(from OMIM) Platelet-activating factor (PAF) is a biologically active phospholipid with diverse potent biologic effects. Stafforini et al. (1996) noted that PAF has been implicated as a mediator of physiologic processes, such as signaling and activation of proinflammatory cells, alteration of vascular permeability, and stimulation of glycogen metabolism among many others. In addition to its role as a physiologic mediator, PAF is associated with a pathology of several human diseases, particularly allergy and inflammation, affecting the respiratory, vascular, digestive, and reproductive systems.PAF is degraded to inactive products by hydrolysis of the acetyl group at the sn-2 position to produce the biologically inactive products LYSO-PAF and acetate. This reaction is catalyzed by PAF acetylhydrolase. Miwa et al. (1988) described an autosomal recessive form of PAF acetylhydrolase deficiency which has been observed only in Japanese. PAF acetylhydrolase activity was absent in 4% of the Japanese population. Previously known loss-of-function mutations were not found but 3 common variants of the PAFAH gene were identified: arg92 to his (exon 4), ile198 to thr (exon 7), and ala379 to val (exon 11). The variant allele thr198 was found to be highly associated with total IgE 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 the asthmatic population. There is an association between lipoprotein-associated phospholipase A2 gene polymorphism and coronary artery disease
References
Title: Association Lp-PLA2 Gene Polymorphisms with Coronary Heart Disease Ma S, Ding L, Cai M, Chen L, Yan B, Yang J Ref: Dis Markers, 2022:9775699, 2022 : PubMed
OBJECTIVES: The study evaluated the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) gene polymorphisms and coronary heart disease (CHD), in order to explore the molecular genetics of CHD. METHODS: Groups of CHD patients (n = 283) and healthy controls (n = 261) were involved in this study. R92H, V279F, and A379V polymorphisms of LP-PLA2 gene were confirmed using polymerase chain reaction (PCR) and direct DNA sequencing. These polymorphisms and their interaction were also analyzed as potential risk factors of CHD. RESULTS: In this study population, the genotypes of R92H (GG, GA, and AA), V279F (CC, AC, and AA) and A379V (GG, GA, and AA) were studied. There was a significantly difference in frequencies of R92H between CHD patients and controls (P < 0.05). In contrast, no significant difference in frequencies of V279F and A379V existed between CHD patients and controls. Furthermore, R92H and A379V were in strong linkage disequilibrium. CONCLUSIONS: These results suggested that R92H polymorphism might contribute to increased risk of CHD.
Title: Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme Khan MI, Hariprasad G Ref: J Inflamm Res, 13:1125, 2020 : PubMed
PURPOSE: To investigate the structural features of wild and mutant forms of the pPAF-AH enzyme that are responsible for coronary artery disease. METHODS: Mutant variants of human pPAF-AH having either V279F, Q281R, or both were modelled and evaluated for stereo chemical and structural correctness. The 3D coordinates of substrate PAF were retrieved from the PubChem database was solvated and minimized on Discovery Studio, and docked to the wild and mutant enzyme models. The top docked pose complex was refined by MD simulation. RESULTS: pPAF-AH model comprises of 420 amino acids in a alpha/beta-hydrolase fold that contains a substrate-binding hydrophobic channel with an active site pocket having a catalytic triad of Ser273, Asp296 and His351. Mutations at positions 279 and 281 are opposite one another on the middle of 12 residues long H5 helix that forms the hydrophobic core of the enzyme. V279F causes a tilt on the axis of the mutation bearing helix to avoid steric clashes with the hydrophobic residues on the beta-sheets adjacent to it, inducing subtle conformational changes on the H5-beta8 loop, beta8 sheet, and the loop bearing Asp296. A cascade of conformational changes induces a change in the orientation of His351 resulting in loss of hydrogen bonded interaction with catalytic Ser273. Q281R causes a shortening of H5 and beta8, which induces conformational changes of the loops bearing Ser273 and Asp296, respectively. Simultaneous conformational changes of secondary structural elements result in the flipping of His351 causing a break in the catalytic triad. Also, there is a compromise in the substrate-binding area and volume in the mutants resulting in loss of binding to its substrate. CONCLUSION: Mutant enzymes show changes at the site of the mutation, secondary motif conformations and global structural conformations that adversely affect the active site, decrease substrate channel volume and decrease stability, thereby affecting enzymatic function.
