钠离子转运系统基因与原发性高血压关联性的进化研究

Our ancestors developed in environments characterized by salt scarcity, and efficient physiological and genetic mechanisms were evolved to retain salt. Salt consumption has greatly changed over the millennia, its intake is increasing significantly due to the recent consumption of highly salted industrialized food. Whereas sodium retention is once favorable to survival, it may become deleterious when salt is no longer scarce, by contributing to elevated blood pressure (BP). Therefore, the discrepancy between the comparatively stable genetic background to retain salt and new dietary habit with overdosed salt will lead to various disorders. Epidemiological studies have found that salt intake, usually judged by 24-hour urinary sodium excretion, is closely related with the BP and the subsequent development of essential hypertension (EH). Evidence supports that salt sensitivity, the phenomenon that BP response to changes in salt intake varies considerably among individuals, is partially under genetic control. Furthermore, natural selection signals have been detected on several well-known EH predisposition genes, including AGT, CYP3A5 and GNB3. Taken together, it is logical to hypothesize that BP-related or EH predisposition genes, especially those encoding sodium ion transporters, have undergone a natural selection in our African ancestors. Therefore, it is practically that we can use an evolutionary strategy to screen multiple EH candidates, as guided by the rule that genes under natural selection usually are functionally important and are very potentially EH predisposition genes. This hypothesis has been partially verified by our pioneer study in the well-known RAAS system genes, which obtained two functional single nucleotide polymorphisms (SNPs) from the AGTR1 gene in Chinese EH patients. Furthermore, an efficient and accurate evolutionary methodology has been established accordingly. In this study, we will utilized the founded methodology to screen the sodium ion transport system, which contains 41 genes including those encoding epithelial sodium channels (ENaC), sodium-potassium-ATPase (Na,K-ATPase), sodium channel, voltage-gated channel (NaV) and several solute carrier family members. Furthermore, the entire candidate SNPs will be verified by EH case-control study. Finally, the gene-gene interaction and gene-environment interaction will be examined using both bioinformatic and experimental approaches. Based on these work, we can identify more true genetic risk factor for EH, which will also promote the better understand the roles of dietary salt intake in the mechanism of EH genetic predisposition, and more importantly contributes diagnostic tools for the detection and screening of EH in Chinese populations.

人群流行病学调查发现饮食钠盐摄入与原发性高血压（EH）密切相关，但遗传易感性成因未明。Na+转运系统是连接环境（钠盐）与血压盐敏感性的重要中介，对该系统基因的分子流行病学研究有助于阐明EH的形成机制。环境温度与人体钠盐代谢密切相关，是人类环境适应的重要因素之一。流行病学调查和进化分析均提示环境温度对人类EH遗传易感性的形成具有重要作用。我们在前期通过“进化分析为先导、分子流行病学为主体、功能实验为辅证”的方法筛选了肾素-血管紧张素系统基因，建立了高效、准确的EH易感基因的筛选方法。因此，本研究拟以Na+转运系统所有41个基因作为研究对象，以进化分析获取受环境温度选择的单核苷酸多态性（SNP）；随后通过EH病例-对照研究、基因-基因及基因-环境交互作用分析和功能学研究，明确Na+转运系统基因、环境温度和钠盐摄入在EH遗传易感性形成中的作用。研究结果对EH的临床诊治和人群早期干预具有重要意义。

钠离子转运系统是连接环境（水盐代谢）与血压盐敏感性的重要中介，对该系统基因的分子进化研究有助于阐明原发性高血压（EH）的形成机制。我们在前期通过环境适应性进化选择分析筛选了肾素-血管紧张素系统基因，建立了高效、准确的EH易感基因的检测方法。因此，本研究以钠离子转运系统41个基因作为研究对象，采用经典的分子进化分析方法（iHS和FST）和环境因素关联分析相结合，发现ATP2B1基因的rs2681472在非洲人群中受到环境降水正选择，且亚非人群显著分化。进一步的病例-对照研究证实，非洲祖先型T等位基因与高血压易感性密切相关。该SNP也在多个高血压全基因组关联研究中被证实与高血压或血压性状相关。本研究不仅高效、准确地筛选出该系统中真正的高血压遗传易感因素，更能进一步明确其进化成因，对高血压的发病机制进行进化学上的充分阐释，从而更有效地制定高血压的人群干预策略。