16 to determine the genotype of our subjects (see Methods for details). First, genomic DNA was extracted from whole blood, and a 234 base pair fragment spanning the two polymorphisms was generated by using the PCR. Genotype was then determined with probes specific for each polymorphism. Fig. 1 shows a representative ASO result on samples from 15 individuals who had previously been genotyped by direct sequencing.

In this sample of families multiplex for asthma, the

Discussion

The main findings of this study are (1) that the Gln 27 β2 adrenoceptor polymorphism is significantly associated with elevated levels of serum IgE and (2) that neither the Arg-Gly 16 nor the Gln-Glu 27 β2 adrenoceptor polymorphism was associated with an increased risk of asthma or atopy in the families studied. The potential contribution of the amino acid 27 polymorphism to IgE variability in this population was further supported by linkage analysis.

An association between total serum IgE and

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  • Cited by (0)

    From athe Department of Therapeutics, University Hospital, Nottingham; bthe Departments of Medicine and Cancer Research Campaign Genetic Epidemiology Research Group, Princess Anne Hospital, Southampton; and cPulmonary and Critical Care Medicine, University of Cincinnati.

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    Supported by the National Asthma Campaign, the National Institutes of Health (USA), and the Medical Research Council.

    Reprint requests: I. P. Hall, DM, National Asthma Campaign, University Hospital, Nottingham, NG7 2UH, United Kingdom.

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