前列腺素 E2 合成和信号转导、前列腺素脱氢酶的遗传变异与结直肠腺瘤风险的关系。
Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma.
机构信息
Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
出版信息
Cancer Epidemiol Biomarkers Prev. 2010 Feb;19(2):547-57. doi: 10.1158/1055-9965.EPI-09-0869. Epub 2010 Jan 19.
BACKGROUND
Prostaglandins are important inflammatory mediators; prostaglandin E2 (PGE2) is the predominant prostaglandin in colorectal neoplasia and affects colorectal carcinogenesis. Prostaglandins are metabolites of omega-6 and omega-3 polyunsaturated fatty acids; their biosynthesis is the primary target of nonsteroidal anti-inflammatory drugs (NSAID), which reduce colorectal neoplasia risk.
METHODS
We investigated candidate and tagSNPs in PGE2 synthase (PGES), PGE2 receptors (EP2 and EP4), and prostaglandin dehydrogenase (PGDH) in a case-control study of adenomas (n = 483) versus polyp-free controls (n = 582) and examined interactions with NSAID use or fish intake, a source of omega-3 fatty acids.
RESULTS
A 30% adenoma risk reduction was observed for EP2 4950G>A (intron 1; OR(GA/AA vs. GG), 0.71; 95% confidence interval, 0.52-0.99). For the candidate polymorphism EP4 Val294Ile, increasing fish intake was associated with increased adenoma risk among those with variant genotypes, but not among those with the Val/Val genotype (P(interaction) = 0.02). An interaction with fish intake was also observed for PGES -664A>T (5' untranslated region; P(interaction) = 0.01). Decreased risk with increasing fish intake was only seen among those with the AT or TT genotypes (OR(>2 t/wk vs. <1 t/wk), 0.56; 95% confidence interval, 0.28-1.13). We also detected interactions between NSAIDs and EP2 9814C>A (intron 1) and PGDH 343C>A (intron 1). However, none of the observed associations was statistically significant after adjustment for multiple testing. We investigated potential gene-gene interactions using the Chatterjee 1 degree of freedom Tukey test and logic regression; neither method detected significant interactions.
CONCLUSIONS
These data provide little support for associations between adenoma risk and genetic variability related to PGE(2), yet suggest gene-environment interactions with anti-inflammatory exposures.
背景
前列腺素是重要的炎症介质；前列腺素 E2（PGE2）是结直肠肿瘤中的主要前列腺素，影响结直肠癌变。前列腺素是 ω-6 和 ω-3 多不饱和脂肪酸的代谢产物；它们的生物合成是非甾体抗炎药（NSAID）的主要靶点，可降低结直肠肿瘤的风险。
方法
我们在腺瘤（n=483）与无息肉对照（n=582）的病例对照研究中，研究了 PGE2 合酶（PGES）、PGE2 受体（EP2 和 EP4）和前列腺素脱氢酶（PGDH）中的候选和标签单核苷酸多态性（SNP），并检查了它们与 NSAID 使用或鱼类摄入（ω-3 脂肪酸的来源）的相互作用。
结果
观察到 EP2 4950G>A（内含子 1；OR（GA/AA 与 GG），0.71；95%置信区间，0.52-0.99）的腺瘤风险降低 30%。对于候选多态性 EP4 Val294Ile，增加鱼类摄入量与变异基因型个体的腺瘤风险增加相关，但 Val/Val 基因型个体则不相关（P（交互作用）=0.02）。PGES-664A>T（5'非翻译区；P（交互作用）=0.01）也观察到与鱼类摄入的相互作用。仅在 AT 或 TT 基因型个体中观察到随着鱼类摄入增加而风险降低（OR（>2 次/周与<1 次/周），0.56；95%置信区间，0.28-1.13）。我们还检测到 NSAIDs 与 EP2 9814C>A（内含子 1）和 PGDH 343C>A（内含子 1）之间的相互作用。然而，在进行多次检验校正后，观察到的关联均无统计学意义。我们使用 Chatterjee 1 自由度 Tukey 检验和逻辑回归法研究了潜在的基因-基因相互作用；两种方法均未检测到显著的相互作用。
结论
这些数据几乎没有提供支持与 PGE（2）相关的腺瘤风险和遗传变异之间的关联的证据，但提示与抗炎暴露的基因-环境相互作用。
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