Insulin resistance-related genes and advanced left-sided colorectal adenoma
Insulin resistance-related genes and advanced left-sided colorectal adenoma
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DOI：
10.1158/1055-9965.epi-06-0849
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发表时间：
2007-04-01
影响因子：
3.8
通讯作者：
Peters, Ulrike
中科院分区：
文献类型：
--
作者：
Gunter, Marc J.;Hayes, Richard B.;Peters, Ulrike
背景：通过大量的机制性和观察性研究，胰岛素抵抗与结直肠肿瘤有关。编码胰岛素途径组分（包括胰岛素（INS）、胰岛素受体（INSR）、胰岛素受体底物-1和胰岛素受体底物-2）的基因的等位基因变体IRS 1和IRS 2与高胰岛素血症和胰岛素抵抗相关，因此可能预测结直肠肿瘤的易感性。我们研究了INS、INSR、IRS 1和IRS 2基因的单核苷酸多态性（SNP）是否与晚期左侧结直肠腺瘤（一种癌症前体）的风险相关。我们分析了一个主要为白人的研究人群中的20个SNP，该研究人群包括766例远端结肠晚期腺瘤患者和771例对照，所有这些患者都接受了可弯曲乙状结肠镜检查，作为前列腺、肺、结直肠和卵巢癌筛查试验筛查臂的一部分。总的来说，我们发现胰岛素信号通路的基因变异和晚期结直肠腺瘤的患病率的作用的证据有限。我们观察到INSR基因型和体重指数（BMI）与结直肠腺瘤患病率之间存在统计学显著的相互作用（总体检验的P值= 0.003）并提示INSR基因型与血糖负荷之间存在相互作用（总体检验的P值= 0.06）;但是，在此情况下，探索BMI和血糖负荷与INSR中单个SNP的相互作用，没有发现一个SNP可以解释这些全球性的显著性。结论：这些研究结果并没有提供强有力的证据表明胰岛素信号通路基因的多态性变异与晚期左侧结直肠腺瘤之间存在关联。INSR变异体与BMI和血糖负荷之间相互作用对晚期左侧结直肠腺瘤风险的证据需要独立确认，并且在更广泛的区域和更大密度下进行INSR基因分型可能是完全阐明这些相互作用的性质所必需的。
Background: Insulin resistance has been linked with colorectal neoplasia through a number of mechanistic and observational studies. Allelic variants of genes encoding components of the insulin pathway, including insulin (INS), insulin receptor (INSR), and insulin receptor substrate-1 and insulin receptor substrate-2 (IRS1 and IRS2) have been associated with hyperinsulinemia and insulin resistance and may, therefore, predict susceptibility to colorectal neoplasia.Methods: We investigated whether single nucleotide polymorphisms (SNP) in the INS, INSR, IRS1, and IRS2 genes are associated with risk of advanced left-sided colorectal adenoma, a cancer precursor. We analyzed 20 SNPs in a largely Caucasian study population comprising 766 cases with advanced adenomas of the distal colon and 771 controls, all of whom had undergone flexible sigmoidoscopy as part of the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.Results: Overall, we found limited evidence for a role of gene variants of the insulin signaling pathway and prevalence of advanced colorectal adenoma. We observed a statistically significant interaction between INSR genotypes and body mass index (BMI) with colorectal adenoma prevalence (P value for global test = 0.003) and suggestion of an interaction between INSR genotypes and glycemic load (P value for global test = 0.06); however, exploration of the interaction of BMI and glycemic load with the individual SNPs in INSR did not suggest a single SNP that may explain the significance of these global tests of interaction and did not yield any consistent patterns.Conclusion: These findings do not provide strong evidence for associations between polymorphic variation in genes of the insulin signaling pathway and advanced left-sided colorectal adenoma. Evidence for interaction between INSR variants and BMI and glycemic load for risk of advanced left-sided colorectal adenoma requires independent confirmation, and genotyping of INSR across a broader region and at greater density may be necessary to fully elucidate the nature of these interactions.