Turki J, Pak J, Green S A, Martin R J, Liggett S B
Department of Medicine (Pulmonary), University of Cincinnati College of Medicine, Ohio 45267-0564, USA.
J Clin Invest. 1995 Apr;95(4):1635-41. doi: 10.1172/JCI117838.
Nocturnal asthma represents a unique subset of patients with asthma who experience worsening symptoms and airflow obstruction at night. The basis for this phenotype of asthma is not known, but beta 2-adrenergic receptors (beta 2AR) are known to downregulate overnight in nocturnal asthmatics but not normal subjects or nonnocturnal asthmatics. We have recently delineated three polymorphic loci within the coding block of the beta 2AR which alter amino acids at positions 16, 27, and 164 and impart specific biochemical and pharmacologic phenotypes to the receptor. In site-directed mutagenesis/recombinant expression studies we have found that glycine at position 16 (Gly16) imparts an accelerated agonist-promoted downregulation of beta 2AR as compared to arginine at this position (Arg16). We hypothesized that Gly16 might be overrepresented in nocturnal asthmatics and thus determined the beta 2AR genotypes of two well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34 +/- 2% nocturnal depression of peak expiratory flow rates, and 22 nonnocturnal asthmatics with virtually no such depression (2.3 +/- 0.8%). The frequency of the Gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the Arg16 allele was present in 19.6 and 47.8%, respectively. This overrepresentation of the Gly16 allele in nocturnal asthma was significant at P = 0.007 with an odds ratio of having nocturnal asthma and the Gly16 polymorphism being 3.8. Comparisons of the two cohorts as to homozygosity for Gly16, homozygosity for Arg16, or heterozygosity were also consistent with segregation of Gly16 with nocturnal asthma. There was no difference in the frequency of polymorphisms at loci 27 (Gln27 or Glu27) and 164 (Thr164 or Ile164) between the two groups. Thus the Gly16 polymorphism of the beta 2AR, which imparts an enhanced downregulation of receptor number, is overrepresented in nocturnal asthma and appears to be an important genetic factor in the expression of this asthmatic phenotype.
夜间哮喘是哮喘患者中的一个独特亚组，这些患者在夜间会出现症状加重和气流阻塞的情况。这种哮喘表型的发病机制尚不清楚，但已知β2肾上腺素能受体（β2AR）在夜间哮喘患者中会在夜间下调，而在正常受试者或非夜间哮喘患者中则不会。我们最近在β2AR的编码区内确定了三个多态性位点，这些位点改变了第16、27和164位的氨基酸，并赋予受体特定的生化和药理表型。在定点诱变/重组表达研究中，我们发现第16位的甘氨酸（Gly16）与该位置的精氨酸（Arg16）相比，会使β2AR的激动剂促进的下调加速。我们推测Gly16在夜间哮喘患者中可能过度表达，因此确定了两个明确的哮喘队列的β2AR基因型：23名夜间哮喘患者，其夜间呼气峰值流速下降34±2%，以及22名非夜间哮喘患者，几乎没有这种下降（2.3±0.8%）。夜间组中Gly16等位基因的频率为80.4%，而非夜间组为52.2%，而Arg16等位基因分别为19.6%和47.8%。Gly16等位基因在夜间哮喘中的这种过度表达在P = 0.007时具有统计学意义，患夜间哮喘和Gly16多态性的优势比为3.8。对两个队列在Gly16纯合性、Arg16纯合性或杂合性方面的比较也与Gly16与夜间哮喘的分离一致。两组在第27位（Gln27或Glu27）和第164位（Thr164或Ile164）的多态性频率没有差异。因此，β2AR的Gly16多态性会导致受体数量的下调增强，在夜间哮喘中过度表达，似乎是这种哮喘表型表达的一个重要遗传因素。
