ADAM33基因位点单核苷酸多态性与山东地区支气管哮喘患者的相关性

支气管哮喘(简称哮喘)是一种受环境因素和遗传因素双重影响的疾病,与多基因遗传有关.解整合素-金属蛋白酶33(ADAM33)基因是近年来新发现的ADAM家族成员,与气道高反应性和哮喘密切相关[1].本研究中应用现代分子生物学方法,对ADAM33基因F+1、S2、T2和V4位点多态性进行检测,旨在了解ADAM33基因单核苷酸多态性(SNP)与哮喘的相关性,从而在分子水平探索遗传因素在哮喘发病中的作用.     

ADAM33基因多态性与慢性气道疾病相关研究进展

ADAM33基因位于第20号染色体短臂上(20p13),是ADAM家族的一个成员.ADAM33基因可以影响多种疾病表型.近期研究发现,ADAM33基因在慢性气道疾病中发挥重要作用;ADAM33在间质细胞限制性表达,参与气道结构的改变,与支气管高反应性和加速肺功能下降有关.目前已经确认ADAM33基因是哮喘的易感基因,而该基因与COPD也有关联.ADAM33基因与不同种族及区域人群慢性气道疾病的相关性成为研究热点.本文以ADAM33的结构功能为基础,从哮喘链接到COPD,对ADAM33基因多态性与慢性气道疾病的相关性作一综述.     

ADAM33与支气管哮喘

ADAM33是一种新近发现的ADAM家族成员,其基因的多态性与气道高反应性和支气管哮喘密切相关,该基因表达后影响气道功能更甚于影响气道炎症。显然,理解AD-AM33的功能及其对支气管哮喘的作用,将有助于从新的角度研究支气管哮喘的发病机制,为哮喘诊疗提供新思路。     

ADAM33基因在支气管哮喘中的作用及吸烟对其影响的研究进展

解整合素金属蛋白酶33(ADAM33)基因是一种新近发现的ADAM家族成员,其基因的多态性与支气管哮喘(简称哮喘)、气道高反应性(BHR)及哮喘的严重程度密切相关.该基因还与早期肺功能和第1秒用力呼气容积下降有关.吸烟能增加气道的反应性,使气道重塑,导致哮喘难以控制.已有研究表明吸烟与ADAM33基因多态性相互作用影响哮喘患者的肺功能和BHR.现综述ADAM33基因在哮喘的作用和吸烟对其影响.     

PAI-1基因多态性与支气管哮喘的相关性研究

支气管哮喘(简称哮喘)是一种由遗传因素和环境因素共同作用的变态反应性疾病.遗传因素在哮喘发病中起重要作用,大规模的舣胞胎研究结果显示遗传度在35%～70%[1],这更加确市了遗传因素在哮喘发病机制中的地位.至2004年已发现了 80个相关基因与哮喘有关,几乎涵盖了人类所有染色体,但是并未确定某个基因或某些基因在哮喘发病中起决定性作用.哮喘的基因研究主要从免疫反应过程和炎症过程中细胞表而抗原、细胞因子和细胞受体基因人手.纤溶酶原激活物抑制剂-1(PAI-1)是参与哮喘的气道炎症和气道重塑的细胞因子之一,且其基因多态性可能影响哮喘发病和血浆PAI-1水平.     

解整合素-金属蛋白酶与哮喘

解整合素-金属蛋白酶(a disintegrin and metalloproteinase，ADAM)是近年发现的细胞膜结合糖蛋白家族，属金属蛋白酶家族的亚家族。研究表明，ADAM在体内具有重要的生物学功能，而ADAM33基因核苷酸序列的改变对哮喘发病具有重要影响。本就ADAM33与哮喘发病关系综述如下。     

支气管哮喘患者ADAM33基因S2位点多态性的研究

目的检测ADAM33基因S2位点多态性在支气管哮喘患者中的分布频率,探讨S2位点单核苷酸多态性与支气管哮喘的相关性。方法采用等位基因特异性聚合酶链反应（AS—PCR）技术及DNA测序的方法,对126例哮喘患者及121例健康人进行ADAM33基因S2位点单核苷酸多态性分析。结果ADAM33基因S2位点在哮喘组和对照组中基因型分布均符合Hardy—Weinburg平衡定律;ADAM33基因S2位点3种基因型（CC、CG、GG）在哮喘组分布为64例（50．8％）、45例（35．7％）、17例（13．5％）,在对照组分布为72例（59．5％）、44例（36．4％）、5例（4．1％）,两组比较有统计学差异（x^2=6．929,P〈0．05）。哮喘组与对照组C及G等位基因频率比较差异有显著性（x^2=5．122,P〈0．05）。结论ADAM33基因S2位点在支气管哮喘人群中存在CC、CG、GG多态性;ADAM33基因S2位点多态性与支气管哮喘有明显相关性。     

