Complex promoter and coding region beta(2)-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness

The human beta(2)-adrenergic receptor gene has multiple single-nucleotide p olymorphisms (SNPs), but the relevance of chromosomally phased SNPs (haplot ypes) 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 orga nized into 12 haplotypes out of the theoretically possible 8,192 combinatio ns. Deep divergence in the distribution of some haplotypes was noted in Cau casian, African-American. Asian, and Hispanic-Latino ethnic groups with >20 -fold differences among the frequencies of the four major haplotypes. The r elevance of the five most common beta(2)-adrenergic receptor haplotype pair s was determined in vivo by assessing the bronchodilator response to beta a gonist in asthmatics. Mean responses by haplotype pair varied by > 2-fold, and response was significantly related to the haplotype pair (P = 0.007) bu t not to individual SNPs. Expression vectors representing two of the haplot ypes differing at eight of the SNP loci and associated with divergent in vi vo responsiveness to agonist were used to transfect HEK293 cells. beta(2)-a drenergic receptor mRNA levels and receptor density in cells transfected wi th the haplotype associated with the greater physiologic response were appr oximate to 50% greater than those transfected with the lower response haplo type. The results indicate that the unique interactions of multiple SNPs wi thin a haplotype ultimately can affect biologic and therapeutic phenotype a nd that individual SNPs may have poor predictive power as pharmacogenetic l oci.