Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness
Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness
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DOI：
10.1073/pnas.97.19.10483
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发表时间：
2000-09-12
影响因子：
11.1
通讯作者：
Liggett, SB
中科院分区：
文献类型：
--
作者：
Drysdale, CM;McGraw, DW;Liggett, SB
人类β 2肾上腺素能受体基因具有多个单核苷酸多态性（SNP），但染色体定相SNP（单倍型）的相关性尚不清楚。在多种族参考人群和哮喘队列中描述了5'上游和ORF变异的遗传学和体外和体内后果。在理论上可能的8，192种组合中，发现13种SNP被组织成12种单倍型。在高加索人、非洲裔美国人中，一些单倍型的分布存在很大差异。亚洲人和西班牙裔-拉丁裔种族群体的四种主要单倍型的频率之间的差异>20倍。通过评估哮喘患者对β受体激动剂的支气管扩张反应，确定了5种最常见的β（2）-肾上腺素能受体单倍型对的相关性。单倍型对的平均应答变化> 2倍，并且应答与单倍型对显著相关（P = 0.007），但与单个SNP无关。代表在8个SNP基因座上不同的两种单倍型的表达载体被用于转染HEK 293细胞，所述表达载体与对激动剂的不同体内反应性相关。在用与更大生理反应相关的单倍型转染的细胞中，β 2肾上腺素能受体mRNA水平和受体密度比用较低反应单倍型转染的细胞高约50%。结果表明，一个单倍型内的多个SNP的独特相互作用最终会影响生物学和治疗表型，并且单个SNP作为药物遗传学位点的预测能力可能较差。
The human beta(2)-adrenergic receptor gene has multiple single-nucleotide polymorphisms (SNPs), but the relevance of chromosomally phased SNPs (haplotypes) is not known. The phylogeny and the in vitro and in vivo consequences of variations in the 5' upstream and ORF were delineated in a multiethnic reference population and an asthmatic cohort. Thirteen SNPs were found organized into 12 haplotypes out of the theoretically possible 8,192 combinations. Deep divergence in the distribution of some haplotypes was noted in Caucasian, African-American. Asian, and Hispanic-Latino ethnic groups with >20-fold differences among the frequencies of the four major haplotypes. The relevance of the five most common beta(2)-adrenergic receptor haplotype pairs was determined in vivo by assessing the bronchodilator response to beta agonist in asthmatics. Mean responses by haplotype pair varied by > 2-fold, and response was significantly related to the haplotype pair (P = 0.007) but not to individual SNPs. Expression vectors representing two of the haplotypes differing at eight of the SNP loci and associated with divergent in vivo responsiveness to agonist were used to transfect HEK293 cells. beta(2)-adrenergic receptor mRNA levels and receptor density in cells transfected with the haplotype associated with the greater physiologic response were approximate to 50% greater than those transfected with the lower response haplotype. The results indicate that the unique interactions of multiple SNPs within a haplotype ultimately can affect biologic and therapeutic phenotype and that individual SNPs may have poor predictive power as pharmacogenetic loci.