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 Val379 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 microM) and Thr198 markedly increased (42 microM) KM values compared to the wild type (7 microM); 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.

Association of PLA2G7 polymorphisms with carotid atherosclerosis in hypertensive Japanese

“…16 I198T and A379V were associated with atopy and asthma, probably due to a decrease in the affinity of pPAF-AH for substrate. 17 However, the frequencies and the effects on atherosclerosis of these variants in the Japanese have not been fully examined.…”

Polymorphisms in the interleukin 17F gene (IL17F) and asthma

“…[8][9][10] On the basis of experimental findings and studies of gene expression, IL17F is a good positional candidate gene for asthma. We sequenced IL17F to characterize polymorphisms in this gene.…”

Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A₂ Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a <i>PLA₂G7</i> Gene Polymorphism of Val279Phe

“…9, 10 The prevalence of 279FF was reported to be 0.4%, 1.2%, and 3% in the Chinese, Korean, and Japanese populations, respectively, 11-13 but this variant is rare in non-Asian populations. 14 In a recent meta-analysis including 79,036 participants in 32 prospective studies, Lp-PLA2 activity and mass each showed continuous associations with risk of CAD, similar in magnitude to that with non-high-density lipoprotein cholesterol and systolic blood pressure. 15 In addition, it has been shown that Lp-PLA2 is an independent predictor of cardiovascular disease (CVD) that is not influenced by traditional risk factors or other inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP).…”