Association between beta2 adrenergic receptor ( ADRβ2 ) haplotype pair and severe asthma in an Australian caucasian population

Background: Studies in mild asthmatics showed adverse outcomes with chronic use of short or long acting beta agonists in individuals with β2 adrenergic receptor ( ADRβ2) polymorphisms including ADRβ2 +46G>A. The extent to which ADRβ2 polymorphisms contribute to severe asthma is unknown, hence the association of ADRβ2 polymorphisms with asthma severity was investigated. Methods: Caucasians with mild (n=201) or severe asthma (n=118, defined by ATS criteria 2000) and non-asthmatics (n=200) were recruited. All subjects (mean age 53.1, 60% atopic) were genotyped for 12 ADRβ2 polymorphisms (-1023, -709, -654, -468, -367, -47, -20, +46, +79, +252, +491, +523). Haplotype frequency and haplotype pair was determined via PHASE. Results: Severe, mild and non-asthmatic cohorts were matched by age but distinguishable from each other in terms of symptoms, lung function, medication use and health care utilisation (p <0.001). Genotypic and allelic frequency was similar across cohorts for all polymorphisms. Nine Caucasian haplotypes were identified and not associated with asthma diagnosis or severity per se. In addition, 12 new haplotypes were identified, 2 (frequency ≥ 1%) and were found exclusively in asthmatics. Haplotype pair 2/4 was associated with severe compared with mild (OR 1.84 95%CI 1.13, 2.97, p value=0.01) or non-asthmatics (OR 1.92, 95%CI 1.19, 3.11, p value=0.008). Conclusions: ADRβ2 haplotype pair 2/4 is associated with severe asthma. Known haplotypic difference in receptor expression and acute bronchodilator response in mild compared to severe asthmatics suggests a role for ADRβ2 haplotypes in the development and/or treatment response in severe asthmatics.