Are β3-adrenoceptor gene polymorphisms relevant for urology?

Abstract

Aims β3-adrenoceptors (ARs) are an important drug target for the treatment of overactive bladder syndrome (OAB) and are under investigation for other indications. The human β3-AR gene is polymorphic; an exchange of amino acid tryptophan (Trp) for arginine (Arg) in position 64 of the receptor protein is the most frequent and best-studied polymorphism. A narrative review on the impact of β3-AR polymorphisms on urological disease and its treatment is presented.

Results Two out of four studies have reported that the 64Arg allele was found more frequently in subjects with OAB than in healthy controls. A large study in a highly selective population (men undergoing prostatectomy for cancer treatment) did not confirm this. On the other hand, studies examining symptom severity typically found little difference between 64Arg and 64Trp carriers. In vitro studies with endogenously expressed β3-AR reported a decreased lipolytic response in human adipose tissue. Studies with heterologously expressed receptors sometimes found a decreased responsiveness to agonists including β3-AR agonists, but others did not confirm that.

Conclusions The overall evidence points to carriers of the 64Arg genotype expressing fewer and/or hypofunctional β3-ARs and being associated with the presence of OAB but such findings were only detected inconsistently. If this hypofunctionality exists, the consequences may be of insufficient magnitude to allow a robust detection. Only adequately powered studies comparing responses with a β3-AR agonist in 64Arg carriers versus wild-type patients can address this.