最近研究提示胰岛素样生长因子-1（IGF-1）与心脑血管疾病关系密切。我们通过miRNA筛选并验证高血压患者有3种miRNA（miR-511，miR-520a-3p和miR-1274a）异常表达。生物信息学分析预测，上述miRNA参与了生长激素-胰岛素样生长因子-1（GH-IGF-1）内分泌代谢轴信号通路。目前有关IGF-1信号调控通路其它调控和效应因子及遗传变异与心脑血管疾病的关系少见报道。本课题采用病例对照研究设计,宏观人群研究与分子遗传学研究相结合，通过检测GH、IGF-1、IGF-1受体和IGF-1结合蛋白-3，并分析其遗传变异与血压变化及高血压和脑卒中的关系，应用广义多因子降维法(GMDR)分析基因-基因、基因-环境交互作用，研究结果有助于深入探讨IGF-1信号通路在高血压和脑卒中发病机制中的分子机制，可为高血压及脑卒中临床预后评价提供敏感指标，为筛选治疗药物靶点提供理论依据。

Recent studies indicate that insulin-like growth factor -1 (IGF-1) is significantly associated with cardiovascular and cerebrovascular diseases including hypertension and stroke. We conducted a miRNA screening for hypertension and vivificated 3 kinds of miRNA (miR-511, miR-520a-3p and miR-1274a) presented abnormal expression comparing to control subjects. Further bioinformatics analysis predicted these miRNA might be involved in the signal pathway regulating growth hormone (GH)-insulin-like growth factor -1 (GH-IGF-1) endocrine metabolic axis. Besides IGF-1, there is rarely study investigating the relationship between the regulatory factors of IGF-1 signal pathway as well genetic variation and cardiovascular disease. The project would conduct a case-control study combing population study and molecular genetics, detect GH, IGF-1, IGF-1 receptor and IGF-1 binding protein -3 and analyze and evaluate the association of the genetic variants of these genes with the blood pressure, hypertension and stroke. In addition, the generalized multifactor dimensionality reduction (GMDR) analysis will be used to evaluate gene-gene and gene-environment interaction. The expected results of this study would be helpful to illuminate the molecular mechanism of IGF-1 signaling pathway in the pathogenesis of hypertension and stroke, provide sensitive biomarkers for evaluation of clinical prognosis of hypertension and stroke and theoretical basis for the screening of drug targets.

近年来，大量的动物实验研究发现血清胰岛素样生长因子（IGF-1）作为一种细胞因子，可以调节血管内皮功能障碍和动脉平滑肌细胞增生，并且研究提示GH-IGF-1 信号通路参与了高血压及其靶器官损害的过程，与高血压病及脑卒中有着密切的关系。但是，GH-IGF-1 信号通路与高血压的遗传关联研究却少见报道。本研究采用以社区人群为基础的病例对照和前瞻性研究相结合的研究设计，分析IGF-1信号通路上IGF-1基因、IGF-1R基因、IGFBP-1基因、IGFBP-3基因、GHRL基因、GHRH基因和SST基因共7个基因26个位点的遗传变异与高血压及脑卒中遗传易感性的关系。并探讨IGF-1、 IGF-1R、 IGFBP-1和IGFBP-3 水平与血压变化及高血压、脑卒中的关系。研究发现IGF-1R基因rs1815009（T＞C）、rs2654981（T＞C）和rs13379905（C＞T），IGFBP-3基因rs3110697（G＞A）和rs2132572（C＞T），GHRL基因rs10490816（C＞G）、rs26802（T＞G）和rs2619507（A＞G）的变异与高血压遗传易感性存在显著关联。并且年龄、性别、BMI、吸烟、饮酒和家族史对IGF-1基因、GHRH基因和SST基因变异与高血压的关联效应具有修饰作用。同时还发现IGFBP-1基因rs1874479位点A＞G突变增加脑卒中发病风险。IGFBP-1水平升高可能是高血压的独立危险因素。验证了前期筛选的miR-511编码基因上rs4748424 的A>G变异与高血压存在显著关联。本研究结果为进一步探讨高血压及脑卒中的分子遗传机制提供理论依据。