MUTATIONS IN THE GENE ENCODING FOR THE BETA-2-ADRENERGIC RECEPTOR IN NORMAL AND ASTHMATIC SUBJECTS
MUTATIONS IN THE GENE ENCODING FOR THE BETA-2-ADRENERGIC RECEPTOR IN NORMAL AND ASTHMATIC SUBJECTS
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DOI：
10.1165/ajrcmb/8.3.334
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发表时间：
1993-03-01
影响因子：
6.4
通讯作者：
LIGGETT, SB
中科院分区：
文献类型：
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作者：
REIHSAUS, E;INNIS, M;LIGGETT, SB
长期以来，已经假设有缺陷的β2-肾上腺素能受体（betA2AR）可能是支气管哮喘的致病因素。我们检查了编码β2AR的基因，以评估51例中度至重度哮喘患者和56名正常受试者的多态性频率。在核酸残基46、79、100、252、491、523、1053、1098和1239中，在杂合和纯合形式中发现了九个不同的点突变。未检测到导致大量缺失或帧的突变。在这九种多态性中，发现有四种在16、27、34和164的残基中导致编码的氨基酸变化。最常见的多态性是精氨酸16到甘氨酸（arg16-> gly）和谷氨酰胺27对谷氨酸（谷氨酸）（ GLN27-> GLU）。其他两种多态性，即甲氨酸34至蛋氨酸，苏氨酸164到异亮氨酸，仅在四个受试者中出现。与对照组相比，哮喘患者的β2AR纯合多态性的发生率并没有更大（arg16-> gly：53％对59％，GLN27-> GLU：24％和29％； p = ns）。发现某些受试者同时具有这两种多态性，但是两组之间的发病率没有差异，其中23％的哮喘患者和28％的正常受试者对这两种多态性都是纯合的。通过甲基苯胺挑战测试确定，具有两种多态性的显然正常受试者没有亚临床高反应性气道疾病。在哮喘组中，一个突变（arg16-> gly）确定了一部分具有不同临床特征的患者。与没有这种多态性的患者相比，这种多态性患者更可能是类固醇依赖性并需要免疫治疗的患者。哮喘严重程度或药物使用的其他参数与任何基因座的多态性存在无关。因此，哮喘似乎主要不是由β2AR中的遗传缺陷引起的。但是，ARG16-> GLY多态性可能与不同的临床状况有关，表明编码β2AR的基因的改变在某些患者的哮喘发病机理中起辅助作用。
It has long been hypothesized that a defective beta2-adrenergic receptor (beta2AR) may be a pathogenic factor in bronchial asthma. We examined the gene encoding the beta2AR to assess the frequency of polymorphisms in 51 patients with moderate to severe asthma and 56 normal subjects. Nine different point mutations were found in both heterozygous and homozygous forms at nucleic acid residues 46, 79, 100, 252, 491, 523, 1053, 1098, and 1239. No mutations resulting in large deletions or frame shifts were detected. Of these nine polymorphisms, four were found to cause changes in the encoded amino acids at residues 16, 27, 34, and 164. The most frequent polymorphisms were arginine 16 to glycine (Arg16-->Gly) and glutamine 27 to glutamic acid (Gln27-->Glu). The other two polymorphisms, valine 34 to methionine, and threonine 164 to isoleucine, occurred in only four subjects. The incidence of beta2AR homozygous polymorphisms was no greater in asthmatic patients as compared with controls (Arg16-->Gly: 53 % versus 59%, Gln27-->Glu: 24% versus 29%, respectively; P = NS). Some subjects were found to have both of these polymorphisms simultaneously, but there was no difference in incidence between the two groups, with 23% of asthmatics and 28% of normal subjects being homozygous for both polymorphisms. The apparently normal subjects with both polymorphisms did not have subclinical hyperreactive airways disease as determined by methacholine challenge testing. In the asthma group, one mutation (Arg16-->Gly) identified a subset of patients with a distinct clinical profile. Patients with this polymorphism were more likely to be steroid dependent and to require immunization therapy, as compared with those without this polymorphism. Other parameters of asthma severity or medication use were not related to the presence of a polymorphism at any locus. Thus, asthma does not appear to be primarily caused by a genetic defect in the beta2AR. However, the Arg16-->Gly polymorphism may be associated with a different clinical status, suggesting that an alteration in the gene encoding for the beta2AR plays an accessory role in the pathogenesis of asthma in certain patients.