Department of Preventive Medicine, Genetic Epidemiology, University of Southern California Keck School of Medicine, NRT 1450 Biggy Street Room 1509A, Los Angeles, CA 90033, USA.
Int J Colorectal Dis. 2012 Dec;27(12):1587-95. doi: 10.1007/s00384-012-1505-8. Epub 2012 May 30.
Insulin, glucose, and other insulin-related proteins that mediate insulin signaling are associated with colorectal neoplasia risk, but associations with common genetic variation in insulin axis genes are less clear. In this study, we used a comprehensive tag single-nucleotide polymorphisms (SNPs) approach to define genetic variation in six insulin axis genes (IGF1, IGF2, IGFBP1, IGFBP3, IRS1, and IRS2) and three genes associated with estrogen signaling (ESR1, ESR2, and PGR).
We assessed associations between SNPs and distal colorectal adenoma (CRA) risk in a case-control study of 1,351 subjects. Cases were individuals with one or more adenomas diagnosed during sigmoidoscopy, and controls were individuals with no adenomas at the sigmoidoscopy exam. We used unconditional logistic regression assuming an additive model to assess SNP-specific risks adjusting for multiple comparisons with P (act).
Distal adenoma risk was significantly increased for one SNP in IGF2 [per minor allele OR = 1.41; 95 % confidence interval (CI) = 1.16, 1.67; P (act) = 0.005] and decreased for an ESR2 SNP (per minor allele OR = 0.78; 95 % CI = 0.66, 0.91; P (act) = 0.041). There was no statistically significant heterogeneity of these associations by race, sex, BMI, physical activity, or, in women, hormone replacement therapy use. Risk estimates did not differ in the colon versus rectum or for smaller (<1 cm) versus larger (>1 cm) adenomas.
These data suggest that selected genetic variability in IGF2 and ESR2 may be modifiers of CRA risk.
胰岛素、葡萄糖和其他介导胰岛素信号的胰岛素相关蛋白与结直肠肿瘤的发生风险相关，但与胰岛素轴基因常见遗传变异的关联尚不清楚。在这项研究中，我们使用了一种全面的标签单核苷酸多态性 (SNP) 方法来定义六个胰岛素轴基因 (IGF1、IGF2、IGFBP1、IGFBP3、IRS1 和 IRS2) 和三个与雌激素信号相关的基因 (ESR1、ESR2 和 PGR) 的遗传变异。
我们在一项 1351 例病例对照研究中评估了 SNP 与远端结直肠腺瘤 (CRA) 风险之间的关联。病例是在乙状结肠镜检查中诊断出一个或多个腺瘤的个体，对照是在乙状结肠镜检查中没有腺瘤的个体。我们使用无条件逻辑回归，假设加性模型来评估 SNP 特异性风险，同时调整多个比较的 P (act) 值。
IGF2 中的一个 SNP 与远端腺瘤风险显著相关[每个次要等位基因的比值比 = 1.41；95%置信区间 (CI) = 1.16, 1.67；P (act) = 0.005]，而 ESR2 SNP 则与远端腺瘤风险降低相关[每个次要等位基因的比值比 = 0.78；95%CI = 0.66, 0.91；P (act) = 0.041]。这些关联在种族、性别、BMI、体力活动以及女性中激素替代疗法的使用方面没有统计学上的显著异质性。风险估计在结肠和直肠之间或在大小（<1 厘米）和较大（>1 厘米）腺瘤之间没有差异。
这些数据表明，IGF2 和 ESR2 中的某些遗传变异可能是 CRA 风险的修饰因子。
