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

血小板活化因子（PAF）是一种参与哮喘病理生理的脂质介质。对PAF的反应性存在较大的受试者间差异，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的反应性部分是由基因决定的。我们检测了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。我们对8例血浆PAF乙酰水解酶缺乏症患者和16例血浆PAF酶活性正常的患者采用PAF吸入试验检测了PAF的反应性。我们发现受试者对PAF的反应性存在较大差异，然而，血浆PAF乙酰水解酶基因型或活性与PAF反应性之间没有显著关联。然后我们检查了PAF受体基因的遗传结构，发现了一个错义突变，在第三个细胞内环中将丙氨酸与天冬氨酸转化为224。当在CHO细胞中稳定转染时，突变受体表现出对PAF的反应受损（Ca^<2+>瞬态，肌醇磷酸转换，CAMP合成抑制和趋化性）。A224D突变与哮喘无直接关系，但可能与PAF拮抗剂反应性有关。

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.