Slattery Martha L, Samowitz Wade, Hoffman Michael, Ma Khi Ne, Levin Theodore R, Neuhausen Susan
Health Research Center and Department of Pathology, School of Medicine, University of Utah, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108, USA
Cancer Epidemiol Biomarkers Prev. 2004 Apr;13(4):538-45.
Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce risk of colorectal cancer. Although inhibition of cyclooxygenase (COX)-2 is generally thought to be the relevant mechanism, aspirin-like drugs apparently are involved in other pathways and mechanisms. We explore the associations between aspirin/NSAIDs, the insulin-related pathway, and the risk of colorectal cancer.
Genetic polymorphisms of five genes identified as being involved in an insulin-related pathway were genotyped using data collected in a case-control study of 1346 incident colon cancer cases and 1544 population-based controls and 952 incident rectal cancer cases and 1205 controls. Genotypes assessed were the 3' untranslated region poly(A) and the intron 8 BsmI polymorphisms of the VDR gene, a CA repeat polymorphism of the IGF1 gene, the A/C polymorphism at nucleotide -202 of the IGFBP3, the Gly972Arg polymorphism of the IRS1 gene, and the Gly1057Asp polymorphism of the IRS2 gene.
Use of aspirin and NSAIDs was associated with a decreased risk of colorectal cancer, with slightly greater protection from NSAIDs than aspirin for rectal cancer. We observed a significant interaction between IRS1 genotype and aspirin/NSAIDs use and risk of colorectal cancer. Relative to the GR/RR IRS1 genotype, a protective effect from the GG IRS1 genotype was seen in those who did not use NSAIDs; use of NSAIDs was protective for all genotypes. These associations were especially strong for those diagnosed prior to age 65 (P interaction = 0.0006). We also observed a significant interaction between aspirin/NSAIDs use and the VDR gene. Having the SS or BB VDR genotypes reduced risk of colorectal cancer among non-aspirin/NSAID users; however, aspirin/NSAIDs reduced risk for all VDR genotypes.
These data support the protective effect of aspirin and NSAIDs on colorectal cancer risk. In addition, the observed interactions for aspirin/NSAIDs and IRS1 and VDR genotypes suggest that mechanisms other than COX-2 inhibition may be contributing to the protective effect of aspirin and NSAIDs on colorectal cancer risk.
阿司匹林和非甾体抗炎药（NSAIDs）已被证明可降低结直肠癌风险。虽然一般认为抑制环氧化酶（COX）-2是相关机制，但阿司匹林类药物显然还涉及其他途径和机制。我们探讨了阿司匹林/NSAIDs、胰岛素相关途径与结直肠癌风险之间的关联。
利用在一项病例对照研究中收集的数据，对确定参与胰岛素相关途径的五个基因的基因多态性进行基因分型，该研究包括1346例新发结肠癌病例和1544例基于人群的对照，以及952例新发直肠癌病例和1205例对照。评估的基因型包括维生素D受体（VDR）基因的3'非翻译区多聚腺苷酸和内含子8 BsmI多态性、胰岛素样生长因子1（IGF1）基因的CA重复多态性、胰岛素样生长因子结合蛋白3（IGFBP3）核苷酸-202处的A/C多态性、胰岛素受体底物1（IRS1）基因的Gly972Arg多态性以及胰岛素受体底物2（IRS2）基因的Gly1057Asp多态性。
使用阿司匹林和NSAIDs与结直肠癌风险降低相关，对于直肠癌，NSAIDs的保护作用略强于阿司匹林。我们观察到IRS1基因型与阿司匹林/NSAIDs使用以及结直肠癌风险之间存在显著相互作用。相对于GR/RR IRS1基因型，在未使用NSAIDs的人群中，GG IRS1基因型具有保护作用；使用NSAIDs对所有基因型均有保护作用。这些关联在65岁之前诊断出的患者中尤为明显（P相互作用 = 0.0006）。我们还观察到阿司匹林/NSAIDs使用与VDR基因之间存在显著相互作用。具有SS或BB VDR基因型可降低非阿司匹林/NSAIDs使用者的结直肠癌风险；然而，阿司匹林/NSAIDs可降低所有VDR基因型的风险。
这些数据支持阿司匹林和NSAIDs对结直肠癌风险的保护作用。此外，观察到的阿司匹林/NSAIDs与IRS1和VDR基因型之间的相互作用表明，除COX-2抑制作用外的其他机制可能有助于阿司匹林和NSAIDs对结直肠癌风险的保护作用。
