Beta2 Adrenergic Receptor (ADRbβ) Haplotype Pair (2/4) Is Associated with Severe Asthma

Background: ss 2 adrenergic receptor (ADRb2) polymorphisms including ADRb2+46G > A have been reported to cause adverse outcomes in mild asthmatics. The extent to which ADRb2 polymorphisms and in particular their haplotypes contribute to severe asthma is unknown. Objective: To determine the association of ADRb2 polymorphisms and haplotypes with asthma severity. Methods: Caucasians (n = 2979) were genotyped for 11 ADRb2 polymorphisms. The cohort (mean age 39.6, 60% female) included 2296 non-asthmatics, 386 mild asthmatics, 172 moderate asthmatics and 125 severe asthmatics. Haplotype frequency and haplotype pair for each subject was determined using the PHASE algorithm. Results: The three asthmatic cohorts were comparable in age and gender but were distinguishable from each other in terms of symptoms, spirometry, medication use and health care utilisation (p < 0.001). None of the polymorphisms showed a genotypic or allelic association with asthma diagnosis or severity. Nine haplotypes were identified and no association was found with asthma diagnosis or severity per se. Haplotype pair 2/4 was associated with asthma severity (Trend Test, OR 1.42, p = 0.0008) but not with asthma per se. Prevalence of haplotype pair 2/2 appeared to decrease with asthma severity ( Trend Test, OR 0.78, p = 0.067). Two new haplotypes were identified, occurring exclusively in asthmatics at a frequency of >= 1%. In addition, a positive association between carriage of ADRb2 +523*C and increased risk of atopy was discovered. Conclusions: ADRb2 haplotype pair 2/4 is associated with severe asthma and is consistent with findings of poor bronchodilator response in mild asthmatics who are also haplotype 2/4.