deCODE genetics, IS-101 Reykjavik, Iceland.
Sci Transl Med. 2010 Dec 15;2(62):62ra92. doi: 10.1126/scitranslmed.3001513.
Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
测量前列腺特异性抗原（PSA）的血清水平是前列腺癌最常见的筛查方法。然而，PSA 水平除了受肿瘤影响外，还受到许多其他因素的影响。值得注意的是，在普通人群中，PSA 水平的大约 40%的变异性是由遗传因素决定的，这表明通过调整遗传效应的测试结果，可能提高敏感性和特异性。为了寻找与 PSA 水平相关的序列变异，我们对来自 15757 名冰岛人和 454 名英国未被诊断患有前列腺癌的男性的 PSA 信息进行了全基因组关联研究和后续分析。总的来说，我们在六个基因座上检测到 PSA 水平与单核苷酸多态性（SNP）之间存在全基因组显著关联：5p15.33（rs2736098），10q11（rs10993994），10q26（rs10788160），12q24（rs11067228），17q12（rs4430796）和 19q13.33 [rs17632542（KLK3：I179T）]，每个基因座的 P（综合）均<3×10(-10)。在 3834 名接受前列腺活检的男性中，与 PSA 水平升高相关的 10q26、12q24 和 19q13.33 等位基因与阴性活检的可能性更高相关（比值比在 1.15 到 1.27 之间）。在来自冰岛、荷兰、西班牙、罗马尼亚和美国的 5325 例病例和 41417 例对照中评估六个基因座与前列腺癌风险之间的关联表明，10q26 和 12q24 上的 SNP 仅与 PSA 水平相关，而其他四个基因座也与前列腺癌风险相关。我们提出，在决定进行前列腺活检时，应根据基因型使用个性化 PSA 截止值。