Title: Phospholipase A2 is an Inflammatory Predictor in Cardiovascular Diseases: Is there any Spacious Room to Prove the Causation? Santoso A, Heriansyah T, Rohman MS Ref: Curr Cardiol Rev, 16:3, 2020 : PubMed
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme family of phospholipase A2 produced by the inflammatory cell in atherosclerotic plaque. It is transported in the circulation, attached mainly to low-density lipoprotein-cholesterol (LDL-C). It hydrolyzes glycerophospholipids particularly fatty acids at the sn-2 position and produces numerous bioactive lipids; and leads to endothelial dysfunction, atherosclerotic plaque inflammation, and development of the necrotic core in plaques. There are two kinds of phospholipase A2, namely: secretory phospholipase A2 (sPLA2) and Lp- PLA2. They are deemed as evolving predictors of cardiovascular disease (CVD) risk in hospitaland population-based studies, including healthy subjects, acute coronary syndromes (ACS) and patients with CVD. Unfortunately, Lp-PLA2 inhibitor (darapladib) and s-PLA2 inhibitor (varespladib methyl) failed to prove to lower the risk of composite CVD mortality, myocardial infarction and stroke in those with stable CVD and ACS. Herein, we describe the explanation based on the existing data why there is still a discrepancy among them. So, it highlights the opinion that phospholipase A2 is merely the inflammatory biomarkers of CVD and playing an important role in atherosclerosis. Further, there is more spacious room to prove the causation.
Title: The association between the D166E polymorphism of the lipoprotein associated phospholipase A2 and risk of myocardial infarction Zhang MM, Zhang CG, Yang CJ, Zhao P, Li YL Ref: Eur Rev Med Pharmacol Sci, 23:3960, 2019 : PubMed
OBJECTIVE: Although numerous studies have evaluated the association between lipoprotein associated phospholipase A2 (Lp-PLA2) gene polymorphisms and coronary heart disease, the conclusions are still inconsistency. Here we detected the correlation between D166E polymorphism of Lp-PLA2 and myocardial infarction (MI). Further, its clinical value as biomarker was assessed. PATIENTS AND METHODS: A total of 297 patients were enrolled, all diagnosed as MI at the Hebei General Hospital between May 2017 and May 2018, with 262 healthy subjects recruited as controls. Blood specimens of all participants were collected for testing serum lipid, blood glucose, Lp-PLA2, HsCRP, IL-17 and IL-35. The D166E polymorphism was genotyped. The correlation between D166E polymorphism and MI was explored using multiple logistic regression analysis. RESULTS: We detected higher levels of TC, TG, LDLC, Lp-PLA2, HsCRP and IL-17 but lower levels of HDLC and IL-35 in MI patients, compared with healthy controls (p<0.05). Also, the positive ratio of family history is higher in MI patients than that in control. Indexes were collected after one-week and one-month hospitalization, respectively, and levels of Lp-PLA2, HsCRP, IL-17 and IL-35 decreased to the normal levels (p>0.05). We also observed positive correlations between Lp-PLA2 with HsCRP and IL-17 (r=0.6517, 0.2689), and negative correlations between IL-35 with Lp-PLA2, HsCRP and IL-17 (r=-0.3142, -0.3968, -0.2516), respectively. The G allele at D166E accounted for a higher percentage in MI patients than in controls, and so as the GG and GC genotypes (p<0.05). Logistic regression analysis showed close associations between MI with Lp-PLA2 and GG genotype at D166E, with odds ratios of 1.239 (1.023-2.017) and 9.863 (4.107-21.331), which suggested they were independent risk factors for the development of coronary heart disease. CONCLUSIONS: The D166E (C/G) mutation of Lp-PLA2 was a potential risk factor of MI.
