Association of Androgen Receptor, Prostate-Specific Antigen, andCYP19Gene Polymorphisms with Prostate Carcinoma and Benign Prostatic Hyperplasia in a North Indian Population

Abstract

The genes involved in androgen pathway and metabolism have been reported to contribute considerably to prostate carcinoma (CaP) risk. The present study investigated the association of androgen receptor (AR), prostate-specific antigen (PSA or KLK3), and cytochrome P450 (CYP19) gene polymorphisms in CaP (n=105) and benign prostatic hyperplasia (BPH) (n=120) in comparison to normal healthy controls (n=106) in an Indian population. We also evaluated the functional consequences of these gene variants on AR and PSA mRNA expression. Significant association of short AR CAG repeats (≤24) with risk of CaP (odds ratios [OR]=2.98, p<0.001) and BPH (OR=1.96, p=0.01) was observed; however, CYP19 gene polymorphism was not found to be associated with disease phenotype (p>0.05). PSA G-158A SNP was found to be significantly associated with risk of CaP (AA: OR=2.68, p=0.016 and GA: OR=2.07, p=0.018) p-trend 0.031 and BPH (AA: OR=3.46, p<0.001 and GA: OR=2.47, p=0.03) p-trend 0.009, respectively. PSA G-158A genotype independently increased the risk of developing BPH (OR=16.37, p<0.001), irrespective of AR CAG repeat length. Using quantitative real-time polymerase chain reaction, we found a significant upregulation of AR and PSA mRNA expression in CaP comparison to BPH. While short AR CAG (≤24) repeats were associated with higher AR mRNA expression in CaP (p=0.002), the PSA SNP did not correlate with its mRNA expression. Interestingly, significantly higher risk estimates for CaP were observed for the combined analysis of short AR CAG and CYP19 genotypes (A2A2) (OR=7.18, p<0.001) or A2A3 (OR=7.60, p=0.004). Our results suggest significant association of androgen signaling gene polymorphisms with risk of CaP and BPH and provide evidence for a putative functional role of AR CAG repeat in regulating its mRNA expression and warrant the need of larger studies in the Indian population to confirm our results.

Genetic association between PSA-158G/A polymorphism and the susceptibility of benign prostatic hyperplasia: a meta-analysis

“…Among the rest of 22 studies, 15 more were removed due to letter ( n = 1), review ( n = 1) and without controls ( n = 13). Therefore, a total of 7 independent studies [15–21] were ultimately included in this meta-analysis, containing 758 cases and 752 controls. The principal characteristics of included studies are listed in Table 1.…”

“…In a Turkey population, Gunes et al found an increasing effect of the GG genotype of PSA -158G/A polymorphism on BPH susceptibility, with an age-adjusted OR of 2.77 (95% CI = 1.277-6.012) [20]. On the contrary, Abha Soni et al insisted that the genotypes AA and GA of this polymorphism were significantly related to elevated risk of BPH in their study involving 120 BPH cases and 105 controls in Indians [21]. Whereas, a study by Alptekin and colleagues detected no statistically significant difference in the frequencies of genotypes or alleles of PSA -158G/A polymorphism between controls and BPH cases in Turks, suggesting that the polymorphism might not have independent influence on the disease onset [18].…”

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“…Many studies showed that increased risk of symptomatic BPH and LUTS when deletions of Glutathone S-transferase enzyme genes 18 . Another study demonstrated that 16-fold risk of BPH in the presence of the prostate specific antigen (PSA) G-158A single nucleotide polymorphism 19 .…”

Epidemiology and etiology of benign prostatic hyperplasia and bladder outlet obstruction

“…[39] Another North Indian study demonstrated a 2-fold risk of histologic BPH in men with CAG repeats in the androgen receptor gene and a 16-fold risk in the presence of the prostate specific antigen (PSA) G-158A single nucleotide polymorphism. [40]…”