Weir T D, Mallek N, Sandford A J, Bai T R, Awadh N, Fitzgerald J M, Cockcroft D, James A, Liggett S B, Paré P D
Respiratory Health Network of Centres of Excellence, University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, Canada.
Am J Respir Crit Care Med. 1998 Sep;158(3):787-91. doi: 10.1164/ajrccm.158.3.9801035.
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.
哮喘患者过度使用β2激动剂与死亡率和发病率增加有关。导致这些观察结果的机制尚不清楚。我们推测，已知在体外可改变受体功能的β2肾上腺素能受体（β2AR）第16、27和164位氨基酸的多态性，可能使哮喘患者易患致命性/接近致命性哮喘和/或改变哮喘严重程度。在初步研究中，我们发现由于种族背景导致等位基因频率存在显著差异：白种人、黑人、亚洲人，Gly16分别为0.61、0.50、0.40，Gln27分别为0.57、0.73、0.80。对分类为非哮喘/非特应性（n = 84）、致命性/接近致命性哮喘患者（n = 81）和轻度/中度哮喘患者（n = 86）的白种人的DNA进行β2AR基因分型。未发现任何多态性或单倍型与致命性/接近致命性哮喘相关。然而，在体外经历增强下调的Gly16/Gln27单倍型在中度哮喘患者中比在轻度哮喘患者中更为普遍（p = 0.003，优势比 = 3.1）。我们得出结论，β2AR基因型不是致命性或接近致命性哮喘的主要决定因素。此外，在哮喘β2AR多态性的临床研究中必须考虑种族群体之间的等位基因频率差异。
