花生四烯酸脂氧合酶（ALOX）和环氧化酶（COX）基因多态性与结肠癌风险
Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk.
作者信息
Goodman Julie E, Bowman Elise D, Chanock Stephen J, Alberg Anthony J, Harris Curtis C
机构信息
Laboratory of Human Carcinogensis, Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA.
出版信息
Carcinogenesis. 2004 Dec;25(12):2467-72. doi: 10.1093/carcin/bgh260. Epub 2004 Aug 12.
In the human colon, arachidonic acid is metabolized primarily by cyclooxygenase (COX) and arachidonate lipoxygenase (ALOX) to bioactive lipids, which are implicated in colon cancer risk. Several polymorphisms in ALOX and COX genes have been identified, including G-1752A, G-1699A and Glu254Lys in ALOX5; Gln261Arg in ALOX12; Leu237Met and Val481Ile in COX1; and C-645T and Val511Ala in COX2. Because of the significant role of arachidonic acid metabolism in colon cancer, we hypothesized that these polymorphisms could influence susceptibility to colon cancer. We addressed this hypothesis in African-Americans and Caucasians using colon cancer cases (n = 293) and hospital- (n = 229) and population-based (n = 304) control groups. Polymorphisms did not differ between the control groups (P > 0.05); thus, they are combined for all analyses presented. ALOX5 Glu254Lys and COX2 C-645T and Val511Ala allele frequencies differed between Caucasians and African-American controls (P < 0.001). The ALOX5 -1752 and -1699 polymorphisms were in linkage disequilibrium (P < 0.001) and associated with a decreased risk in Caucasians in ALOX5 haplotype analyses (P = 0.03). Furthermore, an inverse association was observed between A alleles at positions -1752 and -1699 of ALOX5 and colon cancer risk in Caucasians, but not in African-Americans. Caucasians with A alleles at ALOX5 -1752 had a reduced odds of colon cancer versus those with G alleles [odds ratio (OR) (GA versus GG), 0.63; 95% confidence interval (CI), 0.39-1.01; OR (AA versus GG), 0.33; 95% CI, 0.07-1.65, P(trend) = 0.02]. Similar results were observed for ALOX5 G-1699A [OR (GA versus GG), 0.59, 95% CI, 0.37-0.94; OR (AA versus GG), 0.27, 95% CI, 0.06-1.32, P(trend) = 0.01]. Statistically significant associations with colon cancer were not observed for the other polymorphisms investigated. We have shown for the first time that a haplotype containing ALOX5 G-1752A and G-1699A in a negative regulatory region of the promoter may influence colon cancer risk in Caucasians.
在人类结肠中，花生四烯酸主要通过环氧化酶（COX）和花生四烯酸脂氧合酶（ALOX）代谢为生物活性脂质，这些脂质与结肠癌风险有关。已鉴定出ALOX和COX基因中的几种多态性，包括ALOX5中的G-1752A、G-1699A和Glu254Lys；ALOX12中的Gln261Arg；COX1中的Leu237Met和Val481Ile；以及COX2中的C-645T和Val511Ala。由于花生四烯酸代谢在结肠癌中具有重要作用，我们推测这些多态性可能影响患结肠癌的易感性。我们在非裔美国人和白种人中，利用结肠癌病例（n = 293）以及医院对照组（n = 229）和基于人群的对照组（n = 304）对这一假设进行了验证。对照组之间的多态性没有差异（P > 0.05）；因此，在所有呈现的分析中，将它们合并在一起。白种人和非裔美国对照组之间，ALOX5 Glu254Lys以及COX2 C-645T和Val511Ala的等位基因频率存在差异（P < 0.001）。ALOX5的 -1752和 -1699多态性处于连锁不平衡状态（P < 0.001），并且在ALOX5单倍型分析中与白种人风险降低相关（P = 0.03）。此外，在白种人中观察到ALOX5 -1752和 -1699位点的A等位基因与结肠癌风险呈负相关，但在非裔美国人中未观察到这种相关性。与具有G等位基因的白种人相比，ALOX5 -1752位点具有A等位基因的白种人患结肠癌的几率降低[优势比（OR）（GA对GG），0.63；95%置信区间（CI），0.39 - 1.01；OR（AA对GG），0.33；95% CI，0.07 - 1.65，P（趋势）= 0.02]。在ALOX5 G-1699A中也观察到了类似结果[OR（GA对GG），0.59，95% CI，0.37 - 0.94；OR（AA对GG），0.27，95% CI，0.06 - 1.32，P（趋势）= 0.01]。对于所研究的其他多态性，未观察到与结肠癌具有统计学意义的关联。我们首次表明，启动子负调控区域中包含ALOX5 G-1752A和G-1699A的单倍型可能影响白种人患结肠癌的风险。
Zotero 插件