Simons Colinda C J M, Schouten Leo J, Godschalk Roger W, van Engeland Manon, van den Brandt Piet A, van Schooten Frederik J, Weijenberg Matty P
Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
Department of Toxicology, NUTRIM-School for Nutrition and Translational Research on Metabolism, Maastricht University, Maastricht, the Netherlands.
Int J Cancer. 2017 Jan 15;140(2):272-284. doi: 10.1002/ijc.30439. Epub 2016 Oct 18.
The energy restriction (ER)-colorectal cancer (CRC) association is inconsistent in literature. To strengthen the biological plausibility of the ER-CRC association, we investigated whether genetic variation in the insulin-like growth factor (IGF) pathway, a putative underlying mechanism, modulated this association in the Netherlands Cohort Study. Participants completed a questionnaire (n = 120,852) and provided toenail clippings for DNA (∼75%) at baseline. Individuals living in a Western city during the Hunger Winter (1944-45) or Western rural versus non-Western area were exposed to (severe) ER at young age. Genotyping was performed for 3,768 subcohort members and 2,580 CRC cases (case-cohort with 16.3 years follow-up). Cox hazard ratios for CRC were estimated across combined categories of ER and a genetic sum score of unfavorable alleles based on 18 single nucleotide polymorphisms in IGF-related genes and ER and an IGF1 19-CA repeat polymorphism. The reference included ER exposed individuals, so that increased hazard ratios were expected in higher combined categories for calculating relative excess risks due to interaction (additive interactions). Wald tests for multiplicative interactions were also performed. Multiplicative and additive interactions were nonsignificant. Combined ER-genetic sum score categories showed increasing CRC risks in men, but confidence intervals were wide. Women carrying two variant IGF1 19-CA repeat alleles versus those carrying two wild type IGF1 19-CA repeat alleles were at an ∼50% decreased CRC risk, irrespective of ER exposure. In conclusion, data indicate that the IGF pathway might be involved in the ER-CRC association in men, but not women, although interactions were nonsignificant, hampering definite conclusions.
能量限制（ER）与结直肠癌（CRC）之间的关联在文献中并不一致。为了增强ER与CRC关联的生物学合理性，我们在荷兰队列研究中调查了胰岛素样生长因子（IGF）通路中的基因变异（一种可能的潜在机制）是否调节了这种关联。参与者在基线时完成了一份问卷（n = 120,852），并提供了用于DNA检测的趾甲剪片（约75%）。在饥饿冬天（1944 - 1945年）期间生活在西部城市或西部农村与非西部地区的个体在年轻时暴露于（严重的）ER。对3768名亚队列成员和2580例CRC病例进行了基因分型（病例 - 队列，随访16.3年）。基于IGF相关基因中的18个单核苷酸多态性以及ER和IGF1 19 - CA重复多态性，估计了ER和不利等位基因遗传总和评分的组合类别中CRC的Cox风险比。参考组包括暴露于ER的个体，因此在较高的组合类别中预期风险比会增加，以便计算由于相互作用（相加相互作用）导致的相对超额风险。还进行了乘法相互作用的Wald检验。乘法和相加相互作用均无统计学意义。ER - 遗传总和评分的组合类别显示男性患CRC的风险增加，但置信区间较宽。携带两个变异IGF1 19 - CA重复等位基因的女性与携带两个野生型IGF1 19 - CA重复等位基因的女性相比，无论ER暴露情况如何，患CRC的风险降低约50%。总之，数据表明IGF通路可能参与男性而非女性的ER - CRC关联，尽管相互作用无统计学意义，妨碍了得出明确结论。
