Interaction between single nucleotide polymorphisms in selenoprotein P and mitochondrial superoxide dismutase determines prostate cancer risk.
Interaction between single nucleotide polymorphisms in selenoprotein P and mitochondrial superoxide dismutase determines prostate cancer risk.
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DOI：
10.1158/0008-5472.can-08-1827
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Rayman MP
中科院分区：
文献类型：
--
作者：
Cooper ML;Adami HO;Grönberg H;Wiklund F;Green FR;Rayman MP
硒可能通过其血浆载体硒蛋白P影响前列腺癌(PC)的风险，该蛋白在前列腺癌肿瘤和细胞系中的表达显著降低。硒蛋白P(SEPP1)Ala234SNP等位基因与男性血浆硒蛋白P降低有关，从而降低其他抗氧化性硒蛋白的浓度/活性。硒状态还会改变线粒体超氧化物歧化酶(SOD2)SNP Ala16Val对PC风险的影响。我们调查了这些SNP与PC风险的关系。来自瑞典前列腺癌人群研究(CAPS)的2,975例患者和1,896名年龄匹配的对照组的DNA使用TaqMan®分析进行了基因分型。根据临床标准诊断为侵袭性(APC)或非侵袭性(NPC)。用Logistic回归分析与PC的相关性；用一般线性模型研究基因-基因交互作用。16 9名健康体检者的平均血浆硒水平较低(76.0±17.2μg/L)。SNP基因分布符合Hardy-Weinberg平衡。与SOD2-Val16纯合子相比，SOD2-Ala16+男性患前列腺癌的风险更高(OR 1.19，95%可信区间1.03-1.37)。同时携带SOD2-Ala16+的SEPP1-Ala234纯合子患PC(OR 1.43，95%CI 1.17~1.76)和APC(OR 1.60，95%CI 1.22~2.09)的危险性高于SOD2-Val16纯合子(交互作用，PC P=0.05，APC P=0.01)。这种交互作用在吸烟者中更强：Sod2-Ala16+SEPP1-Ala234纯合子男性患PC的风险几乎增加一倍(OR1.97，95%CI1.33-2.91；交互作用P=0.001)。在低硒人群中，SEPP1-Ala234纯合子SOD2-Ala16+男性患前列腺癌/APC的风险增加，特别是如果经常吸烟，因为他们可能产生更多无法清除的线粒体过氧化氢，从而促进前列腺肿瘤细胞的增殖和迁移。
Selenium may affect prostate-cancer (PC) risk via its plasma carrier selenoprotein P which shows dramatically reduced expression in PC tumors and cell-lines. The selenoprotein P (SEPP1) Ala234 SNP allele is associated with lower plasma selenoprotein P in men, reducing the concentration/activity of other antioxidant selenoproteins. Selenium status also modifies the effect of mitochondrial superoxide dismutase (SOD2) SNP Ala16Val on PC risk. We investigated the relationship of these SNPs with PC risk. DNA from 2,975 cases and 1,896 age-matched controls from the population-based Prostate Cancer in Sweden (CAPS) study were genotyped using TaqMan® assays. Cases were designated aggressive (APC) or non-aggressive (NPC) at diagnosis by clinical criteria. Association with PC was investigated by logistic regression; gene-gene interaction using a general linear model. Mean plasma selenium measured in 169 controls was relatively-low (76.0±17.2μg/L). SNP genotype-distributions were in Hardy-Weinberg Equilibrium. SOD2-Ala16+ men were at greater PC risk (OR 1.19, 95%CI 1.03-1.37) compared to SOD2-Val16 homozygotes. Men homozygous for SEPP1-Ala234 who were also SOD2-Ala16+ had a higher risk of PC (OR 1.43, 95%CI 1.17-1.76) and APC (OR 1.60, 95%CI 1.22-2.09) than those who were SOD2-Val16 homozygotes (interaction, PC P=0.05, APC P=0.01). This interaction was stronger in ever-smokers: SOD2-Ala16+ men homozygous for SEPP1-Ala234 had an almost doubled risk of PC (OR 1.97, 95%CI 1.33-2.91; interaction P=0.001). In a low selenium population, SOD2-Ala16+ men homozygous for SEPP1-Ala234 are at increased risk of PC/APC especially if ever-smokers, because they are likely to produce more mitochondrial H2O2 that they cannot remove, thereby promoting prostate tumor-cell proliferation and migration.