Alternative titles; symbols
HGNC Approved Gene Symbol: PLA2G7
Cytogenetic location: 6p12.3 Genomic coordinates (GRCh38): 6:46,704,201-46,735,721 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
6p12.3 | Platelet-activating factor acetylhydrolase deficiency | 614278 | Autosomal recessive | 3 |
The PLA2G7 gene encodes platelet-activating factor (PAF) acetylhydrolase (EC 3.1.1.47), a secreted enzyme that catalyzes the degradation of PAF to inactive products by hydrolysis of the acetyl group at the sn-2 position, producing the biologically inactive products LYSO-PAF and acetate.
Tjoelker et al. (1995) isolated a cDNA encoding the human plasma PAF acetylhydrolase from a macrophage cDNA library. The deduced 441-amino acid protein has a molecular mass of 44 kD with a putative hydrophobic signal peptide within the first 20 residues and a Gly-Xaa-Ser-Xaa-Gly (GXSXG) motif characteristic of lipases and esterases. Northern blot analysis detected a 1.8-kb mRNA in thymus, tonsil, and placenta, and Tjoelker et al. (1995) concluded that macrophages are the primary source of PAF acetylhydrolase. In vitro studies showed that differentiated macrophages, but not freshly isolated monocytes, secreted the enzyme.
Stafforini et al. (1996) determined that the PLA2G7 gene contains 12 exons.
By fluorescence in situ hybridization, Stafforini et al. (1996) mapped the PLA2G7 gene to chromosome 6p21.1-p12.
Platelet-activating factor is a biologically active phospholipid that provokes inflammation by its ability to activate polymorphonuclear neutrophils and increase vascular permeability. Tjoelker et al. (1995) found that, in vitro and in vivo, pretreatment with PAF acetylhydrolase blocked PAF-induced inflammation and vascular permeability.
Caplan et al. (1990) found increased levels of plasma PAF and decreased levels of plasma PAF acetylhydrolase activity in 12 neonates with necrotizing enterocolitis compared to controls, and suggested a role for PAF in the pathophysiology of the disorder. In mucosal samples from the distal ileum in 11 patients with Crohn disease (see IBD1, 266600), Kald et al. (1996) found decreased PAF acetylhydrolase activity compared to controls, but found no difference in activity between the 2 groups in samples from the colon and jejunum. Plasma PAF acetylhydrolase activity was also reduced in patients with Crohn disease compared to controls, and was lowest in patients with high disease activity. Kald et al. (1996) suggested that PAF acetylhydrolase is involved in protecting the intestinal mucosa against PAF-mediated inflammation.
Stafforini et al. (1996) cited reports showing that the level of PAF acetylhydrolase is altered in several disease states; for example, acquired deficiency of PAF acetylhydrolase activity has been reported in patients with systemic lupus erythematosus (152700) and asthma (600807), and increased levels of PAF have been reported in children with acute asthmatic attacks.
Using a human colonic adenocarcinoma cell line, Claud et al. (2002) found that PAF induced active transepithelial chloride ion transport at the apical membrane. The authors noted that increased PAF levels had been associated with inflammatory gastrointestinal disorders, and suggested that a direct effect of PAF on intestinal epithelial cells may play a pathogenic role in addition to indirect modulation of inflammation.
Chronic inflammation is thought to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. In the West of Scotland Coronary Prevention Study, Packard et al. (2000) evaluated lipoprotein-associated phospholipase A2 in 580 men who had had a coronary event and in 1,160 men matched for age and smoking status who had not had a coronary event. Elevated levels of lipoprotein-associated phospholipase A2 appeared to be a strong risk factor for coronary heart disease.
Wilensky et al. (2008) showed that selective inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA2 activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general antiinflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. Wilensky et al. (2008) concluded that selective inhibition of Lp-PLA2 inhibits progression to advanced coronary atherosclerotic lesions and confirmed a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.