Title: Interaction between nonsynonymous polymorphisms in PLA2G7 gene and smoking on the risk of coronary heart disease in a Chinese population Chi Y, Shi C, Zhang X, Xi Y Ref: J Thromb Thrombolysis, 46:125, 2018 : PubMed
To investigate the impact of PLA2G7 polymorphism, and additional their interactions with smoking and drinking on coronary heart disease (CHD) risk based on Chinese population. GMDR model was used to screen the best gene-smoking and gene-drinking interaction combinations. Logistic regression was performed to investigate association between 4 SNPs and CHD, and the interaction effect between rs1805017 and smoking. For CHD patient-control haplotype analyses, the SHEsis online haplotype analysis software ( http://analysis.bio-x.cn/myAnalysis.php ) was employed. CHD risks were higher in carriers of homozygous mutant of rs1805017 and rs1805018 than those with wild-type homozygotes, OR (95% CI) were 1.45 (1.16-1.92) and 1.51 (1.23-1.97), respectively, but the other two SNPs, rs16874954 and rs1051931 were not significant associated with CHD risks. GMDR analysis indicated that there was a significant two-locus model (p = 0.0107) involving rs1805017 and smoking, indicating a potential gene-environment interaction between rs1805017 and smoking. But we did not found any gene-drinking and gene-gene interaction combinations in GMDR models. The haplotype R-I was observed most frequently in two groups, with 47.43 and 54.38% in the case and control group of the population, respectively. The results also indicated that the haplotype containing the rs1805017-H and rs1805018-T alleles were associated with a statistically increased CHD risk, OR (95% CI) 1.43 (1.10-1.86), p = 0.0021. Polymorphisms in rs1805017 and rs1805018, additional interaction between rs1805017 and smoking, and haplotype containing the rs1805017-H and rs1805018-T alleles were associated with increased CHD risk.
Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA(2) enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA(2). We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA(2) activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA(2)-lowering alleles. Results Lp-PLA(2) activity was decreased by 64% ( p = 2.4 x 10(-25)) with carriage of any of the four loss-of-function variants, by 45% ( p < 10(-300)) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 x 10(-12)) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA(2) activity by 65% ( p < 10(-300)). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA(2) activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA(2)-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA(2) is unlikely to be a causal risk factor.
Title: Effects of overweight and the PLA2G7 V279F polymorphism on the association of age with systolic blood pressure Kim M, Yoo HJ, Jang HY, Lee SH, Lee JH Ref: PLoS ONE, 12:e0173611, 2017 : PubMed
This prospective study aimed to determine the effects of the persistence of overweight for three years and the PLA2G7 V279F polymorphism, as well as the interaction between these factors, on the association of age with blood pressure (BP). Healthy middle-aged subjects with normotensive BP were divided into the normal-weight and overweight groups. The PLA2G7 V279F genotype, BP, lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, and oxidized low-density lipoprotein (ox-LDL) were determined. Lp-PLA2 activity was lower in the F allele subjects (n = 111) than in those with the VV genotype (n = 389). The overweight individuals with the F allele had lower Lp-PLA2 activity and ox-LDL at both baseline and after three years and lower systolic and diastolic BP and LDL cholesterol after three years compared with those with the VV phenotype. After three years, the overweight subjects with the VV phenotype exhibited greater increases in Lp-PLA2 activity, systolic BP, and ox-LDL than those with the F allele and normal-weight subjects with the VV phenotype. A multivariate analysis revealed that the PLA2G7 V279F genotype, baseline BMI, changes in Lp-PLA2 activity and ox-LDL remained independently and positively associated with changes in systolic BP. The simultaneous presence of the PLA2G7 279VV genotype and persistence of overweight synergistically increases the risk for hypertension, whereas lower Lp-PLA2 activity in PLA2G7 279F allele carriers might offer certain protection against hypertension, even in individuals who have been overweight for over three years.
Title: Association of Lp-PLA2 G994T gene polymorphism with risk of ischemic stroke in Chinese population Ni J, Gu H, Hu W, Zhou F, Zhu X, Wang K Ref: J Biochem Mol Toxicol, 31:, 2017 : PubMed
The association between lipoprotein-associated phospholipase A2 (Lp-PLA2) G994T gene polymorphism and the risk of ischemic stroke is unclear. The aim of this study is to investigate the influence of Lp-PLA2 G994T genetic variant on the pathogenesis of ischemic stroke in Chinese population. A total of 348 patients with a clinical diagnosis of ischemic stroke and 260 gender-matched control subjects under physical examination were recruited from hospitals and genotyped for G994T gene polymorphism. The results showed that there was a significant difference in the genotype distribution between the two groups and people with GT or TT genotype were associated with the higher risk of ischemic stroke even after adjusting the effects of potential confounding factors. In addition, both ischemic stroke patients and control subjects carrying T allele showed relatively lower Lp-PLA2 activity and higher oxLDL level. Therefore, Lp-PLA2 G994T gene polymorphism may be an independent risk factor of ischemic stroke in Chinese population.