表观遗传学在支气管哮喘发病机制中的研究进展

气道炎症与气道重塑是支气管哮喘(哮喘)长期反复发作以及病死率逐渐升高的主要原因。近年来,随着对表观遗传学认识的深入,人们逐步发现了表观遗传学在哮喘发生发展中的重要作用。本文综述了DNA甲基化、组蛋白修饰和microRNA基因调控三大表观遗传学在哮喘发病机制中的作用。     

ADAM33基因多态性与支气管哮喘易感性的研究

目的 检测ADAM33基因位点多态性在支气管哮喘(简称哮喘)患者中的分布频率,探讨ADAM33单核苷酸多态性与哮喘的相关性.方法 采用等位基因特异性聚合酶链反应(Allele-Specific Polymerase chain reaction,AS-PCR)技术及DNA测序的方法,对126例哮喘患者及121名健康人进行ADAM33基因F+1、S2、T2和V4位点单核苷酸多态性分析.结果 ADAM33基因位点病例组和对照组中基因型分布均符合Hardy- Weinburg平衡定律;哮喘组与对照组F+1、T2和V4位点基因型比较差异无统计学意义(x2 =1.638,P=0.441＞0.05;x2=1.050,P=0.592＞0.05;x2=0.310,P=0.856＞0.05).哮喘组与对照组S2位点基因型及等位基因频率差异均具有统计学意义(x2=6.929,P＜0.05).根据病情严重程度把哮喘患者分为轻、中、重3组,经非参数检验分析,S2位点x2值为0.335,P=0.855＞0.05,S2位点多态性与哮喘病情严重度差异无统计学意义.方差分析计算基因型构成和肺功能指标FEV1实/预、FVC实/预和FEV1/FVC的关联,S2位点的P值分别为0.255、0.143、0.404,均＞0.05,S2位点多态性与肺功能指标无显著相关性.结论 ADAM33基因位点在哮喘人群中存在多态性;ADAM33基因S2位点基因多态性与哮喘明显相关,与哮喘患者病情严重程度和肺功能没有显著关联.     

Toll样受体与支气管哮喘的相关性研究进展

支气管哮喘（哮喘）是一种发病率较高的免疫性疾病。近年来，尤其在发达国家，发病率有持续升高的趋势，有关其发病机制及治疗策略的研究越来越受到重视。哮喘的本质是由多种炎症细胞、免疫细胞参与的慢性气道炎症，其免疫学基础与Th1和Th2细胞反应失衡密切相关。Toll样受体（TLR）属于模式识别受体，是一个介导天然免疫的跨膜信号转导受体家族，近年来提出的“卫生学假说”提示了TLR与哮喘之间存在密切的关联性，并且哮喘的发病与遗传因素关系密切，而遗传因素可以决定TLR的多态性。目前有关TLR基因的多态性与哮喘相关性的研究不断出现，本文结合近年来众多相关文献，就TLR的信号转导及其多态性与哮喘关系的研究作一综述。     

The genetics of asthma: ADAM33 as an example of a susceptibility gene

The ability to identify novel disease genes by positional cloning led to the identification of a disintegrin and metalloprotease (ADAM)33 gene on chromosome 20p13 as a susceptibility gene for asthma. Case-control and family-based association studies have mostly confirmed a link between ADAM33 and asthma. Its restricted expression to mesenchymal cells as well as its association with bronchial hyperresponsiveness and accelerated decline in lung function over time point strongly to its involvement in the structural airway components of asthma, such as remodeling. Extensive alternative splicing, expression during branching morphogensis in the developing fetus, impaired lung function in childhood, the production of a soluble form linked to chronic asthma, and tight epigenetic regulation indicate a level of complexity in the way ADAM33 influences disease phenotype. Its recent association with chronic obstructive pulmonary disease as well as with asthma and lung development points to functions relating to airway wall modeling and remodeling as a general morphogenetic repair gene rather than being restricted to asthma.     

