Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
Department of Toxicology & Pharmacology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Sci Rep. 2018 Nov 8;8(1):16540. doi: 10.1038/s41598-018-34728-6.
Sirtuin 1 (SIRT1) is an energy-sensing protein, which may affect tumorigenesis. We used SIRT1 variants as time-independent indicators of SIRT1 involvement in carcinogenesis and we studied two tagging SIRT1 variants in relation to colorectal cancer (CRC) risk. We also evaluated known energy balance-related CRC risk factors within SIRT1 genotype strata. The Netherlands Cohort Study includes 120,852 individuals and has 20.3 years follow-up (case-cohort: n = 5000; n = 4667). At baseline, participants self-reported weight, weight at age 20, height, trouser/skirt size reflecting waist circumference, physical activity, and early life energy restriction. SIRT1 rs12778366 and rs10997870 were genotyped in toenail DNA available for ~75% of the cohort. Sex- and subsite-specific Cox hazard ratios (HRs) showed that the rs12778366 CC versus TT genotype decreased CRC and colon cancer risks in women (HR = 0.53, 95% confidence interval: 0.30-0.94) but not men. Multiplicative interactions were observed between SIRT1 variants and energy balance-related factors in relation to CRC endpoints, but the direction of associations was not always conform expectation nor specific to one genotype stratum. In conclusion, these results support SIRT1 involvement in colon cancer development in women. No conclusions could be made regarding a modifying effect of SIRT1 variants on associations between energy balance-related factors and CRC risk.
Sirtuin 1（SIRT1）是一种能量感应蛋白，可能会影响肿瘤的发生。我们使用 SIRT1 变体作为 SIRT1 参与致癌作用的时间独立指标，并研究了与结直肠癌（CRC）风险相关的两种标记 SIRT1 变体。我们还在 SIRT1 基因型范围内评估了已知的与能量平衡相关的 CRC 风险因素。荷兰队列研究包括 120852 人，随访时间为 20.3 年（病例对照：n=5000；n=4667）。在基线时，参与者自我报告了体重、20 岁时的体重、身高、反映腰围的裤子/裙子尺寸、身体活动和早年的能量限制。SIRT1 rs12778366 和 rs10997870 基因型在可用于约 75%队列的趾甲 DNA 中进行了检测。性别和亚部位特异性 Cox 风险比（HR）显示，rs12778366 CC 与 TT 基因型降低了女性的 CRC 和结肠癌风险（HR=0.53，95%置信区间：0.30-0.94），但对男性没有影响。在 CRC 终点方面，SIRT1 变体与与能量平衡相关的因素之间观察到了乘法相互作用，但关联的方向并不总是符合预期，也不是特定于某一基因型范围。总之，这些结果支持 SIRT1 参与女性结肠癌的发展。关于 SIRT1 变体对与能量平衡相关因素和 CRC 风险之间的关联的修饰作用，无法得出结论。
