Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype.
Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype.
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夜间和非夜间哮喘中β2-肾上腺素能受体的遗传多态性。
DOI：
10.1172/jci117838
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Liggett,SB
中科院分区：
文献类型：
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作者：
Turki,J;Pak,J;Green,SA;Martin,RJ;Liggett,SB
夜间哮喘是一种独特的哮喘患者亚群，他们在夜间出现症状恶化和气流阻塞。这种哮喘表型的基础尚不清楚，但已知β 2-肾上腺素能受体（β 2AR）在夜间哮喘患者中过夜下调，而在正常受试者或非夜间哮喘患者中则不下调。我们最近描绘了三个多态性基因座内的编码区的β 2 AR改变氨基酸的位置16，27和164，并赋予特定的生化和药理学表型的受体。在定点突变/重组表达研究中，我们发现，与此位置的精氨酸（Arg16）相比，16位的甘氨酸（Gly16）可加速激动剂促进的β 2AR下调。我们假设Gly16可能在夜间哮喘患者中过度表达，因此确定了两个明确定义的哮喘队列的β 2AR基因型：23名夜间哮喘患者，夜间呼气峰流速下降34 ± 2%，22名非夜间哮喘患者，几乎没有这种下降（2.3 ± 0.8%）。Gly16等位基因的频率在夜间组中为80.4%，而在非夜间组中为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过度表达在P = 0.007时具有显著性，夜间哮喘和Gly16多态性的比值比为3.8。两个队列的Gly16纯合性、Arg16纯合性或杂合性的比较也与Gly16与夜间哮喘的分离一致。27（Gln27或Glu27）和164（Thr164或Ile164）位点的多态性频率在两组间无差异。因此，β 2AR的Gly16多态性（其增强了受体数量的下调）在夜间哮喘中过度表达，似乎是这种哮喘表型表达的重要遗传因素。
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.Images