PAF Acetylhydrolase Deficiency
Miwa et al. (1988) described an autosomal recessive form of PAF acetylhydrolase deficiency (PAFAD; 614278) observed in Japanese individuals, and estimated that PAF acetylhydrolase activity is absent in 4% of the Japanese population. Stafforini et al. (1996) showed that this inherited deficiency is the result of a mutation in exon 9 of the PLA2G7 gene (V279F; 601690.0001), and that the mutation completely abolishes enzymatic activity. They estimated that 27% of Japanese are heterozygous for the mutation. Nadel (1996) discussed the findings and noted that even the small decrease in activity in heterozygotes could have a significant physiologic effect in the presence of inflammatory responses.
Saleheen et al. (2017) sequenced the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. Saleheen et al. (2017) identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. They identified 49,138 rare (less than 1% minor allele frequency) pLoF mutations which were estimated to knock out 1,317 genes, each in at least 1 participant. Saleheen et al. (2017) identified 2 participants in the PROMIS study who were homozygous for a splice-site mutation, c.663+1G-A (601690.0004), and 106 who were heterozygous for this same mutation. There was a dose-dependent response relationship between genotype and enzymatic activity. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2.
Associations Pending Confirmation
---Asthma and Atopy
Kruse et al. (2000) identified 3 common variants of the PAFAH gene: arg92-to-his (R92H), I198T (601690.0002), and A379V (601690.0003) in a Caucasian population. The variant allele thr198 was highly associated with total IgE (147050) concentrations in an atopic population and with asthma in an asthmatic population. The variant allele val379 was found to be highly associated with specific sensitization in the atopic population and with asthma in an asthmatic population. By study of recombinant PAFAH enzymes, Kruse et al. (2000) showed that the val379 variant had increased, and the thr198 variant markedly increased, K(m) values compared to the wildtype; furthermore, Vmax of val379 was highly increased (132%). Thr198 and val379 influenced plasma PAFAH toward lower substrate affinities and therefore were very likely to prolong the activity of the platelet-activating factor. At the same time, they were associated with increased risk of asthma and atopy. The finding of this association with PAFAH was consistent with the previous identification of linkage between microsatellite markers in the 6p region, where PAFAH maps, and asthma and atopy phenotypes (Ober et al., 1998; Wjst et al., 1999).
---Risk of Coronary Heart Disease
Because elevated lipoprotein-associated phospholipase A2 activity is positively associated with coronary heart disease (Lp-PLA2 Studies Collaboration, 2010), Polfus et al. (2015) sequenced the exomes of 6,325 participants in the ARIC (Atherosclerosis Risk in Communities) study to find genetic variants that lowered phospholipase A2 activity. They identified 4 loss-of-function variants that lowered activity significantly but that had no effect on coronary heart disease risk over an average of 25.1 years of follow-up.
Among the 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, Saleheen et al. (2017) identified participants who were naturally deficient in the Lp-PLA2 enzyme. Two participants were homozygous for a splice-site mutation, c.663+1G-A (601690.0004), and 106 were heterozygous for this same mutation. Saleheen et al. (2017) tested the association of the PLA2G7 mutation with myocardial infarction across all participants and found that carriers did not have reduced risk (OR 0.97; 95% CI, 0.70-1.34; p = 0.87). In contrast, the authors were able to replicate previous observations at the LDLR (606945) and PCSK9 (607786) genes. Saleheen et al. (2017) noted that in 2 randomized controlled trials, pharmacologic Lp-PLA2 inhibition failed to reduce risk for coronary heart disease.
In Japanese patients with platelet-activating factor acetylhydrolase deficiency (614278), Stafforini et al. (1996) identified a homozygous 994G-T transversion in exon 9 of the PLA2G7 gene, resulting in a val279-to-phe (V279F) substitution. They noted that val279 is conserved in plasma PAF acetylhydrolases from different species (human, mouse, dog, cow, and chicken), and that it is located in the active site of the enzyme. Functional expression of the V279F mutation in E. coli resulted in an inactive protein.