BACKGROUND: Previous studies suggested that some types of single nucleotide polymorphisms (SNPs) in PLA2G7 genes, encoding Lp-PLA2 have been reported to yield an antiatherogenic effect, but other studies mentioned otherwise. Thus, a comprehensive study to explore the effect of SNPs in PLA2G7 genes (V279F, A379V, R92H, I198T) toward clinical atherosclerosis is needed. METHODS: We searched eligible studies from PubMed, EBSCO, ProQuest, Science Direct, Springer, and Cochrane databases for case-control studies to assess the between four types of SNPs in PLA2G7 gene with risk of clinical atherosclerosis (CVD = cardiovascular disease, CAD = coronary artery disease, PAD = peripheral artery disease, ischemic stroke). All studies were assessed under Hardy-Weinberg Equilibrium, an additive model. This meta-analysis was performed by RevMan 5.3 to provide pooled estimate for odds ratio (ORs) with 95% confidence intervals (95% CIs). RESULTS: Fourteen clinical studies met our inclusion criteria. Those included 12,432 patients with clinical atherosclerosis and 10,171 were controls. We found that ORs of two variants SNPs (V279F, R92H) were associated with clinical atherosclerosis {V279F, OR = 0.88 (95% CI, 0.81-0.95); p = 0.0007, I(2) = 40%}, {R92H, OR = 1.29 (95% CI, 1.09-1.53); p = 0.003, I(2) = 73%}. Meanwhile, there was no significant associations between the other two, A379V {OR = 1.08 (95% CI, 0.93-1.26); p = 0.31, I(2) = 78%} and I198T {OR = 1.12 (95% CI = 0.79-1.59); p = 0.53, I(2) = 81%}. CONCLUSIONS: These results suggested that V279F polymorphism in PLA2G7 gene has a protective effect for clinical atherosclerosis, whereas R92H polymorphism might contribute toward increased risk of clinical atherosclerosis.
Title: Association between Lp-PLA2 and coronary heart disease in Chinese patients Yang L, Liu Y, Wang S, Liu T, Cong H Ref: J Internal Medicine Res, 45:159, 2017 : PubMed
Objective To evaluate the association between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2; known to release inflammatory mediators that promote atherosclerosis) and coronary heart disease (CHD) in Chinese patients. Methods This observational, cross-sectional study included a patient cohort who were assessed by coronary angiography and divided into patients with coronary heart disease and patients with normal coronary angiography (controls). Data for several biochemical indicators were collected. Plasma Lp-PLA2 concentrations were measured by enzyme-linked immunosorbent assay. Univariate and multivariate logistic regression were used to analyse the association between Lp-PLA2 concentration and CHD. Results A total of 531 patients were included, comprising 391 with CHD and 140 with normal coronary angiography (controls). Plasma Lp-PLA2 concentration was significantly higher in patients with CHD versus controls (median, 251 microg/l versus 219 microg/l, respectively), and particularly among patients with acute myocardial infarction and stable angina pectoris (249 microg/l and 266 microg/l, respectively). Multivariate analysis showed that Lp-PLA2 <= 292 microg/l (upper quartile of the whole cohort) was independently associated with CHD (odds ratio 2.814, 95% confidence interval 1.519, 5.214). Conclusion Plasma Lp-PLA2 concentration was independently associated with CHD in Chinese patients.
Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P<=5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11-1.33, but was protective in darapladib subjects, HR 0.79 (95% CI 0.71-0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA2 levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a member of the phospholipase A(2) superfamily, is an enzyme that hydrolyses phospholipids, is found in blood circulation as a sign of inflammation, and takes a role in atherogenesis. There is an epidemiologic relation between increased Lp-PLA(2) levels and coronary heart disease. Lp-PLA(2) is an enzyme that is produced by macrophages and takes a role as an independent predictor of a coronary event. A genetic variant of Val279Phe on the Lp-PLA(2) gene has been reported with various results in Japan, China, Korea, and Caucasian populations. This study aims to analyse the influence of the Val279Phe genetic variant on acute myocardial infarction (AMI) at Saiful Anwar Hospital, Indonesia. This study was conducted on 151 patients (111 AMI patients and 40 non-AMI patients). The genetic variant of Val279Phe was identified through a genotyping method. There were no significant differences in age, total cholesterol level, LDL-C (low-density lipoprotein cholesterol) level, and family history data between AMI and non-AMI patients. However, AMI patients had low HDL-C (high-density lipoprotein cholesterol), triglyceride levels, dyslipidaemia, and hypertension risk factors compared to non-AMI patients. The frequency of the GG genotype (279Val) was dominant in both AMI and non-AMI groups. Further analysis suggested that the GG genotype has a 2.9 times greater risk of AMI compared to the GT/TT genotype (279Phe). This study concluded that the Val279Phe genetic variant undoubtedly influenced AMI risk, which is a warrant for further development of early detection and improving strategy to prevent AMI in patients.
