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MPO的氧化能力与涉及Cys残基错义突变的APOE基因多态性的交互作用与高血压严重程度的关联和机制研究

项目来源

国家自然科学基金(NSFC)

项目主持人

刘雅文

项目受资助机构

吉林大学

立项年度

2019

立项时间

未公开

项目编号

81973120

研究期限

未知 / 未知

项目级别

国家级

受资助金额

55.00万元

学科

医学科学-预防医学-非传染病流行病学

学科代码

H-H30-H3010

基金类别

面上项目

关键词

交互作用 ; 载脂蛋白E ; 髓过氧化物酶 ; 高血压 ; 基因多态性 ;

参与者

乔乙春；谷雨璐；刘思宇；李勇；刘云恺；史记康；任亚璇；邱爽；赵倩

参与机构

未公开

项目标书摘要：微血管结构和功能改变是阻碍血流流速、形成高血压的主要原因。MPO和apoE是HDL和LDL结合的蛋白。HDL和LDL从血浆跨过内皮进入外周微血管的细胞间液，导致MPO和apoE与微血管细胞相互作用。MPO的氧化作用改变微血管结构和功能,MPO水平增加与舒张压正关联,MPO水平降低与血压降低相关。涉及Cys残基错义突变的APOE基因多态性决定不同个体apoE抗氧化能力强弱，但是不同个体apoE被氧化状态由MPO氧化能力决定。我们前期研究发现：高血压合并动脉粥样硬化患者血清MPO过氧化体系与LDL的活性醛基渐进性修饰增强相关;APOE基因中突变成无抗氧化能力氨基酸残基的基因多态性位点可能是高血压的危险因素。基于MPO的氧化能力与apoE的抗氧化能力的直接对抗关系，本项目旨在研究HDL和LDL所结合MPO的氧化能力与涉及Cys残基错义突变的APOE基因多态性的交互作用与高血压严重程度的关联和机制

Application Abstract: Myeloperoxidase(MPO)and apolipoprotein E(apoE)are high-density-lipoprotein-binding and low-density-lipoprotein-binding proteins.LDL and HDL transfer from plasma into interstitial fluid across the peripheral vascular endothelium via passive ultrafiltration in humans,reflecting that MPO and apoE interact with microvascular cells.MPO oxidation leads to the changes in microvascular structure and function,conferring hypertension process.Notably,there are two cysteine(Cys)-correlating missense mutations in APOE polymorphisms(rs429358 and rs7412).Cys is susceptible to oxidation to give the disulfide derivative cystine,serving as an important structural and anti-oxidative role.ApoE restricts MPO oxidation,and there are differences in the antioxidant capacity and oxidized state of apoE in different individuals.Our previous investigations indicated that ⑴ the shift from the reaction system of paraoxonase 1 to the peroxidation reaction system of MPO correlates with atherosclerosis;⑵ the peroxidation reaction system of MPO correlated with progressive LDL modifications via reactive aldehydes in atherosclerotic patients with hypertension;and ⑶ APOE genotypes(ε2/ε2 and ε2/ε3)showed a possible association with hypertension,and APOE genotypes(ε3/ε4 and ε4/ε4)had a 2.08-fold risk of developing hypertension.Based on substantial confrontation between MPO oxidation and apoE anti-oxidation,we shall investigate the contribution of interactions between the oxidative capacity of MPO and APOE polymorphism involved in cysteine-missense mutations to the severity of hypertension.

项目受资助省

吉林省

项目结题报告(全文)

微血管结构和功能改变是阻碍血流流速、形成高血压的主要原因。APOE基因中突变成无抗氧化能力氨基酸残基的基因多态性位点可能是高血压的危险因素。我前期发现:ApoE基因型(ε3/ε4和ε4/ε4)可能是高血压的危险因素。由于Cys残基数量的差别，从apoE2、apoE3到apoE4,呈现出明显下降的抗氧化能力，可见apoE2、apoE3和apoE4的功能存在差异。由于apoE无法穿透内皮细胞膜，我们推测apoE与内皮损伤之间可能存在可以穿过内皮细胞膜的中介分子。在本项目的资助下，我们发现miR-3656是apoE2、apoE3和apoE4富集的miR之一，富集程度差异明显,miR-3656是apoE4所致血管内皮损伤差异的中介分子:miR-3656通过靶向eNOS和ADAMTS13诱导血管内皮细胞损伤;miR-3656驱动的KLF10表达抑制是高血压内皮功能障碍的关键机制环节。我们进一步研究eNOS基因多态性与高血压的关系，发现eNOS rs1799983多态性与高血压风险增加相关。我们进行了长春地区高血压流行病学调查研究工作，发现长春市高血压的知晓率、治疗率和控制率均高于中国，说明长春市高血压防治工作是有效的。然而，中国老年人群中高血压的患病率低于长春，这也使得长春对高血压的监管面临巨大挑战。我们研究了老年人高血压前期或高血压向糖尿病发展的发病率及危险因素，发现与高血压前期参与者相比，高血压患者患糖尿病的风险较高。抗高血压药物与高血压患者从非糖尿病到糖尿病的趋势降低有关。同时，我们也研究了老成年居民多发病的社会地理和行为影响，发现高血压家族史和糖尿病家族史与高并发症风险显着相关。

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  • 2.Nexus between genome-wide copy number variations and autism spectrum disorder in Northeast Han Chinese population.

    • 关键词：
    • 0 / MicroRNAs;

    BACKGROUND: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder, with an increasing prevalence worldwide. Copy number variation (CNV), as one of genetic factors, is involved in ASD etiology. However, there exist substantial differences in terms of location and frequency of some CNVs in the general Asian population. Whole-genome studies of CNVs in Northeast Han Chinese samples are still lacking, necessitating our ongoing work to investigate the characteristics of CNVs in a Northeast Han Chinese population with clinically diagnosed ASD.; METHODS: We performed a genome-wide CNVs screening in Northeast Han Chinese individuals with ASD using array-based comparative genomic hybridization.; RESULTS: We found that 22 kinds of CNVs (6 deletions and 16 duplications) were potentially pathogenic. These CNVs were distributed in chromosome 1p36.33, 1p36.31, 1q42.13, 2p23.1-p22.3, 5p15.33, 5p15.33-p15.2, 7p22.3, 7p22.3-p22.2, 7q22.1-q22.2, 10q23.2-q23.31, 10q26.2-q26.3, 11p15.5, 11q25, 12p12.1-p11.23, 14q11.2, 15q13.3, 16p13.3, 16q21, 22q13.31-q13.33, and Xq12-q13.1. Additionally, we found 20 potential pathogenic genes of ASD in our population, including eight protein coding genes (six duplications [DRD4, HRAS, OPHN1, SHANK3, SLC6A3, and TSC2] and two deletions [CHRNA7 and PTEN]) and 12 microRNAs-coding genes (ten duplications [MIR202, MIR210, MIR3178, MIR339, MIR4516, MIR4717, MIR483, MIR675, MIR6821, and MIR940] and two deletions [MIR107 and MIR558]).; CONCLUSION: We identified CNVs and genes implicated in ASD risks, conferring perception to further reveal ASD etiology. © 2023. The Author(s).

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