van Veen Anneke, Wierenga Eddy A, Westland Robert, Weller Frank R, Hart Guus A M, Jansen Henk M, Jonkers René E
Department of Pulmonology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Respir Res. 2006 Jan 31;7(1):19. doi: 10.1186/1465-9921-7-19.
In vitro and some in vivo studies suggested that genetic haplotypes may have an impact on beta2-agonist mediated airway responses in asthmatics. Due to strong linkage disequilibrium the single nucleotide polymorphisms (SNPs) in the beta2-adrenoceptor gene result in only a limited number of haplotypes. We intended to evaluate the impact of beta2-adrenoceptor haplotypes on beta2-agonist mediated airway responses and the development of tolerance in mild to moderate asthmatics.
Patients were genotyped for the part of the beta2-adrenoceptor gene with a known bearing on receptor function and regulation. Cumulative dose response curves of fenoterol versus PD20 methacholine and FEV1 were constructed after 2 week treatment periods with either terbutaline or placebo in a double blind, randomised and cross-over design. Analysis of the dose response curves was based on a repeated measurement analysis of covariance.
In our study population comprising 45 asthmatic patients, we found three limited allelic haplotypes, resulting in six different genotypes. Our data support the existence of differences between these six genotypes both in the shape of the dose response relationship of the beta2-adrenoceptor agonist fenoterol as well as in the propensity to develop tolerance for these effects by pre-treatment with terbutaline. However, this could only be substantiated for the endpoint PD20 methacholine.
Between beta2-adrenoceptor genotypes differences exist both in baseline beta2-agonist induced airway responses as well as in the propensity to develop tolerance during maintenance beta2-agonist therapy. The net differences after two weeks of therapy are, however, of magnitudes that are unlikely to be of clinical significance.
体外及一些体内研究表明，基因单倍型可能对哮喘患者中β2受体激动剂介导的气道反应产生影响。由于存在强连锁不平衡，β2肾上腺素能受体基因中的单核苷酸多态性（SNP）仅导致有限数量的单倍型。我们旨在评估β2肾上腺素能受体单倍型对轻度至中度哮喘患者中β2受体激动剂介导的气道反应及耐受性发展的影响。
对患者β2肾上腺素能受体基因中已知与受体功能及调节相关的部分进行基因分型。在双盲、随机及交叉设计中，患者接受特布他林或安慰剂为期2周的治疗后，构建非诺特罗与PD20乙酰甲胆碱及第一秒用力呼气量（FEV1）的累积剂量反应曲线。剂量反应曲线分析基于重复测量协方差分析。
在我们纳入45例哮喘患者的研究群体中，我们发现了三种有限的等位基因单倍型，产生了六种不同的基因型。我们的数据支持这六种基因型在β2受体激动剂非诺特罗的剂量反应关系形状以及通过特布他林预处理对这些效应产生耐受性的倾向方面存在差异。然而，这仅在终点指标PD20乙酰甲胆碱方面得到证实。
β2肾上腺素能受体基因型之间在基线β2受体激动剂诱导的气道反应以及维持β2受体激动剂治疗期间产生耐受性的倾向方面均存在差异。然而，两周治疗后的净差异幅度不太可能具有临床意义。