Among 120 consecutive patients with cerebral thrombosis and 134 controls, Hiramoto et al. (1997) found the V279F mutation in 43.4% of stroke patients (39.2% heterozygotes and 4.2% homozygotes) and 25.4% of control subjects (22.4% heterozygotes and 3.0% homozygotes). The authors discussed the relationship of plasma PAFAH deficiency to the relatively high prevalence of stroke in Japan, noting that the mutation is more common among Japanese than Caucasians.
Stafforini et al. (1999) found that the prevalence of PAF acetylhydrolase deficiency was higher in Japanese asthmatics than in healthy Japanese subjects, and that the severity of the asthma was highest in homozygous-deficient subjects.
Jang et al. (2006) studied the association between the PLA2G7 variants V279F and A379V and cardiovascular disease (CVD) in Korean men. The presence of the 279F allele was associated with a lower risk of CVD (OR 0.646, 95% CI 0.490-0.850, P = 0.002), and the association still remained after adjustments for age, body mass index, waist circumference, waist to hip ratio, cigarette smoking, and alcohol consumption (OR 0.683, 95% CI 0.512-0.911, P = 0.009).
This variant, formerly titled ASTHMA AND ATOPY, SUSCEPTIBILITY TO, has been reclassified as a polymorphism.
Kruse et al. (2000) identified a common variant of the PLA2G7 gene in exon 7, ile198-to-thr (I198T), and found that the variant allele thr198 was highly associated with total IgE (147180) concentrations in an atopic population (147050) and with atopic asthma (see 600807) in an asthmatic population.
Hamosh (2023) noted that the I198T variant was present in 20,099 of 282,600 alleles and in 1113 homozygotes in the gnomAD database, with an allele frequency of 0.07111.
This variant, formerly titled ASTHMA AND ATOPY, SUSCEPTIBILITY TO, has been reclassified as a polymorphism.
Kruse et al. (2000) identified an ala379-to-val (A379V) variant in exon 11 of the PLA2G7 gene, which was found to be highly associated with specific sensitization in an atopic population (147050) and with asthma (see 600807) in an asthmatic population.
Oxidation of low density lipoproteins is an initial step of atherogenesis that generates proinflammatory phospholipids, including PAF and its analogs. PAFAH activity has been postulated to be a risk factor for coronary artery disease (CAD; see 608320). Ninio et al. (2004) genotyped a prospective cohort of 1,314 CAD patients and 485 controls at several polymorphisms in PAFAH. The whole-gene variability was investigated in relation to case-control status, prospective cardiovascular outcome, and plasma PAFAH levels by haplotype analyses. The val379 allele was less frequent in CAD patients than the ala379 allele, was associated with a lower risk of future cardiovascular events, and was also associated with a weak increase of plasma PAFAH activity. The authors hypothesized that the A379V polymorphism might modify the enzyme function towards a more antiatherogenic form.
Hamosh (2023) noted that the A379V variant was present in 226,767 of 282,112 alleles and in 91,327 homozygotes in the gnomAD database, with an allele frequency of 0.8038.
Among the 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), Saleheen et al. (2017) identified participants who were naturally deficient in the Lp-PLA2 enzyme (PAFAD; 614278). Two participants were homozygous for a splice-site mutation, c.663+1G-A (c.663+1G-A, ENST00000274793.7), and 106 were heterozygous for the same mutation. Saleheen et al. (2017) observed a dose-dependent response relationship between genotype and enzymatic activity. Compared with noncarriers, c.663+1G-A homozygotes had markedly lower Lp-PLA2 enzymatic activity (-245 nmol/ml/min, p = 2 x 10(-7)), whereas the 106 heterozygotes had an intermediate effect (-120 nmol/ml/min, p = 2 x 10(-77)). Homozygosity for predicted loss-of-function mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2.
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