BACKGROUND: Migraine is a common neurovascular disorder with multifactorial and polygenic inheritance. The aim of this study was to investigate the association of a migraine without aura and Ala379Val polymorphism of lipoprotein-associated phospholipase A2 (Lp-PLA2) gene in the Iranian population. METHODS: In this study, 103 migraine patients and 100 healthy controls were enrolled. DNA samples were extracted and the Ala379Val polymorphism of Lp-PLA2 gene was investigated. To assess severity of a headache, patients filled out the headache impact test (HIT-6) and migraine severity (MIGSEV) questionnaires. RESULTS: Allele V had significantly lower frequency in the case group than control subjects [P = 0.001, odds ratio (OR) = 0.25, confidence interval (CI): 0.15-0.40]. The frequency of migraine patients that were a carrier of V allele (V/V and A/V) was statistically significant lower than the control group (P = 0.003, OR = 2.39, CI: 1.35-4.23). There was no significant difference of alleles frequency between three grades of MIGSEV (P = 0.316). Furthermore, total HIT-6 score was not significantly different between different genotypes (P = 0.466). CONCLUSION: Our results showed that Ala379Val gene polymorphism of LP-PLA2 is associated with lower risk of migraine but not with severity of headaches in an Iranian population.
BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA(2) inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA(2) METHODS: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories. RESULTS: PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) = 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. CONCLUSIONS: Lifelong lower Lp-PLA(2) activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.
Title: Naturally Occurring Missense Mutation in Plasma PAF-AH Among the Japanese Population Karasawa K Ref: Enzymes, 38:117, 2015 : PubMed
A single nucleotide polymorphism in the plasma PAF-AH enzyme, i.e., G994T, which causes the substitution of Val at amino acid 279 with Phe (V279F), has been found in the Japanese population. This enzyme preferentially degrades oxidatively modulated or truncated phospholipids; therefore, it has been suggested that this enzyme may prevent the accumulation of proinflammatory and proatherogenic oxidized phospholipids. This hypothesis is supported by the higher prevalence of the V279F mutation in patients with asthmatic and atherosclerotic diseases, as compared with healthy controls. This mutation is rare in the Caucasian population. The plasma PAF-AH mass and enzyme activity are distributed over a wide range in the plasma and they are positively correlated with low-density lipoprotein (LDL) cholesterol. However, several clinical studies in the Caucasian population have suggested that this enzyme has the opposite role. This enzyme plays an active role in the development and progression of atherosclerosis via proinflammatory and proatherogenic lysophosphatidylcholine and oxidized fatty acids produced through the oxidation of LDL by this enzyme. Thus, plasma PAF-AH is a unique enzyme with dual roles in human inflammatory diseases. In this chapter, on the basis of recent findings we describe the association between a naturally occurring missense mutation in plasma PAF-AH and human diseases especially including atherosclerosis and asthma.
BACKGROUND: The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA(2)) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA(2) in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted. METHODOLOGY/PRINCIPAL FINDINGS: PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66-0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69-0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA(2) activity and CAD risk. CONCLUSIONS: Natural deficiency in Lp-PLA(2) activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA(2) and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.
Title: Association between lipoprotein-associated phospholipase A2 gene polymorphism and coronary artery disease in the Chinese Han population Li L, Qi L, Lv N, Gao Q, Cheng Y, Wei Y, Ye J, Yan X, Dang A Ref: Ann Hum Genet, 75:605, 2011 : PubMed
The role of the lipoprotein-associated phospholipase A(2) gene (PLA2G7) in atherosclerosis remains controversial. We investigated the frequency of single-nucleotide polymorphisms (SNPs) of PLA2G7 (rs16874954 and rs1051931) and their association with coronary artery disease (CAD) in a cohort of CAD patients (n= 806) and age-matched healthy controls (n= 482) in the Chinese Han population. The VF and FF genotype of rs16874954 was significantly more frequent in the CAD patients (13.5%) than in the controls (9.3%, P= 0.024). The association remained after adjustment for age, gender, body mass index, smoking status, history of diabetes, positive family history of CAD, high-density lipoprotein cholesterol, and triglyceride (OR = 1.922; 95% CI [1.146-3.224]; P= 0.013). There was no significant difference in the frequency of any genotype of rs1051931 between the two groups. However, the frequency of the allele V379 was significantly greater in CAD patients with a history of myocardial infarction (MI) than in those without a history of MI (18.7% and 14.8%, P= 0.038). We conclude that there is significant association between the rs16874954 mutation and CAD in the Chinese Han population. The expression of rs1051931 variant in CAD patients may entail increased risk of MI.