ADAM33: a newly identified protease involved in airway remodelling

Asthma is a complex disorder in which major genetic and environmental factors interact to both initiate the disease and modify its progression. While asthma is recognised as a disorder of the conducting airways characterised by Th2-directed inflammation, it is being increasingly apparent that alteration of the structural cells of the airways (airway remodelling) is also fundamental to disease chronicity and severity. The gene ADAM33, encoding a novel member of a identified as an asthma susceptibility gene as the result of a positional cloning effort in a cohort of families recruited form the UK and USA. Subsequent genetic studies have now provided evidence that ADAM33 may be involved in determining lung function throughout life, associated with early life lung function as well as increased decline therapeutic intervention in asthma and future work will focus on the mechanisms by which it alters lung function and bronchial hyperresponsiveness.     

Allergic airway inflammation

Several genes, including ADAM33, DPP10, PHF11, GPRA, and TIM-1, have been implicated in the pathogenesis and susceptibility to atopy and asthma. Advances have been made in defining the mechanism for the control of allergic airway inflammation in response to inhaled antigens. There is growing evidence that associates asthma with a systemic propensity for allergic type 2 T-cell cytokines. Disordered coagulation and fibrinolysis could also exacerbate asthma symptoms. Major emphasis on immunotherapy for asthma during the past decade has been to direct the immune response to a type 1 response. Recent literature supports the pivotal role of plasmacytoid dendritic cells and allergen-specific T-regulatory cells in the development of tolerance to allergens. In this review article, we discuss the current information on the pathogenesis of allergic airway inflammation and potential allergen immunotherapies, which could be beneficial in the treatment of airway inflammation, allergy, and asthma.     

A disintegrin and metalloproteinase 33 protein in patients with asthma: Relevance to airflow limitation

BACKGROUND: ADAM33 has been identified as a novel asthma susceptibility gene in genomewide screening and association studies. High-level expression in smooth muscles and fibroblasts suggests that ADAM33 plays a role in airway remodeling in patients with asthma. METHODS: The ADAM33 protein was identified in the bronchoalveolar lavage (BAL) fluids of patients with asthma and normal control subjects using Western blotting antibody against the catalytic domain. ADAM33 expression was analyzed using immunohistochemical staining of mucosal biopsy specimens. The levels of ADAM33 protein in the BAL fluids were measured by dot blotting, and were correlated with the FEV1 values of the patients with asthma. RESULTS: Western blot analysis revealed the presence of the ADAM33 protein, with a molecular mass of approximately 55 kD in the BAL fluids. ADAM33 was expressed in the smooth muscles and basement membranes of almost all the patients with asthma, but was absent in the normal control subjects. The ADAM33 levels were increased significantly in patients with moderate to severe asthma and in patients with mild asthma, as compared with normal control subjects (p = 0.001 and p = 0.016, respectively). The ADAM33 protein levels correlated inversely with the FEV(1)% predicted in the patients with asthma (r = -0.486, p = 0.018). CONCLUSIONS: ADAM33 is associated with asthma development, and the levels of ADAM protein are related to asthma severity.     

Genetic variants of ADAM33 are associated with asthma susceptibility in the Punjabi population of Pakistan

Objective: A disintegrin and metalloproteinase 33 (ADAM33) gene has been considered as an asthma susceptibility gene due to its possible role in airway remodeling, abnormal cell proliferation, and differentiation. Association of this gene with asthma has been reported in several genetic studies on various populations. The current study aims to evaluate the association of ADAM33 gene polymorphisms with the risk of asthma in the Punjabi population of Pakistan. Method: A total of 101 asthma patients and 102 age-matched healthy controls from Lahore, a city in Punjab, were recruited. ADAM33 single nucleotide polymorphisms (SNPs) T?+?1[rs2280089], T2[rs2280090], T1[rs2280091], ST?+?5[rs597980], ST?+?4[rs44707], S2[rs528557], Q???1[rs612709], and F?+?1[rs511898] were genotyped in both patients and controls using single base extension and capillary electrophoresis-based genetic analyzer. The basic allelic and genotypic model was analyzed for association of the SNPs with asthma using SHEsis software. Haploview software was used to calculate pairwise linkage disequilibrium (LD) among six of the genotyped SNPs. Results: Of the 8 SNPs genotyped, only S2[rs528557] showed significant association with asthma (Allele p?=?0.0189, Genotype p?=?0.021). SNPs T?+?1[rs2280089], T2[rs2280090], T1[rs2280091], ST?+?4[rs44707], S2[rs528557], and Q???1[rs612709] were found to be in moderate to strong LD. The significantly higher frequency of haplotype “AAGTCG” in healthy controls suggests a protective effect against asthma risk in the studied population (p?=?0.0059). Conclusion: These findings suggest that genetic variants of ADAM33 gene may play important roles in asthma susceptibility in the Punjabi population of Pakistan.     

