The Ile198Thr and Ala379Val variants of plasmatic Paf-acetylhydrolase impair catalytical activities and are associated with atopy and asthma

Abstract

The platelet-activating factor (PAF) represents a phospholipid with complex biological functions, including involvement in inflammatory processes. The degrading enzyme PAF acetylhydrolase (PAFAH) represents a candidate for asthma and other atopic diseases. Two loss-of-function mutations of PAFAH are associated with severe asthma in Japanese individuals. Our aim was to look for further PAFAH variants in white populations, their possible association with atopic and asthmatic phenotypes, and their functional importance. We picked up three common variants in the PAFAH gene: Arg92His (exon 4), Ile198Thr (exon 7), and Ala379Val (exon 11). The known loss-of-function mutations were not seen. The variant allele Thr198 was found to be highly associated with total IgE concentrations in an atopic population (P = .009) and with 'atopic asthma' in an asthmatic population (P = .008). The variant allele Va1379 was found to be highly associated with 'specific sensitization' in the atopic population (P = .002) and with 'asthma' in the asthmatic population (P = .003). By use of recombinant PAFAH enzymes, the variant Val379 showed increased (14. μM) and Thr198 markedly increased (4.2 μM) K(M) values compared to the wild type (7 μM); furthermore, Vmax of Val379 was highly increased (132%). Thr198 and Val379 influence plasmatic PAFAH toward lower substrate affinities and therefore are very likely to prolong the activities of PAF. At the same time, they are associated with an increased risk to develop asthma and atopy. Thus, two PAFAH variants seem to play a key role in atopic and asthmatic processes in Caucasian populations.