Soni Abha, Bansal Anju, Mishra Ashwani Kumar, Batra Jyotsna, Singh Laishram Chandreshwor, Chakraborty Anurupa, Yadav Dhirendra Singh, Mohanty Nayan K, Saxena Sunita
National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, India.
Genet Test Mol Biomarkers. 2012 Aug;16(8):835-40. doi: 10.1089/gtmb.2011.0322. Epub 2012 Jun 25.
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.
据报道，参与雄激素途径和代谢的基因对前列腺癌（CaP）风险有很大影响。本研究调查了印度人群中，与正常健康对照者（n = 106）相比，雄激素受体（AR）、前列腺特异性抗原（PSA或KLK3）和细胞色素P450（CYP19）基因多态性在CaP患者（n = 105）和良性前列腺增生（BPH）患者（n = 120）中的相关性。我们还评估了这些基因变异对AR和PSA mRNA表达的功能影响。观察到AR基因短CAG重复序列（≤24）与CaP风险（优势比[OR]=2.98，p<0.001）和BPH风险（OR=1.96，p=0.01）显著相关；然而，未发现CYP19基因多态性与疾病表型相关（p>0.05）。发现PSA基因G-158A单核苷酸多态性与CaP风险（AA：OR=2.68，p=0.016；GA：OR=2.07，p=0.018）p趋势0.031以及BPH风险（AA：OR=3.46，p<0.001；GA：OR=2.47，p=0.03）p趋势0.009分别显著相关。无论AR CAG重复长度如何，PSA G-158A基因型独立增加了发生BPH的风险（OR=16.37，p<0.001）。使用定量实时聚合酶链反应，我们发现与BPH相比，CaP中AR和PSA mRNA表达显著上调。虽然AR基因短CAG（≤24）重复序列与CaP中较高的AR mRNA表达相关（p=0.002），但PSA单核苷酸多态性与其mRNA表达无关。有趣的是，对于AR基因短CAG和CYP19基因联合基因型（A2A2）（OR=7.18，p<0.001）或A2A3（OR=7.60，p=0.004）的联合分析，观察到CaP的风险估计值显著更高。我们的结果表明雄激素信号基因多态性与CaP和BPH风险显著相关，并为AR CAG重复序列在调节其mRNA表达中的假定功能作用提供了证据，并且有必要在印度人群中进行更大规模的研究以证实我们的结果。