Lipoprotein-associated phospholipase A2 (LP-PLA2) may play an important role in the pathophysiology of coronary heart disease (CHD). The polymorphism of LP-PLA2 gene caused LP-PLA2 enzyme activity depressing or lost. But there is not a definite conclusion for the association of between the LP-PLA2 gene polymorphism and CHD risk. To assess the relationship between LP-PLA2 gene V279F polymorphism and CHD, a comprehensive Meta-analysis was performed. All the case-control studies evaluating the association of between the LP-PLA2 gene V279F polymorphism and CHD risk were identified. Seven case-control studies involving 3,614 patients with CHD and 4,334 controls were included. The crude odds ratios (ORs) of meta-analysis under the different gene model were not significant. But in the stratified analysis by study size, ethnicity, cases definition, and source of controls under the additive model, the association was evident in ethnicity for Japanese group (OR=1.38, 95%CI=1.22-1.56), cases definition for MI (OR=1.22, 95%CI=1.01-1.49), source of controls for the based-hospital (OR=1.42, 95%CI=1.24-1.59). These data suggested that the V279F polymorphism in LP-PLA2 gene may contribute to CHD development. But there is necessary that more well-designed large studies are required for the validation of this association.
Title: Identification of the G994T polymorphism in exon 9 of plasma platelet-activating factor acetylhydrolase gene as a risk factor for polycystic ovary syndrome Fan P, Liu Hw, Wang XS, Zhang F, Song Q, Li Q, Wu HM, Bai H Ref: Hum Reprod, 25:1288, 2010 : PubMed
BACKGROUND: Low-grade chronic inflammation and greater risks of cardiovascular diseases are often present in patients with polycystic ovary syndrome (PCOS). Platelet-activating factor (PAF) acetylhydrolase (PAF-AH) hydrolyzes and inactivates PAF and PAF-like oxidized phospholipids that are potent lipid mediators involved in inflammation and atherosclerosis. Deficiency of this enzyme is caused by a missense mutation (G994 --> T) in exon 9 of the plasma PAF-AH gene. The aim of the study was to investigate a possible association of this polymorphism with the risk of PCOS and to evaluate the effects of the genotype on the activity and distribution of PAFAH in Chinese patients. METHODS: A total of 661 subjects (346 patients with PCOS and 315 healthy control women) from a population of Chinese Han nationality in Chengdu area were included in this study. PAFAH G994T genotype was studied using PCR and restriction fragment length polymorphism analysis. Total plasma PAF-AH, high-density lipoprotein (HDL)-associated PAF-AH (H-PAF-AH) and low-density lipoprotein (LDL)-associated PAF-AH (L-PAF-AH) activities were measured by the trichloroacetic acid precipitation procedure using [(3)H-acetyl] PAF and PAF C-16 as a substrate. RESULTS: The prevalence of the mutant genotype (GT + TT) was significantly more frequent in patients with PCOS than in control subjects (12.7 versus 6.0%, P = 0.003). Genotype (GT + TT) remained a significant predictor for PCOS (P = 0.020) in prognostic models including age, body mass index, insulin resistance index, triglyceride, HDL and LDL as covariates. There was a significant difference in plasma PAF-AH, L-PAF-AH and H-PAF-AH activities between GG and GT genotypes in both the patient and control groups. The ratio of L-PAF-AH to H-PAF-AH activities was significantly higher after adjustment for multiple variables in patients with GT genotype compared with patients with GG genotype (P = 0.003). There were no significant differences in clinical, biochemical and metabolic parameters according to PAFAH G994T genotyping in patients with PCOS and control women. CONCLUSIONS: The G994T polymorphism in PAFAH gene may be one of the genetic determinants for PCOS in Chinese Han women.
