Polymorphisms in the beta2-adrenoreceptor gene are associated with decreased airway responsiveness

There are a number of candidate genes thought to play a role in the development of asthma. Polymorphisms at amino acid positions 16 (arginine to glycine) and 27 (glutamine to glutamic acid) of the beta2-adrenoreceptor (B2AR) gene are known to be functionally relevant and have been associated with more severe forms of asthma, nocturnal asthma and decreased airway responsiveness in asthmatic subjects.

To determine if these polymorphisms contribute to the development of asthma by investigating the associations between the polymorphisms at amino acid positions 16 and 27 of the B2AR gene and asthma-related parameters in a large, phenotypically well-characterized population which was unselected for asthma.

Subjects (n = 332) were characterized using physiological assessments, immuno-logical data and information obtained from questionnaire. PCR was used to generate a 229 base pair fragment spanning the mutations of interest. Genotype was determined using allele-specific oligonucleotide hybridization and confirmed in 10% of the samples by direct sequencing. Multivariate analysis of the association between genotype and phenotype was then undertaken.

Homozygotes for Glu27 were significantly less responsive to histamine than Gln27 homozygotes. In addition, Arg16 homozygotes were more likely to 'wheeze during a cold', in comparison with Gly16 homozygotes. However, there was no association between either polymorphism and physician-diagnosed asthma, eczema, skin reactivity to common allergens or total and specific serum IgE levels. The two polymorphisms were found to be in significant linkage disequilibrium.

The polymorphism at position 27 was associated with decreased airway responsiveness in the study population and the polymorphism at position 16 was associated with increased wheeze during respiratory infection, but neither was associated with physician-diagnosed asthma or any of the other variables considered.