Despite the lack of association between different genotypes and the presence of prostate cancer, endothelial nitric oxide Synthase a/b (eNOS4a/b) polymorphism may be associated with advanced clinical stage and bone metastasis

Objectives: To investigate the relationship between the distribution of endothelial NO synthase (eNOS4a/b) gene polymorphism and clinical features of prostate cancer (PCa). Methods and materials: One hundred thirty-two patients with PCa (mean age 64.10 ± 7.23 years) and 158 healthy controls (mean age 62.50 ± 7.53 years) with normal serum total prostate specific antigen (PSA) levels (<4 ng/ml) and digital rectal examinations (DRE) were enrolled in this prospectively designed study. PCa patients were classified as clinical T1 and T2 stages (Group 1), clinical T3 and T4 stages without bone metastasis (Group 2), and patients with bone metastasis (Group 3). Genotypes (aa, bb, ab) for eNOS4a/b gene polymorphisms were identified by polymerase chain reaction analysis. Meanwhile, plasma nitrate and nitrite levels (NO_x) were used to estimate the amounts of endogenous NO formation for both groups of patients. Results: Despite lack of statistically significant differences between PCa patients and the control group in terms of distribution of genotypes and frequency of alleles, plasma NO_x levels were found to be significantly increased in PCa patients compared with controls. Meanwhile, there was no significant difference between the group of PCa patients with high and low grade tumors (Gleason score ≥ 7 vs < 7) in terms of genotype (aa + ab genotypes or a-allele vs. bb genotype) distribution. However, bb genotype was observed to be present at a higher frequency (85.1% vs. 60%) in Group 1; whereas a-allele was more frequent in Group 2 (13.3% vs. 5.7%) and Group 3 (26.7 vs. 9.2). In addition, patients with a-allele had a 3.79-fold risk of having advanced disease and bone metastasis in comparison with bb genotype. Moreover, multivariable logistic regression analysis revealed that eNOS4a/b polymorphism and plasma NOx levels were predictive factors for developing bone metastasis and high stage disease after adjustment for age and BMI. Conclusions: Our data did not reveal any relationship between any of these genotypes and the presence of PCa. However, the finding that PCa patients with bb genotype generally manifest localized disease and develop bone metastasis less frequently in comparison patients with a-allele may indicate an important role for this polymorphism in the molecular pathophysiology of PCa.