无症状健康日本受试者中非特异性气道高反应性与Arg16Glyβ2-肾上腺素能受体基因多态性之间的关联

Association between nonspecific airway hyperresponsiveness and Arg16Gly beta2-adrenergic receptor gene polymorphism in asymptomatic healthy Japanese subjects.

作者信息

Fukui Yoshinobu, Hizawa Nobuyuki, Takahashi Daisuke, Maeda Yukiko, Jinushi Eisei, Konno Satoshi, Nishimura Masaharu

机构信息

First Department of Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

出版信息

Chest. 2006 Aug;130(2):449-54. doi: 10.1378/chest.130.2.449.

DOI:10.1378/chest.130.2.449

PMID:16899844

Abstract

BACKGROUND

Nonspecific airway hyperresponsiveness (AHR), a cardinal feature of asthma, is thought to result from several genetic and environmental factors. Asymptomatic AHR in nonasthmatic healthy subjects might be a risk factor for the development of asthma. Genetic variations in codons 16 and 27 of the human beta(2)-adrenergic receptor (beta(2)-AR) alter receptor function in vitro and are associated with various asthma-related phenotypes, including asthma severity and AHR. To date, however, few reports have examined the impact of beta(2)-AR gene polymorphism on AHR in asymptomatic healthy subjects.

OBJECTIVE

To determine whether polymorphism of the beta(2)-AR gene (Arg16Gly and Gln27Glu) might influence nonspecific AHR in asymptomatic healthy Japanese subjects.

DESIGN AND PARTICIPANTS

A cohort of 120 asymptomatic healthy subjects was analyzed using a stepwise linear regression model. Nonspecific airway responsiveness was measured using a continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). We used values of the cumulative dose of inhaled methacholine measured at the inflection point at which respiratory conductance starts to decrease (Dmin) as an index of AHR. Genotyping to identify polymorphisms at codons 16 and 27 was conducted using an assay combining kinetic real-time quantitative polymerase chain reaction with allele-specific amplification.

RESULTS

The Gly16Gly genotype was associated with lower Dmin values. The log Dmin value of asymptomatic healthy subjects carrying the Arg16 allele (Arg16/Arg or Arg16/Gly, n = 90) was 1.09 +/- 0.56 (mean +/- SD), while those homozygous for the Gly16 allele (n = 30) yielded a log Dmin value of 0.85 +/- 0.56 (p < 0.05).

CONCLUSION

This study indicates that a specific beta(2)-AR polymorphism at codon 16 might be a genetic determinant of AHR, as judged by methacholine-induced bronchoconstriction in asymptomatic healthy subjects.

摘要

背景

非特异性气道高反应性（AHR）是哮喘的一个主要特征，被认为是由多种遗传和环境因素导致的。非哮喘健康受试者中的无症状AHR可能是哮喘发生的一个危险因素。人β2-肾上腺素能受体（β2-AR）第16和27密码子的基因变异在体外会改变受体功能，并与各种哮喘相关表型有关，包括哮喘严重程度和AHR。然而，迄今为止，很少有报告研究β2-AR基因多态性对无症状健康受试者AHR的影响。

目的

确定β2-AR基因多态性（Arg16Gly和Gln27Glu）是否可能影响无症状健康日本受试者的非特异性AHR。

设计与参与者

使用逐步线性回归模型对120名无症状健康受试者进行队列分析。采用连续吸入乙酰甲胆碱方法（Astograph；Chest；日本东京）测量非特异性气道反应性。我们将在呼吸传导开始下降的拐点处测得的吸入乙酰甲胆碱累积剂量值（Dmin）作为AHR的指标。采用动力学实时定量聚合酶链反应与等位基因特异性扩增相结合的检测方法，对第16和27密码子的多态性进行基因分型。

结果

Gly16Gly基因型与较低的Dmin值相关。携带Arg16等位基因（Arg16/Arg或Arg16/Gly，n = 90）的无症状健康受试者的log Dmin值为1.09±0.56（平均值±标准差），而纯合Gly16等位基因的受试者（n = 30）的log Dmin值为0.85±0.56（p < 0.05）。