细胞自噬在支气管哮喘中的研究进展与展望

自噬是一种溶酶体降解途径,它对于细胞的生存、分化、发展及内环境的稳定起到重要作用.近年来备受关注,但国内外对细胞自噬的研究多集中在肿瘤、神经肌肉、以及免疫系统疾病的研究,少有其在支气管哮喘(简称哮喘)的研究,本文主要对近几年细胞自噬在肺部疾病及哮喘中的研究进展进行综述,从遗传多态性,免疫应答,气道重塑及纤维化三方面,探讨自噬在哮喘发病过程中可能的机制.     

Effects of IFN-γ on cell growth and the expression of ADAM33 gene in human embryonic lung Mrc-5 fibroblasts in vitro

Objective: To investigate the effects of interferon-γ (IFN-γ) on the proliferation and viability of human embryonic lung Mrc-5 fibroblasts in vitro and the expression of the A Disintegrin and Metalloprotease 33 (ADAM33) gene and to explore the mechanism of airway remodeling. Methods: Mrc-5 fibroblasts were sensitized with Dermatophagoides farinae 1 (Derf1) in vitro to mimic in vivo conditions observed in bronchial asthma. An inverted fluorescence microscope was used to observe changes in cell morphology before and after treatment. The viability of Mrc-5 cells was tested using the Cell Counting kit-8 (CCK8). Expression of the ADAM33 gene and protein in Mrc-5 cells was assessed using qPCR and Western blotting, respectively. Results: Different concentrations of Derf1 increased cell growth and the expression of the ADAM33 gene in Mrc-5 cells, and these changes were most obvious in the 10 µg/ml group. In contrast, IFN-γ decreased cell growth and the expression of the ADAM33 gene in both Mrc-5 cells and Derf1-induced Mrc-5 cells, and these changes were most obvious in the 10 ng/ml group. The negative effects of 10 ng/ml IFN-γ were the most significant at 32 hours. Conclusions: Derf1-induced Mrc-5 cells successfully imitated the in vivo conditions observed in patients with asthma. IFN-γ inhibited the proliferation and viability of Mrc-5 cells, and Derf1-induced Mrc-5 cells were more sensitive to IFN-γ treatment. IFN-γ treatment significantly downregulated the expression of the ADAM33 gene in a concentration- and time-dependent manner. IFN-γ may participate in airway remodeling in asthma by regulating the expression of the ADAM33 gene.     

ADAM33 Gene Polymorphisms Associate with Asthma Susceptibility and Severity in East China Han Population

Objective. Multiple genetic and environmental factors impact the pathogenesis of asthma. ADAM33 (a disintegrin and metalloproteinase domain 33) represents a novel susceptibility gene for asthma in several diverse populations. The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of the ADAM33 gene associate with asthma susceptibility and severity in the Chinese Han population. Methods. A total of 224 subjects were enrolled, including 74 normal controls and 150 asthmatic patients. The asthmatic enrollees were further categorized into high- or low-severity groups according to the percentage of forced expiratory volume in 1 second of predicted value, symptoms, nighttime awakening, requirement for short-acting β2-agonist, and interference with normal activities. Six SNPs (F + 1, ST + 4, S1, S2, T1, and T2) in ADAM33 were genotyped using the polymerase chain restriction fragment length polymorphism method. Results. Three SNPs (F + 1, T1, and T2) of ADAM33 were found to have significant associations with asthma in the study population (p = .0058?.0067). The allele frequencies of two SNPs (F + 1, T1) in both the low- and high-severity groups were significantly different from the allele frequency in the control group. The allelic frequency of the T2 SNP was significantly different from that of the control group only in the high-severity group (p = .0081). Haplotype analysis demonstrated that the frequency of 7575G, 12433T, and 12462C (GTC haplotype) is higher in healthy controls than amongst asthma patients (78.4% vs. 61.8%, p = .0004). Conclusions. Polymorphisms of the ADAM33 gene associate with asthma susceptibility in the east China Han population, and the genetic association is stronger in high-severity asthmatics.     

哮喘神经机制的研究进展

支气管哮喘（哮喘）是全球性的严重健康难题，发病机制错综复杂，至今仍不完全清楚。现在被较多学者接受的理论是气道慢性炎症学说、变态反应学说、气道高反应学说以及气道重构学说。其中气道慢性炎症、高反应性和气道重构均涉及到神经机制的参与。越来越多的研究发现神经机制在哮喘气道高反应性中起至关重要的作用，并与免疫机制相互作用，引起神经源性炎症反应。对神经机制的研究可能成为未来攻克哮喘难关的突破点。