睡眠因素，生物钟基因多态性及其交互作用在原发性高血压发生中作用的研究

The regulation of blood pressure in humans is subjected to circadian variation controlled by the circadian clock system. The circadian locomoter output cycles kaput protein (CLOCK) and brain and muscle Arnt-like protein-1(BMAL1) are the core component of the circadian clock and vital element of the central circadian pacemaker. Animal studies have shown that circadian clock gene polymorphism may be associated with the increased risk of incident essential hypertension (EH). The studies regarding the relationship between sleep duration and quality and EH risk presented conflict 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 diet, physical activity and psychological factors. In addition, All of the studies did not demonstrate the influence of gene susceptibility on the association with sleep and EH. Moreover, there were seldom studies reported the relationship between circadian clock gene polymorphism and EH through human observation study. The potential interaction between sleep factors and circadian clock gene for the risk of EH is still unknown. We hypothesized that genetic variation in the critical circadian clock genes such as CLOCK and BMAL1 may lead to altered protein production or function, and therefor investigate the role of sleep quantity and quality, CLOCK, BMAL1 gene polymorphisms, and their potential interactions in the development of EH. We will perform the Jiujiang Population based Case-control Study for Hpertension(JPCSH), which is focused on the chronic non-communicable diseases, with a detailed face to face survey and anthropometrics, and the collections of blood and 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 EH in China, and will provide guidelines for EH primary prevention, as well as the clues to the biological mechanisms that may explain the putative sleep-EH association.

人体血压水平变化遵循着昼夜节律，生物钟系统在其中起着关键的调节作用。CLOCK与BMAL1基因是生物钟分子系统的重要部分和昼夜节律的起搏点。动物实验提示生物钟系统基因多态性潜在地影响原发性高血压(EH)的发生。与机体昼夜节律紊乱有关的因素如睡眠持续时间与质量等与EH关系的研究结果之间存在分歧，所有研究均未考虑人群易感性的影响可能是分歧原因之一，同时人群流行病研究中，鲜有报道生物钟基因多态性与EH的关系，目前亦未见睡眠因素与生物钟系统相关基因多态性的潜在交互作用与EH发生的关联性研究报道。因此，我们从基因-环境交互作用的角度出发，采用以社区为基础的病例-对照研究，探索睡眠相关因素、生物钟分子系统关键基因（CLOCK与BMAL1）多态性以及他们之间的联合作用在EH发生中的影响。鉴于我国不断上升的EH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。

人体血压水平变化遵循着昼夜节律，生物钟系统在其中起着关键的调节作用。动物实验提示生物钟系统基因多态性潜在地影响原发性高血压(Essential Hypertension, EH)的发生。与机体昼夜节律紊乱有关的因素如睡眠持续时间与质量等与EH关系的研究结果之间存在分歧。因此，我们从基因-环境交互作用的角度出发，采用社区为基础的病例-对照研究，探索1）睡眠相关因素（包括睡眠时间、质量、午睡习惯、夜间睡眠光暴露等）与EH之间的关系；2）生物钟通路关键基因（BMAL1，CLOCK，CRY1，CRY2，CSNK1D，NR1D1，PER1，PER2 ，RORA，RORB，RORC）中的功能性位点SNPs（55个）与EH之间的关系。3）生物钟通路关键基因多态性与睡眠因素的联合作用在EH发生中的作用。本次研究主要结果与结论: 1）夜间睡眠持续时间过长或过短均会增加EH风险(6-7h vs 7-8h, OR=1.42, 95%CI:1.01, 2.00; 8-9h vs 7-8h, OR=1.60, 95%CI:1.07, 2.40;>9h vs 7-8h, OR=2.39, 95%CI: 1.60, 3.58)，午睡习惯可以降低EH发生风险(OR=0.80,95%CI:0.62, 0.97)，联合作用分析显示，在睡眠时间7-8h者中，有午睡习惯者相对于无午睡习惯者，EH发生风险降低(OR=0.64, 95%CI:0.44, 0.92)。2）RORB (rs17060415, rs4376556, rs7846903), NR1D1 (rs4795424), PER1 (rs3027178), PER3 (rs228729), RORC (rs9017)单核苷酸多态性与原发性高血压可能相关。进一步交互作用分析发现，在有午睡习惯者中，携带RORB (rs4376556, rs7846903) GA+AA者，相比于GG者，高血压发生风险均降低，其中rs4376556下降56%（OR=0.44, 95%CI:0.26, 0.73)，rs7846903下降57% (OR=0.43, 95%CI:0.26, 0.72)；3）自制的睡眠因素调查问卷经验证后具有较好的信度与效度，可用于睡眠相关因素与慢性病关系的流行病学研究。