Tellería Juan Jose, Blanco-Quirós Alfredo, Muntión Sandra, Antonio Garrote Jose, Arranz Eduardo, Armentia Alicia, Díez Ignacio, Castro Jesús
Department of Paediatrics, Institute of Biology and Molecular Genetics, IBGM/CSIC, University of Valladolid School of Medicine, Valladolid, Spain.
Respir Med. 2006 Jun;100(6):1072-8. doi: 10.1016/j.rmed.2005.09.028. Epub 2005 Nov 2.
The study of determinants of asthma is a subject of much interest currently, especially the pharmacogenetic aspects of asthma management. Genetic polymorphisms affecting amino-acids at positions 16 and 27 within beta(2)-adrenoceptor (beta(2)AR) gene have been implicated in the asthma phenotypes and influence on the variability observed in response to use of bronchodilator agents used in the treatment of asthma. Whether these polymorphisms alter the bronchoprotection response to beta(2)-agonist treatment in Spanish asthmatic population is unknown. The aim of this study was to investigate whether genetic polymorphisms within beta(2)AR gene modulate the clinical outcomes of the individual response to beta(2)-agonist therapy and the development of desensitization in Spanish asthmatic patients.
In a prospective, case-control study were included 80 asthmatic patients. Based on the standard criteria, patients were classified into two groups: patients with tachyphylaxis and good responders to beta(2)-agonist therapy. DNA samples were genotyped for the Arg(16)Gly and Glu(27)Gln alleles within the beta(2)AR gene as well as in 64 control samples from blood donors.
Arg(16) allele was slightly more frequent within the group with tachyphylaxis (P=0.039), whereas Gly(16) allele carriers were overrepresented within the group of good responders (59.7%, P=0.028). On the other hand, the allele frequency of Gln(27) and the proportion of Gln(27) carriers was higher within the group with tachyphylaxis (P=0.010 and 0.049, respectively) and Glu(27) allele carriers were overrepresented within the group of good responders (P=0.026). The Arg(16) and Gln(27) alleles were in strong linkage disequilibrium across this locus, resulting in the occurrence of disease haplotype.
The predisposition to develop tachyphylaxis in our population seems to be linked to the Arg(16) and Gln(27) alleles and to the Arg(16)/Gln(27) risk haplotype (positive association between the presence of the Arg(16) and Gln(27) alleles and tachyphylaxis). The Arg(16) allele is perhaps overrepresented due to the strong linkage disequilibrium between both polymorphisms. The presence of the Glu(27) allele seems to be a protective factor against tachyphylaxis in this cohort study.
哮喘决定因素的研究是当前备受关注的课题，尤其是哮喘管理的药物遗传学方面。β₂肾上腺素能受体（β₂AR）基因中影响第16和27位氨基酸的基因多态性与哮喘表型有关，并影响哮喘治疗中使用的支气管扩张剂的反应变异性。这些多态性是否会改变西班牙哮喘患者对β₂激动剂治疗的支气管保护反应尚不清楚。本研究的目的是调查β₂AR基因内的基因多态性是否会调节西班牙哮喘患者对β₂激动剂治疗的个体反应的临床结果以及脱敏的发生情况。
在一项前瞻性病例对照研究中纳入了80例哮喘患者。根据标准标准，将患者分为两组：对β₂激动剂治疗出现快速耐受的患者和反应良好的患者。对β₂AR基因内的Arg(16)Gly和Glu(27)Gln等位基因以及来自献血者的64份对照样本进行基因分型。
在出现快速耐受的组中，Arg(16)等位基因的频率略高（P = 0.039），而Gly(16)等位基因携带者在反应良好的组中占比过高（59.7%，P = 0.028）。另一方面，在出现快速耐受的组中，Gln(27)的等位基因频率和Gln(27)携带者的比例更高（分别为P = 0.010和0.049），而Glu(27)等位基因携带者在反应良好的组中占比过高（P = 0.026）。Arg(16)和Gln(27)等位基因在该位点处于强连锁不平衡状态，导致出现疾病单倍型。
在我们的人群中，出现快速耐受的易感性似乎与Arg(16)和Gln(27)等位基因以及Arg(16)/Gln(27)风险单倍型有关（Arg(16)和Gln(27)等位基因的存在与快速耐受之间呈正相关）。由于这两种多态性之间的强连锁不平衡，Arg(16)等位基因可能占比过高。在这项队列研究中，Glu(27)等位基因的存在似乎是预防快速耐受的保护因素。
