单核苷酸多态性预测前列腺增生发病风险及药物疗效的研究

发布时间：2018-08-05 11:48

【摘要】：目的：良性前列腺增生（benign prostatic hyperplasia, BPH）的发病机制不明确，药物疗效存在个体差异，给个体化治疗的实现带来诸多困难。单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）的研究是成功实现个体化治疗的有力手段。本研究针对与BPH发病及药物疗效有关的基因进行检测分析，旨在寻找与BPH相关联的SNPs，为发病机制和个体化治疗提供研究线索和路标。方法：前瞻性收集新华医院2010年1月～2011年1月间就诊的汉族BPH患者和上海市社区汉族非BPH健康人群的血液标本和相关临床资料，包括一般情况、既往史、前列腺相关指标、相关实验室检查等。根据临床BPH诊断标准将实验对象分为BPH病例组和非BPH对照组；根据BPH患者药物疗效的不同将病例组进一步划分为临床进展组和非进展组。采用经典的病例对照研究设计，使用Affymetrix5.0SNParray平台技术对待测基因SNPs位点进行基因分型，利用AffymetrixBRLMM平台进行基因型判读，最终对所得数据进行遗传统计学关联分析。结果：最终共426例BPH患者（184例为BPH进展组，242例为非进展组）和1008例非BPH健康人群纳入研究。待测基因多态性位点48个，其中1个位点不符合哈温平衡，1个位点MAF0.05，予以剔除，剩余46个位点中与前列腺增生发病风险、临床进展及药物疗效相关的有11个。1）在SRD5A基因中，共有11个标签SNPs位点纳入研究，其中3个位点与药物疗效关联；2）在既往中国汉族前列腺癌研究中发现16个与前列腺体积关联的SNPs，通过本研究发现其中3个位点与BPH的发病风险相关，，3个与BPH药物治疗后发生临床进展相关。3个与药物疗效有关；3）在9个胰岛素抵抗相关基因SNPs位点研究中发现1个与前列腺发病风险相关，2个与药物疗效有关；4）选择了12个与BPH相关的阳性SNPs位点（国外非汉族人群中研究所得），发现1个位点与中国汉族人群BPH药物疗效有关。结论：1）SRD5A1和SRD5A2基因的单核苷酸多态性可以预测BPH药物治疗疗效。2）前列腺癌易感基因突变位点与BPH之间存在关联，可以预测BPH的发病风险和药物疗效。3）胰岛素抵抗相关基因多态性与BPH的发病风险和药物治疗疗效关联。4）基因多态性与BPH的关联性存在种族差异性。
[Abstract]:Objective: the pathogenesis of benign prostatic hyperplasia (BPH) (benign prostatic hyperplasia, BPH) is not clear, and there are individual differences in drug efficacy, which makes it difficult to realize individualized treatment. The study of single nucleotide polymorphisms (Single Nucleotide Polymorphisms, SNPs) is a powerful tool for successful individualized therapy. The purpose of this study was to detect and analyze the genes related to the pathogenesis and drug efficacy of BPH, in order to find the SNPs associated with BPH, and to provide clues and signposts for the pathogenesis and individualized therapy. Methods: blood samples and related clinical data were collected from BPH patients of Han nationality and non-BPH healthy population of Han nationality in Shanghai from January 2010 to January 2011, including general situation, past history and prostate related indexes. Related laboratory inspection, etc. According to the diagnostic criteria of clinical BPH, the experimental subjects were divided into BPH case group and non-BPH control group, and the case group was further divided into clinical progress group and non-progressive group according to the different drug efficacy of BPH patients. The classical case-control study design was used. The genotyping of SNPs loci was performed by using Affymetrix5.0SNParray platform technique, and the genotypic interpretation was carried out by AffymetrixBRLMM platform. Finally, the data were analyzed by genetic statistics association analysis. Results: a total of 426 cases of BPH were included in the study (184 cases were BPH progression group, 242 cases were non-progressive group) and 1008 cases were non-BPH healthy people. Among the 48 polymorphic loci to be tested, one locus did not conform to the Harwin equilibrium, one locus MAF0.05 was excluded, and 11 of the remaining 46 loci were associated with the risk of BPH, clinical progress and drug efficacy) in the SRD5A gene. A total of 11 SNPs loci were included in the study, 3 of which were associated with drug efficacy. 2) Sixteen SNPs associated with prostate volume were found in previous studies of prostate cancer in Chinese Han nationality. In this study, 3 loci were found to be associated with the risk of BPH, and 3 sites were associated with clinical progression after BPH drug therapy. Related to the efficacy of drugs; 3) among 9 SNPs loci of insulin resistance related gene, 1 was associated with prostate risk, and 2 was associated with drug efficacy. 4) 12 positive SNPs loci associated with BPH (obtained from non-Han population abroad) were selected and one locus was found to be related to the efficacy of BPH in Chinese Han population. Conclusion the single nucleotide polymorphisms of SRD5A1 and SRD5A2 genes can predict the efficacy of BPH drug therapy. 2) there is an association between the mutation site of susceptibility gene of prostate cancer and BPH. It can predict the risk of BPH and drug efficacy. 3) there is a racial difference between insulin resistance-associated gene polymorphism and BPH risk and drug therapeutic efficacy. 4) there is a racial difference in the association between the polymorphism and BPH.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R697.3

【共引文献】