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

Abstract

The human ␤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 ␤2-adrenergic receptor haplotype pairs was determined in vivo by assessing the bronchodilator response to ␤ 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. ␤2-adrenergic receptor mRNA levels and receptor density in cells transfected with the haplotype associated with the greater physiologic response were Ϸ50% 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.

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

“…This has also been demonstrated for the b2-adrenergic receptor and the response to a b2-bronchodilator. 23 Haplotype determination may be of general utility in the identification of diseaseassociated alleles. 32 In a large family study on the impact of genetic variants and the effect of SNPs and haplotypes on baseline lipid levels, a similar observation was made for several genes involved in lipid metabolism, including the CETP gene, where haplotypes derived from SNP combinations resulted in stronger significance of the genotypephenotype association than did individual SNPs.…”

“…This population provides a representative sampling of human genetic variation and serves as a comparative baseline for genotypic analysis of the study population. 23,53 CETP SNPs in these individual samples were discovered and the unphased genotypes were determined by sequencing the polymerase chain reaction (PCR) products of the genomic DNA. A total of 66 SNPs were discovered for the CETP gene, but only a subset of nine (SNPs1-9) was selected to represent coverage across the entire gene (Figure 1).…”

“…Analyses that employ haplotypes, the ordered array of SNP combinations in individual alleles, may enable more consistent and relevant associations. 23,24 In this study, we sought to determine and compare the contribution of individual SNPs and haplotypes in the CETP gene to plasma CETP levels and activity, to lipid levels and to the response to treatment with 3-hydroxy-3-methylglutaray coenzyme A (HMG-CoA) reductase inhibitors (statins) in patients with previously untreated dyslipidemias.…”

Genetic markers of treatment response in rheumatoid arthritis

“…Pharmacogenetic studies in other diseases with different candidate genes provide hope that SNP haplotypes will be helpful in predicting treatment response in RA. For example, in the human ␤ 2 -adrenergic receptor gene, SNP haplotypes, but not individual SNPs, correlate with responses to bronchodilator treatment with a ␤ agonist (22).…”

Clinical implications of pharmacogenetics for glaucoma therapeutics

“…29 Drysdale et al provided evidence to suggest that b 2 -AR haplotypes, which include polymorphisms in the functionally important b 2 -AR 5 0 -cistron leader, predict the bronchodilator response in patients with asthma. 30 The Gly16 and Arg16 alleles have been examined in relation to IOP lowering and exercise. 31 To date, there are no studies reporting on the effect of the functionally important b 2 -AR SNPs in relation to response to b-AR antagonists.…”