INTRODUCTION: Variants of PLA2G7 gene have been reported to be associated with coronary heart disease (CHD) since ten years ago, but the available data on this relationship are inconsistent. A meta-analysis was conducted to assess the effect of PLA2G7 gene on CHD. MATERIALS AND METHODS: Association studies were identified from the databases of PubMed, EMbase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang by two investigators and pooled effects (odds ratio (OR), together with 95% confidence interval (CI)) were calculated. RESULTS: 14 association studies focusing on three polymorphisms (A379V, V279F and R92H) in PLA2G7 gene and risk of CHD were included in meta-analysis, covering a total of 8,280 cases and 5,656 controls. Concerning R92H, a significantly increased CHD risk was observed in recessive model, with an OR of 1.31(1.02, 1.68). Nevertheless, combined analyses of studies of the A379V and V279F variants showed no significant overall association with CHD, yielding ORs of 0.99(0.85, 1.15) and 1.09(0.88, 1.35) in allelic analysis, with strong evidence of heterogeneity. Similar results were also obtained in dominant and recessive models. CONCLUSIONS: The results indicate 92H allele had probably increased the risk of CHD, while the hypothesized effects of A379V and V279F polymorphisms on CHD cannot be confirmed in present data. However, given the limited number of studies and the potential biases, the influence of these polymorphisms on CHD risk needs further investigation.
BACKGROUND: There is increasing evidence that lipoprotein-associated phospholipase A2 (LpPLA2) is associated with cardiovascular disease. However, it is still unclear whether LpPLA2 is simply a marker or has a causal role as either a pro- or anti-atherogenic factor. METHODS: We analyzed the association of five polymorphisms (-1357G>A, -403T>C, Arg92His, Ile198Thr, Ala379Val) and related haplotypes at the PLA2G7 locus with angiographic coronary artery disease (CAD), plasma LpPLA2 activity, and long-term survival in 3234 patients scheduled for coronary angiography. RESULTS: The promoter variant -403C and His(92) were associated with a decrease and Val(379) with an increase in plasma LpPLA2 activity. Both coding variants revealed a clear gene-dose effect. Interestingly, the rare Thr(198) allele, which was not associated with any change in plasma LpPLA2 activity, was more frequent in subjects without CAD (P = 0.009), with an adjusted odds ratio for CAD of 0.69 (95% CI: 0.49-0.96; P = 0.029). None of the analyzed variants showed any robust association with all-cause or cardiovascular mortality. CONCLUSION: Irrespective of the significant association between some variants with plasma LpPLA2 activity, it is still unclear whether these polymorphisms or haplotypes are associated with the risk and outcome of cardiovascular disease in Caucasians.
Title: Associations of PLA2G7 gene polymorphisms with plasma lipoprotein-associated phospholipase A2 activity and coronary heart disease in a Chinese Han population: the Beijing atherosclerosis study Hou L, Chen S, Yu H, Lu X, Chen J, Wang L, Huang J, Fan Z, Gu D Ref: Hum Genet, 125:11, 2009 : PubMed
The human PLA2G7 gene encodes lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an emerging risk factor for cardiovascular diseases. In the present study, seven single nucleotide polymorphisms (SNPs) in the PLA2G7 gene were genotyped in 827 patients with coronary heart disease (CHD), of which 512 were patients with myocardial infarction (MI), and 947 age- and gender-matched controls in a Chinese Han population. Plasma Lp-PLA(2) activity was measured in 416 randomly selected controls and 689 randomly selected CHD patients, including 423 MI patients. Lp-PLA(2) activity in CHD and MI cases was significantly higher (233.42+/-57.66 and 234.27+/-59.51 nmol ml(-1) min(-1), respectively) than in controls (211.47+/-58.61 nmol ml(-1) min(-1)). After adjusting for traditional risk factors by logistic regression, the odds ratios for CHD and MI per 1 standard deviation increment of Lp-PLA(2) activity were 1.27 (95% CI, 1.07-1.50) and 1.27 (95% CI, 1.05-1.54), respectively. Both single SNP analysis and haplotype analysis showed that the V279F and I198T polymorphisms were significantly associated with the reduced Lp-PLA(2) activity, but neither was associated with increased CHD risk. Both univariate and multivariate analyses, adjusting effects of conventional factors, indicated that the rs13210554 T allele increased the risk of MI in this Chinese Han population. In summary, an independent association of increased plasma Lp-PLA(2) activity with CHD and MI existed in this Chinese Han Population. Although V279F and I198T mutations significantly decreased the activity of Lp-PLA(2), only the promoter rs13210554 polymorphism was associated with MI. Lp-PLA(2) activity appears to influence the CHD and MI risk in Chinese Han population.
