Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma.
Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma.
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DOI：
10.1158/1055-9965.epi-09-0869
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发表时间：
2010-02
期刊：
影响因子：
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通讯作者：
Ulrich CM
中科院分区：
文献类型：
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作者：
Poole EM;Hsu L;Xiao L;Kulmacz RJ;Carlson CS;Rabinovitch PS;Makar KW;Potter JD;Ulrich CM
前列腺素是重要的炎症介质; PGE 2是结直肠肿瘤中主要的前列腺素，并影响结直肠癌的发生。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，可降低结直肠肿瘤形成的风险。我们在腺瘤（n=483）与无息肉对照（n=582）的病例对照研究中调查了PGE 2合酶（PGES）、PGE 2受体（EP 2和EP 4）和前列腺素脱氢酶（PGDH）中的候选和tagSNP，并检查了与NSAID使用或鱼类摄入（ω-3脂肪酸的一种来源）的相互作用。对于EP 2 4950 G>A观察到30%的腺瘤风险降低（内含子1; 0 RGA/AA对比GG：0.71; 95%CI：0.52-0.99）。对于候选多态性EP 4 Val 294 Ile，增加鱼类摄入量与变异基因型患者腺瘤风险增加相关，但与瓦尔/瓦尔基因型患者无关（p-交互作用=0.02）。还观察到PGES-664 A>T与鱼摄入量的相互作用（5 'UTR; p-相互作用=0.01）。随着鱼类摄入量的增加，风险降低仅见于AT或TT基因型人群（OR>2 t/wk vs.<1 t/wk：0.56; 95%CI：0.28-1.13）。我们还检测了NSAID与EP 2 9814 C>A（内含子1）和PGDH 343 C>A（内含子1）之间的相互作用。然而，在调整多重检验后，观察到的相关性均无统计学显著性。我们使用Chatterjee 1df Tukey检验和逻辑回归研究了潜在的基因-基因相互作用;两种方法都没有检测到显著的相互作用。这些数据几乎没有支持腺瘤风险与PGE 2相关的遗传变异性之间的关联，但表明基因-环境相互作用与抗炎暴露。
Prostaglandins are important inflammatory mediators; 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 (NSAIDs), which reduce colorectal neoplasia risk. 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) vs. polyp-free controls (n=582) and examined interactions with NSAID use or fish intake, a source of omega-3 fatty acids. A 30% adenoma risk reduction was observed for EP2 4950G>A (intron 1; ORGA/AA vs. GG: 0.71; 95% CI: 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’UTR; 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% CI: 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 1df Tukey test and logic regression; neither method detected significant interactions. These data provide little support for associations between adenoma risk and genetic variability related to PGE2, yet suggest gene-environment interactions with anti-inflammatory exposures.