Genetic Variation of the β2-AdrenoceptorIts Functional and Clinical Importance in Bronchial Asthma
作者:
D. Robin Taylor,
Martin A. Kennedy,
期刊:
American Journal of PharmacoGenomics
(ADIS Available online 2001)
卷期:
Volume 1,
issue 3
页码: 165-174
ISSN:1175-2203
年代: 2001
出版商: ADIS
关键词: Asthma;Beta 2 adrenoceptor agonists, pharmacodynamics;Genetic polymorphism;Pharmacogenetics
数据来源: ADIS
摘要:
Asthma is a polygenic disease for which no clear genotype-phenotype relationships have emerged. In contrast, although not associated with the diagnosis of asthmaper se,variant forms of the β2-adrenoceptor (β2-AR) gene (ADRB2) display functional effects that may be clinically relevant. Single nucleotide polymorphisms (SNPs) ofADBR2are common and result in amino acid substitutions at positions 16, 27, and 164 of the receptor as well as position 19 of its 5′ upstream peptide. These SNPs influence receptor functionin vitro, although evidence regarding exact relationships is conflicting. This has raised the possibility that phenotypes such as bronchial hyper-responsiveness (BHR) and responses toβ2-agonist drugs may be genetically determined. To date, no unequivocal relationships between SNPs and phenotype have been identified. In some studies the Gly16allele has been associated with increased BHR and asthma severity. In others, the Arg16allele has been shown to determine acute bronchodilator response and adverse events during long term β2-agonist therapy. The latter may provide the basis for clinical application of this new knowledge. More recently, a small number of frequently occurring, functionally relevantADRB2haplotype pairs have been confirmed. These combinations of alleles may be more important in determining genotype/phenotype relationships than individual SNPs, and may explain why earlier investigations have yielded contrasting results. Future studies will be required to clarify the pharmacodynamic effects ofADRB2haplotypes bothin vitroandin vivo.
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