Back to Search
Start Over
The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2000 May; Vol. 66 (5), pp. 1522-30. Date of Electronic Publication: 2000 Mar 24. - Publication Year :
- 2000
-
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.
- Subjects :
- 1-Alkyl-2-acetylglycerophosphocholine Esterase
Adolescent
Adult
Alleles
Asthma enzymology
Asthma immunology
Case-Control Studies
Catalysis
Child
Exons genetics
Gene Frequency genetics
Genetic Predisposition to Disease genetics
Genetic Variation genetics
Humans
Hypersensitivity, Immediate enzymology
Hypersensitivity, Immediate immunology
Immunoglobulin E analysis
Kinetics
Linkage Disequilibrium genetics
Phenotype
Phospholipases A antagonists & inhibitors
Phospholipases A isolation & purification
Polymorphism, Genetic genetics
Recombinant Proteins antagonists & inhibitors
Recombinant Proteins genetics
Recombinant Proteins isolation & purification
Recombinant Proteins metabolism
White People genetics
Amino Acid Substitution genetics
Asthma genetics
Hypersensitivity, Immediate genetics
Mutation genetics
Phospholipases A genetics
Phospholipases A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9297
- Volume :
- 66
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 10733466
- Full Text :
- https://doi.org/10.1086/302901