Genetic Variation Within the β1-Adrenergic Receptor Gene Results in Haplotype-Specific Expression Phenotypes

Abstract

Cardiac beta1-adrenergic receptor (beta1AR) responsiveness in heart failure exhibits interindividual variation that may be attributable to polymorphisms of the intronless beta1AR gene. We sought to ascertain the polymorphisms of the full-length gene and the specific combinations of polymorphisms (haplotypes) in two reference populations. Using whole-gene transfections, we established the impact of beta1AR polymorphisms, within the context of haplotypes, on receptor expression. Fifteen polymorphisms within the 6.1-kb gene with allele frequencies > or =0.05 were found in the 5'-flanking and coding regions, but none in the 3'UTR. These were organized into six common haplotypes. Ethnic-specific and cosmopolitan polymorphisms and haplotypes were noted. Whole-gene transfections of A431 cells revealed an association between haplotype and expression, with as much as twofold differences in expression. Phenotypes clustered into three groups, representing high (two haplotypes), intermediate (three haplotypes), and low (one haplotype) expression. We conclude that the beta1AR gene is highly polymorphic and is commonly found in six haplotypic forms in the population. Receptor expression varies by haplotype, which provides the foundation for cardiovascular association studies with enhanced predictive power using beta1AR haplotypes, or haplotype expression clusters, as compared with individual polymorphisms.

S49G and R389G polymorphisms of the β1-adrenergic receptor influence signaling via the cAMP-PKA and ERK pathways

“…This is important for two reasons. First, glycine is the minor allele at both loci, but there are important racial (14,22). Hence, while the results of this and previous studies in reductionist models that characterize the signaling properties of the S49G polymorphism on a G 389 background are of interest from a theoretical standpoint, the physiological relevance of these findings will require further study.…”

Lack of Association Between Adrenergic Receptor Genotypes and Survival in Heart Failure Patients Treated With Carvedilol or Metoprolol

“…For consistency across patients and sites in this study, we defined the date of catheterization as the index time. Finally, although we examined the most common coding SNPs in ADRA2C, ADRB1, and ADRB2, we cannot exclude that other SNPs in noncoding regions or more extensive haplotypes not tested in this study may be associated with ␤-blocker response in heart failure (25,32,33).…”

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

“…In vitro transfection experiments of whole-gene constructs revealed major differences in ␤ 1 -AR expression levels. At present, it remains open how this translates in altered function in vivo (Small et al, 2008).…”