Ahn Jiyoung, Albanes Demetrius, Berndt Sonja I, Peters Ulrike, Chatterjee Nilanjan, Freedman Neal D, Abnet Christian C, Huang Wen-Yi, Kibel Adam S, Crawford E David, Weinstein Stephanie J, Chanock Stephen J, Schatzkin Arthur, Hayes Richard B
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Bethesda, MD 20892, USA.
Carcinogenesis. 2009 May;30(5):769-76. doi: 10.1093/carcin/bgp055. Epub 2009 Mar 2.
We systematically investigated the association of 48 SNPS in four vitamin D metabolizing genes [CYP27A1, GC, CYP27B1 and CYP24A1] with serum 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels and the association of these SNPS and an additional 164 SNPS in eight downstream mediators of vitamin D signaling [VDR, RXRA, RXRB, PPAR, NCOA1, NCOA2, NCOA3 and SMAD3] with prostate cancer risk in the 749 incident prostate cancer cases and 781 controls of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. 25(OH)D (all cases and controls) and 1,25(OH)(2)D (a subset of 150 controls) levels were measured by radioimmunoassay and SNP data were genotyped as part of a genome-wide scan. Among investigated SNPS, only four tag SNPS in GC, the major serum 25(OH)D carrier, were associated with 25(OH)D levels; no SNPS were associated with 1,25(OH)(2)D levels. None of the 212 SNPS examined were associated with cancer risk overall. Among men in the lowest tertile of serum 25(OH)D (<48.9 nmol/l), however, prostate cancer risk was related to tag SNPS in or near the 3' untranslated region (UTR) of VDR, with the strongest association for rs11574143 [odds ratio (95% confidence interval) for risk allele carriers versus wild-type: 2.49 (1.51-4.11), P = 0.0007]; the genotype associations were null among men in tertile 2 and tertile 3. Results from the most comprehensive evaluation of serum vitamin D and its related genes to date suggest that tag SNPS in the 3' UTR of VDR may be associated with risk of prostate cancer in men with low vitamin D status.
我们系统地研究了四个维生素D代谢基因[CYP27A1、GC、CYP27B1和CYP24A1]中的48个单核苷酸多态性（SNP）与血清25-羟维生素D[25(OH)D]和1,25-二羟维生素D[1,25(OH)₂D]水平的关联，以及这些SNP和维生素D信号传导的八个下游介质[维生素D受体（VDR）、视黄酸X受体α（RXRA）、视黄酸X受体β（RXRB）、过氧化物酶体增殖物激活受体（PPAR）、核受体辅激活因子1（NCOA1）、核受体辅激活因子2（NCOA2）、核受体辅激活因子3（NCOA3）和SMAD3]中的另外164个SNP与前列腺癌风险的关联，研究对象为前列腺、肺、结肠直肠和卵巢癌筛查试验中的749例前列腺癌新发病例和781例对照。通过放射免疫分析法测定了所有病例和对照的25(OH)D水平以及150例对照亚组的1,25(OH)₂D水平，并将SNP数据作为全基因组扫描的一部分进行基因分型。在研究的SNP中，只有主要血清25(OH)D载体GC中的四个标签SNP与25(OH)D水平相关；没有SNP与1,25(OH)₂D水平相关。所检测的212个SNP总体上均与癌症风险无关。然而，在血清25(OH)D处于最低三分位数（<48.9 nmol/L）的男性中，前列腺癌风险与VDR 3'非翻译区（UTR）内或附近的标签SNP相关，其中rs11574143的关联最强[风险等位基因携带者与野生型的比值比（95%置信区间）：2.49（1.51 - 4·11），P = 0.0007]；在第二和第三三分位数的男性中，基因型关联无统计学意义。来自迄今为止对血清维生素D及其相关基因最全面评估的结果表明，VDR 3'UTR中的标签SNP可能与维生素D水平较低男性的前列腺癌风险相关。
