睡眠因素与MTNR1A、MTNR1B、SNAT基因多态性及其交互作用在乳腺癌发生中作用的研究

Experimental studies have shown that exposure to light at night (LAN) is associated with the increased risk of incident breast cancer by decreasing the production of melatonin by the pineal gland. However, human observational studies as well as our previous study regarding the relationship between LAN exposure, sleep duration, endogenous melatonin levels and female breast cancer risk have yielded conflicting results. Although the discrepancy among studies could be due to many factors including differing exposure measures and study designs, and the lack of adjustments for important covariates such as estrogen-related conditions and smoking, all studies did not account for the influence of individual susceptibility, which may partly affect the consistency within each study. It has been hypothesized that three genes are largely responsible for mediating the downstream effects of melatonin, including melatonin receptors 1A (MTNRlA) and 1B (MTNR1B) which exert an anti-proliferative effect via binding melatonin, and serotonin N-acetyltransferase (SNAT) which is a key enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. We hypothesized that genetic variation in these genes may lead to altered protein production or function, and therefore investigate the role of sleep quantity and quality, LAN exposure, MTNR1A, MTNR1B and SNAT gene polymorphisms, and their potential interactions in the development of female breast cancer, using data from Jiujiang Population-Based Case-control Cancer Study (JPCCS), which is a ongoing population-based case-control study focusing on female cancers of breast and lung, with a detailed face to face survey and anthropometrics, and the collections of blood or exfoliated buccal cell sample and a urine sample for most participants. We believe that the findings of our research may be of significant clinical and public health interests given the increasing trend of female breast cancer in China, and will provide guidelines for breast cancer primary prevention, as well as the clues to the biological mechanisms that may explain the putative sleep-breast cancer association.

动物实验提示夜晚对光的暴露可减少松果体分泌褪黑素从而增加乳腺癌的风险，但国内外关于睡眠时间与质量、睡眠的光照环境、内源性褪黑素水平与女性乳腺癌关系的人群观察性研究（含课题组前期研究）较少且研究结论存在显著分歧，所有研究均未考虑人群易感性的影响可能是造成分歧的原因之一。目前认为褪黑素的抗乳腺癌作用主要是通过与褪黑素受体1A（MTNRlA）及1B（MTNRlB）结合而表现抗增殖作用来实现。此外，5-羟色胺-N-乙酰基转移酶（SNAT）为褪黑素合成的主要限速酶，对体内褪黑素浓度的调节起关键作用。因此课题组从新的角度即基因-环境交互作用的角度出发，利用九江地区在研的以人群为基础的癌症病例-对照研究，探讨与褪黑素通路有关的MTNR1A、MTNR1B、SNAT基因多态性与睡眠因素及其联合作用对乳腺癌的影响。鉴于我国不断上升的乳腺癌发病趋势与现代社会日益突出的睡眠问题，预期结果具有一定的公共卫生学价值。

动物实验提示晚间光暴露可减少松果体分泌褪黑素从而增加乳腺癌的风险，但国内外关于睡眠相关因素与女性乳腺癌关系的人群流行病学研究较少且研究结论存在显著分歧。因此，本课题利用九江地区以人群为基础的乳腺癌病例-对照研究验证以下假设：（1）短时间、低质量睡眠，以及与晚间光暴露等有关的睡眠因素可增加乳腺癌的分发生风险；（2）与褪黑素机制通路有关的基因（MTNRlA、MTNRlB、AANAT）多态性可能与乳腺癌易感性有关，且修饰睡眠相关因素与乳腺癌之间的联系。本次研究主要结果与结论：（1）晚间光暴露、晚睡、频繁夜醒、夜班可显著增加乳腺癌发生风险，而其它睡眠因素似乎与乳腺癌的发生无关；（2）MTNRlB （rs10765576、rs1562444）、AANAT（rs8150）基因多态性与乳腺癌易感性有关，且可能与晚间光暴露对乳腺癌发生存在交互作用。携带AANAT rs8150 GC+CC的女性发生乳腺癌的风险是GG携带者的1.35倍；晚间对光暴露程度较强且携带AANAT rs8150 GC+CC的女性与晚间对光暴露较少且携带GG的女性相比，乳腺癌发生风险增加了1.12倍（OR=2.12, 95%CI：1.06-4.15, Pinteraction=0.09）；晚间对光暴露较强且携带MTNR1B rs10765576 AA+GA (OR=1.98, 95%CI：1.07-2.92, Pinteraction=0.06)或者携带MTNR1B rs1562444 GG+GA (OR=2.47, 95%CI：1.02-4.56, Pinteraction=0.08)的女性分别与晚间对光暴露较少且携带GG或者携带AA的女性相比，乳腺癌的发生风险均有显著性增加；（3）MTNRlA基因多态性似乎与乳腺癌的发生无关，也未发现与睡眠相关因素存在交互作用；（4）自制研发了具有良好信度与效度的睡眠因素问卷SFQ，可用于今后的中国女性人群长期睡眠习惯的流行病学研究。