Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
Int J Cancer. 2012 Dec 1;131(11):2547-52. doi: 10.1002/ijc.27564. Epub 2012 Sep 7.
Rotating night shift work is associated with increased risk of breast cancer, likely via circadian disruption. We hypothesized that circadian pathway genes influence breast cancer risk, particularly in rotating night shift workers. We selected 178 common variants across 15 genes pertinent to the circadian system. Using a mixed candidate- and tag-single nucleotide polymorphism approach, we tested for associations between these variants and breast cancer risk in 1,825 women within the Nurses' Health Study II cohort and investigated potential interactions between genotype and rotating shift-work in a subset of 1,318 women. Multiple-testing-adjusted p-values were obtained by permutation (n = 10,000). None of the selected variants was significantly associated with breast cancer risk. However, when accounting for potential effect modification, rs23051560 (Ala394Thr) in the largest circadian gene, Neuronal PAS domain protein 2 (NPAS2) was most strongly associated with breast cancer risk (nominal test for interaction p-value = 0.0005; 10,000-permutation-based main-effects p-value among women with < 24 months of shift-work = 0.003). The observed multiplicative association with breast cancer risk per minor allele (A) was 0.65 (95% CI = 0.51-0.82) among women with < 24 months of shift-work and 1.19 (95% CI = 0.93-1.54) with ≥ 24 months of shift-work. Women homozygous for the minor allele (AA) with ≥ 24 months of shift-work had a 2.83-times higher breast cancer risk compared to homozygous AA women with < 24 months of shift-work (95% CI = 1.47-5.56). In summary, common variation in circadian genes plays at most a small role in breast cancer risk among women of European ancestry. The impact of NPAS2 Ala394Thr in the presence of rotating shift-work requires further investigation.
轮班工作与乳腺癌风险增加有关，可能是通过扰乱生物钟。我们假设生物钟途径基因会影响乳腺癌风险，特别是在轮班夜工的人群中。我们选择了 15 个与生物钟系统相关的基因中的 178 个常见变体。使用混合候选基因和标签单核苷酸多态性方法，我们在护士健康研究 II 队列中的 1825 名女性中测试了这些变体与乳腺癌风险之间的关联，并在 1318 名女性中调查了基因型与轮班工作之间的潜在相互作用。通过置换（n = 10000）获得了多重检验调整后的 p 值。所选的变体均与乳腺癌风险无显著相关性。然而，当考虑到潜在的效应修饰时，最大的生物钟基因神经元 PAS 域蛋白 2（NPAS2）中的 rs23051560（Ala394Thr）与乳腺癌风险的相关性最强（交互作用的名义检验 p 值=0.0005；在轮班工作时间<24 个月的女性中，基于 10000 次置换的主要效应 p 值=0.003）。在轮班工作时间<24 个月的女性中，每一个 minor 等位基因（A）的多效性关联与乳腺癌风险的比值比（OR）为 0.65（95%置信区间（CI）=0.51-0.82），在轮班工作时间≥24 个月的女性中为 1.19（95% CI = 0.93-1.54）。在轮班工作时间≥24 个月的女性中，携带至少一个 minor 等位基因（AA）的女性患乳腺癌的风险比仅携带 AA 等位基因（AA）且轮班工作时间<24 个月的女性高 2.83 倍（95% CI = 1.47-5.56）。总之，欧洲裔女性中，生物钟基因的常见变异对乳腺癌风险的影响很小。NPAS2 Ala394Thr 在轮班工作中的作用需要进一步研究。
