Genetic variation within the beta1-adrenergic receptor gene results in haplotype-specific expression phenotypes

Journal of Cardiovascular Pharmacology
K M SmallStephen B Liggett

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 ...Continue Reading

References

Apr 23, 1999·The Journal of Biological Chemistry·D A MasonS B Liggett
Mar 10, 2001·Nature Genetics·L Kruglyak, D A Nickerson
Mar 20, 2001·American Journal of Human Genetics·M StephensP Donnelly
Jan 16, 2002·Journal of Cardiovascular Pharmacology·Deborah A RathzStephen B Liggett
Jul 18, 2006·Proceedings of the National Academy of Sciences of the United States of America·Stephen B LiggettMichael R Bristow

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Citations

Jul 19, 2013·Gene·S Abdalla, Y Al-Hadeethi
Jan 19, 2012·Anaesthesia·R LandauJ C Kraft
Dec 1, 2009·Heart Failure Clinics·Stephen B Liggett
Dec 17, 2008·Pharmacological Reviews·Dieter Rosskopf, Martin C Michel
Jun 4, 2010·Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Médicas E Biológicas·A BioloL E Rohde
Dec 1, 2009·Heart Failure Clinics·Guinevere A MurphyMichael R Bristow

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