β1-Adrenergic receptor polymorphisms and clinical efficacy of betaxolol hydrochloride in normal volunteers

Objective: To evaluate the relationship between polymorphisms in the gene encoding the beta(1)-adrenergic receptor (beta(1)-AR) and clinical response to betaxolol hydrochloride 0.25% in a small pilot study of normal volunteers. Design: Prospective nonrandomized comparative trial. Participants: Forty-eight consecutive normal volunteers who met all eligibility requirements for inclusion into this study. Methods: Baseline intraocular pressure (IOP) was recorded. Subjects began treatment with betaxolol (1 drop both eyes twice daily) and underwent follow-up IOP recordings at 3 and 6 weeks. Peripheral blood was obtained for genetic analysis. Main Outcome Measures: Response to betaxolol was calculated as the change in mean IOP from baseline (averaged between both eyes and averaged between both follow-up visits). The beta 1-AR genotype was determined by polymerase chain reaction with restriction fragment length polymorphisms at codons 49 (serine [Ser] or glycine [Gly]) and 389 (arginine [Arg] or Gly). Results: There were 32 Ser49 homozygotes and 16 Gly49 carriers. There were no statistically significant differences between the Ser49 homozygotes and the Gly49 carriers with respect to baseline IOP or response to betaxolol therapy. There were 25 Arg389 homozygotes and 23 Gly389 carriers (22 heterozygotes and 1 Gly389 homozygote). As compared with Gly389 carriers, the Arg389 homozygotes had a higher baseline IOP (15.8 mmHg vs. 13.7 mmHg; P = 0.009) and a greater magnitude of response to betaxolol therapy (-3.4 mmHg vs. -1.5 mmHg; P = 0.0009). The Ser49 homozygote genotype was not independently associated with baseline IOP (P = 0.47) or with a response to betaxolol (P = 0.99). The Arg389 homozygote genotype was independently associated with a higher baseline IOP (P = 0.03) and a greater response to betaxolol (P = 0.03), even after adjusting for baseline IOP. Conclusions: In this small pilot series, a single nucleotide polymorphism at codon 389 in the beta(1)-AR seems to correlate with a response to betaxolol therapy in normal, nonglaucomatous volunteers. There was no such correlation at codon 49. The polymorphism at codon 389 may predict short-term response to betaxolol and may serve as a determinant of response to betaxolol and other adrenergic agents in glaucomatous eyes requiring treatment.