Molecular Pathophysiology of Asthma: Relationship between β2-adrenergic receptor gene polymorphisms and pathophysiology of bronchial asthma

哮喘的分子病理生理学：β2-肾上腺素受体基因多态性与支气管哮喘病理生理学的关系

• 批准号: 09470144
• 负责人: MUNAKATA Mitsuru
• 金额: $ 8.19万
• 依托单位: Fukushima Medical University (1999)Hokkaido University (1997-1998)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470144/
• 关键词: bronchial asthma; molecular pathophysiology; polymorphism; β2-adrenoceptor; regular inhalation therapy; c-AMP; racial difference; β_2-アドレナリン受容体遺伝子; PCR; β_2-刺激薬定期吸入療法; 受容体down regulation; ARMS; βz-アドレナリン受容体遺伝子

2. With the established ARMS methods, genotypes of 150 healthy controls and 178 asthmatics. However, in asthmatics, Gly16/Gly16 genotype was related to the severity of asthma and the use of methylxanthin in their treatment. In addition, there was a significant racial differences in methylxanthin in their treatment. In addition, there was a significant racial differences in genotypes. In Japanese, Glu27/Glu27 genotype is extremely rare and only 1% of population has this genotype.Relationships between β2-adrenergic receptor gene polymorphisms and pathophysiology of bronchial asthma were examined and the following results were obtained.1. The ARMS method for the determination of genotype of nucleotide 46, 79 and 523 was established by applying both sequence specific PCR and direct sequencing with di-deoxi method.3. Isoproterenol induced c-AMP response of peripheral mononuclear (PMN) cells were examined. There was no difference in ECィイD250ィエD2 among nucleotide 46 genotype (Arg16 or Gly16), however, Gly16/Gly16 genotype showed relatively weak maximum response compared to other genotypes (P<0.1).4. The effects of 2 weeks-regular inhalational therapy with β2-agonist were examined in 19 asthmatic patients. Patients with Gly16/Gly16 genotype showed significant decrease in baseline FEV1, PCィイD220ィエD2-methacholine and c-AMP responses to inhaled salbutamol after treatment, suggesting that receptor down-regulation may be induced after long-term β2-agonist therapy and may cause worsening of asthma in this genotype.These results suggest that β2-adrenergic receptor gene polymorphisms are one of the genetic background which modify the clinical characteristics of bronchial asthma and the effectiveness of β2-agonist treatment.

2.应用已建立的ARMS方法，对150例健康对照者和178例哮喘患者进行基因分型。然而，在哮喘患者中，Gly 16/Gly 16基因型与哮喘的严重程度和治疗中使用甲基黄嘌呤有关。此外，甲基黄嘌呤在其治疗中存在显著的种族差异。此外，在基因型上存在显著的种族差异。在日本，Glu 27/Glu 27基因型极其罕见，只有1%的人群具有该基因型。我们研究了β2-肾上腺素能受体基因多态性与支气管哮喘病理生理学的关系，得到以下结果。1.采用序列特异性PCR和双脱氧直接测序法，建立了ARMS检测46、79和523位核苷酸基因型的方法.观察异丙肾上腺素诱导的外周血单个核细胞（PMN）cAMP反应。核苷酸46基因型（Arg 16或Gly 16）间EC最大反应D250和D2无差异，但Gly 16/Gly 16基因型的最大反应较其他基因型弱（P<0.1）.本文报告19例哮喘患者定期吸入β_2受体激动剂2周的疗效。Gly 16/Gly 16基因型患者治疗后对沙丁胺醇的基线FEV 1、PC、D220、D2-乙酰甲胆碱和c-AMP反应显著降低，提示长期β2-受体激动剂治疗后可能诱导受体下调，并可能导致该基因型哮喘的恶化。这些结果提示β2-受体激动剂治疗可能导致哮喘的恶化。肾上腺素能受体基因多态性是影响支气管哮喘临床特征和β2受体激动剂治疗效果的遗传背景之一。

项目成果

MUNAKATA,M.: "Genetic aspects of bronchial asthma"Medical Practice. 15. 1873-1876 (1998)

MUNAKATA,M.：“支气管哮喘的遗传方面”医学实践。

棟方 充: "呼吸器患者の分子生物学 : β2-アドレナリン受容体"医学書院. 447 (1998)

Mitsuru Munakata：“呼吸系统患者的分子生物学：β2-肾上腺素受体”Igaku Shoin 447 (1998)。

MUNAKATA,M., et al.: "Pulmonary dysanapsis, methacholine airway responsiveness, and sensitization to airborne antigen"Respirology. 3. 113-118 (1997)

MUNAKATA，M.，等人：“肺呼吸衰竭、乙酰甲胆碱气道反应性和对空气传播抗原的敏化”呼吸学。

MUNAKATA,M., et al.: "Concept, Definition, and Diagnosis of Bronchial Asthma"Asian Med J. 40. 236-242 (1997)

MUNAKATA，M.，等：“支气管哮喘的概念、定义和诊断”Asian Med J. 40. 236-242 (1997)

MUNAKATA,M.: "Differential diagnosis of airway obstruction by cardiac failure and bronchial asthma"Kokyuto Junkan. 45. 13-18 (1997)

MUNAKATA,M.：“心力衰竭和支气管哮喘引起的气道阻塞的鉴别诊断”Kokyuto Junkan。