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

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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.