Association of KLK3 (PSA) genetic variants with prostate cancer risk and PSA levels
Association of KLK3 (PSA) genetic variants with prostate cancer risk and PSA levels
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DOI：
10.1093/carcin/bgr050
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发表时间：
2011-06-01
期刊：
影响因子：
4.7
通讯作者：
Hsu, Stephen I.
中科院分区：
文献类型：
--
作者：
Penney, Kathryn L.;Schumacher, Fredrick R.;Hsu, Stephen I.
全基因组关联研究已经确定了与前列腺癌相关的激肽释放酶相关肽酶3（KLK 3）的遗传标记。然而，这些标志物中的一些也与前列腺特异性抗原（PSA）水平相关，因此尚不清楚多态性是否是因果关系，或者与风险的关联是否仅仅是由于PSA筛查的检测偏倚。PSA是一种生物活性丝氨酸蛋白酶，切割胰岛素样生长因子结合蛋白。我们在1982年开始的医生健康研究中进行了一项病例对照研究，研究了KLK 3单核苷酸多态性（SNP）与前列腺癌风险、疾病特异性生存率和诊断前PSA水平的关系，该研究随访超过27年。我们对跨越整个KLK 3基因座的SNP进行基因分型，以高分辨率捕获常见变异。6个多态性与前列腺癌发病率显著相关（P < 0.05）;每个次要等位基因的优势比范围为0.88至0.73。对于其中的四个，当限制在PSA筛查前（1989年之前）诊断的病例时，优势比较低。与较低PSA水平显著相关的四个等位基因也与较低的前列腺癌风险相关。KLK 3变异与诊断阶段、致死性癌症风险或生存率无显著相关性。我们的研究结果表明，由于KLK 3变异体与PSA水平相关而导致的检测偏倚不能完全解释与前列腺癌风险的相关性。了解KLK 3基因变异影响前列腺癌风险的机制对于研究PSA在前列腺肿瘤发生中的生物学作用具有重要意义。
Genome-wide association studies have identified genetic markers in kallikrein-related peptidase 3 (KLK3) associated with prostate cancer. However, some of these markers are also associated with prostate-specific antigen (PSA) levels, so it is unclear whether the polymorphisms are causal or if the association with risk is solely due to detection bias through PSA screening. PSA is a biologically active serine protease, cleaving insulin-like growth factor-binding protein. We examined the association of single-nucleotide polymorphisms (SNPs) in KLK3 with prostate cancer risk, disease-specific survival and pre-diagnostic PSA levels in a case-control study nested within the Physicians' Health Study, which began in 1982, with over 27 years of follow-up. We genotyped SNPs spanning the entire KLK3 locus to capture common variation at high resolution. Six polymorphisms were significantly associated with prostate cancer incidence (P < 0.05); the odds ratios per minor allele ranged from 0.88 to 0.73. For four of these, the odds ratios were lower when restricting to cases diagnosed in the pre-PSA screening era (before 1989). The four alleles significantly associated with lower PSA levels were also associated with lower prostate cancer risk. KLK3 variants were not significantly associated with stage at diagnosis, risk of lethal cancer or survival. Our results suggest that detection bias due to the association of KLK3 variants with PSA levels cannot completely explain the association with prostate cancer risk. Understanding the mechanism by which genetic variation in KLK3 affects prostate cancer risk has important implications for study of the biological role of PSA in prostate tumorigenesis.