β₂-Adrenergic Receptor Haplotypes in Mild, Moderate and Fatal/Near Fatal Asthma

Abstract

Excess beta2-agonist use in asthmatics has been associated with increased mortality and morbidity. The mechanisms responsible for these observations are unknown. We hypothesized that polymorphisms of the beta2-adrenergic receptor (beta2AR) at amino acid positions 16, 27, and 164, which are known to alter receptor functions in vitro, may predispose asthmatics to fatal/near-fatal asthma and/or modify asthma severity. In preliminary studies we found significant differences in allele frequencies due to ethnic background: Caucasian, Black, Asian Gly16 = 0.61, 0.50, 0.40 and Gln27 = 0.57, 0. 73, 0.80, respectively. beta2AR genotyping was performed on DNA from Caucasians classified as nonasthmatic/nonatopic (n = 84), fatal/near-fatal asthmatics (n = 81) and mild/moderate asthmatics (n = 86). No polymorphism or haplotype was found to be associated with fatal/near-fatal asthma. However, the Gly16/Gln27 haplotype, which undergoes enhanced downregulation in vitro, was substantially more prevalent in moderate asthmatics than in mild asthmatics (p = 0.003, odds ratio = 3.1). We conclude that the beta2AR genotype is not a major determinant of fatal or near-fatal asthma. Furthermore, allele frequency variation among ethnic groups must be considered in clinical studies of beta2AR polymorphisms in asthma.

β2-adrenergic receptor polymorphisms are associated with asthma and COPD in adults

“…Furthermore, many other studies have reported no association with asthma at all Martinez et al 1997;Ramsay et al 1999;Reihsaus et al 1993;Summerhill et al 2000;Turner et al 2004). Only one study has looked at b 2 AR haplotypes and risk of asthma, which found the Gly16/Gln27 haplotype was more prevalent in moderate asthmatics than in mild asthmatics (Weir et al 1998). This is different to our reported association with Arg16/Gln27, which may be because our subjects had milder asthma.…”

“…A previous Australian study also reported an association between wheeze with a cold and the Arg16 allele (Ramsay et al 1999). As mentioned previously, however, Weir et al (1998) found a higher prevalence of the Gly16/Gln27 haplotype in subjects with moderate to severe asthma. The difference from our results may be because our community-based subjects had milder asthma.…”

“…This is different to our reported association with Arg16/Gln27, which may be because our subjects had milder asthma. Unlike Weir et al (1998), we were able to resolve b 2 AR haplotypes for subjects heterozygous at both polymorphisms, because we used the E-M algorithm to infer phase in all subjects. An increased risk of COPD was associated with Arg16 homozygous genotype, and COPD and FEF were associated with possession of the Arg16/Gln27 haplotype.…”

“…However, more recent in vivo work in humans has shown the Arg16Gln27 haplotype is the form of the receptor that is associated with agonist-promoted desensitization (Dishy et al 2001). Genetic studies of these polymorphisms have found them to be associated with asthma severity Weir et al 1998), bronchial hyperreactivity (BHR) Ramsay et al 1999), bronchodilator (BD) response (D'Amato et al 1998;Lima et al 1999;Martinez et al 1997;Ulbrecht et al 2000) and lung function (Summerhill et al 2000).…”

The pharmacogenetics of asthma: a candidate gene approach

“…At amino acid position 16 Arg or Gly can be present, and at position 27 Gln or Glu can be present. These represent the common coding [24][25][26] have been found except for one report in pediatric asthma. 27 It is thus unlikely that any of these polymorphisms or combination of polymorphisms is a major risk factor for asthma.…”