BMAL1-SCAP-SREBP通路基因和饮食因素与儿童高血压及血压昼夜节律的关联研究

Blood pressure (BP) is closely associated with circadian clock regulation. BMAL1 is the most volatile central clock gene, and notably, its mutation is related to BP. SREBPs and PPARα are peripheral clock genes. However, the relationships between SREBPs & PPARα genes and BP & diurnal BP rhythmicity remain unknown. Based upon physiological studies and bioinformatic analysis with DAVID and KEGG database, SREBPs & PPARα are important genes of BMAL1-SCAP-SREBP pathway. We have preliminarily demonstrated that gene mutation of SCAP, an important interacting protein of SREBPs, could individually affect and interact with dietary behavior to change the BP levels of children. Therefore, we hypothesize that circadian clock theory plays an important role in mediating the associations between BMAL1-SCAP-SREBP pathway genes, dietary factors and BP. In this project, we shall combine the study design of cross-sectional study, prospective nested case-control study, and utilize the numerous technologies, including physical examination, questionnaire investigation, ambulatory blood pressure monitoring and high throughput SNP detection, to explore the associations between BMAL1-SCAP-SREBP pathway genes, dietary factors and BP. Using the cross-sectional study, we will demonstrate the epidemiology characteristics of high BP in children and uncover its related risky dietary factors and gene mutations. In the prospective nested case-control study, we will unveil the diurnal BP rhythmicity in children by Matlab Cosinor method, and we shall determine the individual and interactive effect of BMAL1-SCAP-SREBP pathway genes’ mutations and dietary factors on pediatric high BP. Additionally, we will identify the associations between pathway genes’ mutations, dietary factors and diurnal BP rhythmicity. This project will provide novel molecular mechanisms underlying the circadian clock of pediatric high BP. Moreover, it will offer new concepts for developing the strategies of controlling pediatric high BP in early life.

血压与生物钟密切相关，BMAL1是波动最明显的中枢生物钟基因，其基因变异与血压相关；SREBPs、PPARα为外周生物钟基因，它们与血压及其昼夜节律关联尚不明确。生理学功能研究和生物信息学分析显示，这些基因均为BMAL1-SCAP-SREBP通路重要基因。我们前期工作发现，SREBPs相互作用蛋白SCAP的基因变异与饮食行为对儿童血压有单独和交互效应。据此，我们提出科学假说：生物节律理论可能在该通路、饮食与儿童高血压关联中起重要作用。因此，本项目拟从生物节律角度，通过体检、问卷、动态血压监测、高通量基因变异检测等技术，以横断面研究探索儿童高血压易感基因变异和相关饮食行为及饮食节律；基于前瞻性队列开展巢式病例-对照研究，揭示通路基因变异、饮食因素等对儿童高血压的单独、基因-基因、基因-饮食交互作用，阐明其对血压昼夜节律影响。本项目将为儿童高血压发病提供新的分子机制，并为其早期预防提供新思路。

高血压是全球疾病负担的首位危险因素，探索其病因机制是儿童少年卫生领域的重要科学问题之一。血压与生物钟密切相关，BMAL1是波动最明显的中枢生物钟基因，SREBPs、PPARα为外周生物钟基因。生理学功能研究和生物信息学分析显示，这些基因均为BMAL1-SCAP-SREBP通路重要基因。前期工作发现，SREBPs相互作用蛋白SCAP的基因变异与膳食行为对儿童血压有单独和交互效应。本研究基于横断面研究探索BMAL1-SCAP-SREBP通路基因变异与膳食行为对血压表型的作用，并建立动态血压监测队列探索通路基因变异、膳食行为与24h动态血压指标的关联，通过高通量基因变异监测，筛选与儿童青少年血压相关的基因变异和膳食行为，分析基因-基因和基因-膳食交互作用。主要研究结果：（1）BMAL1/rs3816358与儿童舒张压、SCAP/rs76558868与儿童血压偏高，SREBP1/rs11868035、rs2297508与儿童收缩压相关。（2）基于24h动态血压监测数据，发现大学生24小时、白天以及夜间的血压异常率分别为9.40%、5.7%和22.20%。肥胖相关指标与24h/白天/夜间血压水平相关。蔬菜摄入与内脏脂肪等级对24小时/夜间血压异常存在交互作用。水果摄入与全身脂肪率对24小时血压异常存在交互作用，水果摄入与内脏脂肪等级对白天/夜间血压异常存在交互作用。（3）此外研究发现，BMAL1基因rs3789327、rs3816358与儿童血糖相关，BMAL1/rs3789327并与儿童营养状况具有交互作用影响血糖水平。部分通路相关基因多态性eNOS/rs2070744与儿童血压偏高相关。本项目将为儿童青少年高血压发病提供新的分子机制，并为其早期预防提供新思路。