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Genetic factors that determine the responsiveness to platelet activating factor and their association with asthma

决定血小板激活因子反应性的遗传因素及其与哮喘的关系

基本信息

批准号：
12670573
负责人：
ASANO Koichiro
金额：
$ 2.11万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Platelet activating factor (PAF) is a lipid mediator which is involved in the pathophysiology of asthma. There is a large inter-subject variation in the responsiveness to PAF, which may explain the inconsistency of anti-asthma effect of PAF antagonists. There are several evidences that suggest PAF responsiveness is partially determined genetically. We examined the genetic variations in a PAF-degrading enzyme, plasma PAF acetylhydrolase, and in the PAF receptor.Approximately 4% of Japanese subjects lack plasma PAF acetylhydrolase genetically. We examined PAF responsiveness using PAF inhalation test in 8 subjects with plasma PAF acetylhydrolase deficiency and 16 subjects with normal enzyme activity. We found a large inter-subject variation in the responsiveness to PAF, however, there was no significant association between plasma PAF acetylhydrolase genotype or activity and PAF responsiveness.We then examined the genetic structure of PAF receptor gene, finding a missense mutation that converts alanine at 224 with aspartic acid in the third intracellular loop. When stably transfected in CHO cells, the mutant receptor demonstrated impaired responses to PAF (Ca^<2+> transient, inositol phosphate turnover, inhibition of CAMP synthesis, and chemotaxis). There was no direct association between this A224D mutation and asthma, but ,t may be associated with PAF antagonist responsiveness.

血小板活化因子（PAF）是一种脂质介质，参与哮喘的病理生理过程。对PAF的反应性存在较大的个体间差异，这可能解释了PAF拮抗剂抗哮喘作用的不一致性。有一些证据表明PAF反应性部分由遗传决定。我们研究了PAF降解酶，血浆PAF乙酰水解酶和PAF受体的遗传变异。大约4%的日本受试者缺乏血浆PAF乙酰水解酶遗传。我们用PAF吸入试验检测了8例血浆PAF乙酰水解酶缺乏症和16例酶活性正常者的PAF反应性。我们发现PAF的反应性存在很大的个体间差异，然而，血浆PAF乙酰水解酶基因型或活性与PAF反应性无显著相关性，然后我们检查了PAF受体基因的遗传结构，发现在第三胞内环224位的丙氨酸与天冬氨酸发生错义突变。在CHO细胞中稳定转染后，突变型受体表现出对PAF的反应受损（Ca^2+瞬变、磷酸肌醇周转、抑制cAMP合成和趋化性）。A224D突变与哮喘无直接关系，但可能与PAF拮抗剂反应性有关。