Regarding the beta3-adrenoceptor, several single nucleotide polymorphism (SNP) of beta3-adrenoceptor gene have been identified. Among them, Trp64Arg polymorphism which indicated the exchange of amino acid tryptophan (Trp) at position 64 of the receptor protein for arginine (Arg) has been mostly attracted attention, and a number of studies concerning the SNPs of the gene encoding the beta 3-adrenoceptor have been reported. Our institution has already demonstrated that, in the female cohort, there was significantly more patients with 64Arg variant type (Trp64Arg variant type plus Arg64Arg variant type) in the patients afflicting overactive bladder than in the healthy control. 
    To clarify the role of Trp64Arg polymorphism of the gene encoding the beta 3-adrenoceptor for the lower urinary tract function in male, the present study was conducted to investigate the association between the Trp64Arg polymorphism of beta-3 adrenoceptor gene and the lower urinary tract symptom (LUTS) and function.

This prospective observational study included the patients who underwent robot-assisted radical prostatectomy. Before surgery, blood samples were collected, and analyses of gene polymorphism of 3-adrenoceptor were performed using a real-time polymerase chain reaction. The present cohort was divided into patients with wild type (Trp64Trp) and with variant type (Trp64Arg+Arg64Arg). LUTS and lower urinary tract function before surgery were compared between the wild type and variant type. 
   Blood sampling was done in the preoperative period. Genomic DNA was extracted from whole blood using a TaqMan Sample-to SNP (Applied Biosystems, Waltham, MA, USA). Measurement of SNPs of the gene encoding the beta 3-adrenoceptor were performed using a Step One Real-time polymerase chain reaction (PCR) system (Applied Biosystems) and TaqMan SNP Genotyping Assays (Assay IDs: C__2215549_20, Applied Biosystems). PCR reactions were done according to the manufacturer’s protocol, with a final reaction volume of 10 μl per well. The program used considered an initial step of 10 minutes at 95 °C, followed by 50 cycles at 60 °C of 20 seconds each, and 4 minutes at 60 °C. Allelic discrimination was determined by the Step One software applying the fluorescence probes. The fluorescence values were detected in the FAM channel for allele 1 and the VIC channel for allele 2. The dye used as the passive reference was ROX.
    Sample size calculation was performed according to the preliminary feasible study conducted by Honda et al.1) In their study, the proportion between case and control was one to one. The ratio of the patients with the variant type of the gene encoding the 3-adrenoceptor in the case and control were 47.8% and 22.8%, respectively. Thus, odds ratio was 2.9, and a 2-sided significance level of 5% and a power of 80% were chosen. Thus, this study required a minimum of 62 patients with LUTS. ant type.

During the observational period, 376 patients were collected. Detailed breakdowns were as follows. The number of the patients with wild type (Trp64Trp) was 247, the number of the patients with the heterozygous 64Arg variant type (Trp64Arg) was 114, and the number of the patients with homozygous 64Arg variant type (Arg64Arg) was 15. Thus, 129 patients were categorized into the variant type. There were no significant differences in mean age, BMI, preoperative PSA, Gleason score, prostate size, and prevalence rate of comorbidities, such as hypertension and diabetes mellitus, between the two groups. Expectation ratio of wild type (Trp64Trp), of heterozygous 64Arg variant type (Trp64Arg), and of homozygous 64Arg variant type (Arg64Arg) were 0.652, 0.308, and 0.036, respectively (P=0.15). Thus, these data are consistent with Hardy-Weinberg Equilibrium. 
    Significant changes regarding LUTS were not observed between the two groups. Residual urine volume (PVR) (wild type: variant type = 47±53mL: 58±77mL, P=0.04) and voiding time evaluated by uroflowmetry (wild type: variant type = 29±15sec : 33±17sec, P=0.04) have significantly increased in the variant type.

In the present study, the effect of SNPs of beta-3 adrenoceptor gene on the LUTS and lower urinary tract function were investigated. Concerning the lower urinary tract function, residual urine volume has significantly increased regardless of the significant increase of prostate volume in the variant type. In addition, voiding time has significantly increased, and average flow rate has significantly decreased in the variant type composed of the patients without taking medicine relevant to LUTS. This is a first study to demonstrate the lower urinary tract dysfunction was involved in the gene polymorphism of beta-3 adrenoceptor.

Trp64Arg variant of beta 3- adrenoceptor gene significantly increased of the PVR and voiding time in the male. However, that was not significantly associated with the emergence of LUTS. Thus, because the effect of gene polymorphism of beta-3 adrenoceptor on the genitourinary organ might be weak, whether the objects possess the Trp64Arg variant of beta-3 adrenoceptor gene might not critically affect the urinary quality of life.

Honda, K., Yamaguchi, O., Nomiya, M. et al.: Association between polymorphism of beta3-adrenoceptor gene and overactive bladder. Neurourol Urodyn, 33: 400, 2014