Title: Inter-individual variability of plasma PAF-acetylhydrolase activity in ARDS patients and PAFAH genotype Li S, Stuart L, Zhang Y, Meduri GU, Umberger R, Yates CR Ref: J Clin Pharm Ther, 34:447, 2009 : PubMed
BACKGROUND: Platelet activating factor (PAF), a pro-inflammatory phospholipid, stimulates cytokine secretion from polymorphonuclear leukocytes expressing the transmembrane G-protein coupled PAF receptor. Elevated PAF levels are associated with acute respiratory distress syndrome (ARDS) and sepsis severity. The pro-inflammatory effects of PAF are terminated by PAF acetylhydrolase (PAF-AH). OBJECTIVE: We sought to determine whether allelic variants in the human PAFAH gene (Arg92His, Ile198Thr, and Ala379Val) contribute to variability in PAF-AH activity in patient plasma obtained within 72 h of ARDS diagnosis. RESULTS: Plasma PAF-AH activity (mean +/- SD) was higher in patients homozygous for the Arg92 allele compared to His92 allele carriers (2.21 +/- 0.77 vs. 1.64 +/- 0.68 U/min; P < 0.01; n = 31 and 21 respectively). Baseline plasma PAF-AH activity was higher among day 7 survivors vs. day 7 non-survivors (2.05 +/- 0.75 vs. 1.27 +/- 0.63, P = 0.05). CONCLUSION: These data demonstrate an association between PAF-AH allelic variation, plasma activity, and outcome in ARDS.
BACKGROUND: A single-nucleotide polymorphism (SNP), G994T, in the lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) gene is known to have a potent influence on the activity of the enzyme. As this enzyme hydrolyzes oxidized low-density lipoprotein (oxLDL), which is an important player in atherogenesis, the present study evaluated effects of the G994T genotype on the oxLDL level as well as on intima media thickness (IMT) in vivo. METHODS: Participants of a health examination (1,307 in total) were recruited from two rural communities in Shimane, Japan. Genotyping was performed by an allele-specific PCR and the TaqMan method. The oxLDL level was determined by an enzyme immunoassay. RESULTS: The minor allele (994T) frequency (0.19) in the studied populations was consistent with previous reports on Japanese. The 994T allele increased the plasma oxLDL/LDL ratio in a recessive manner, whereas 994T had a codominant effect on the Lp-PLA(2) activity. A multivariate analysis revealed that age and the G994T genotype had independent effects on the oxLDL/LDL level. By contrast, the G994T genotype was not associated with IMT. All of these results were reproducible in the two independent populations studied. CONCLUSIONS: G994T influenced plasma LDL oxidation. Further studies on the effect of this polymorphism in cardiovascular diseases are warranted.
Platelet-activating factor acetylhydrolase (PLA2G7) is a potent pro- and anti-inflammatory molecule that has been implicated in multiple inflammatory disease processes, including cardiovascular disease. The goal of this study was to investigate the genetic effects of PLA2G7 on coronary artery disease (CAD) risk in two large, independent datasets with CAD. Using a haplotype tagging (ht) approach, 19 ht single nucleotide polymorphisms (SNPs) were genotyped in CATHGEN case-control samples (cases = 806 and controls = 267) and in the GENECARD Family Study (n = 1101 families, 2954 individuals). Single SNP analysis using logistic regression revealed nine SNPs with significant association in all CATHGEN subjects (P = 0.0004-0.02). CATHGEN cases were further stratified into subgroups based on age of CAD onset (AOO) and severity of disease; 599 young affecteds (YA, AOO <56) and 207 old affected (OA, AOO >56). Significant genetic effects were observed in both OA and YA (P = 0.0001-0.02). The GENECARD probands demonstrated results similar to those seen in the YA CATHGEN cases (P = 0.002-0.05). Of the 19 SNPs genotyped, 3 SNPs result in nonsynonymous coding changes (I198T, A379V and R92H). Two of the coding SNPs, R92H and A379V, constitute two of the most significantly associated SNPs, even after Bonferroni correction and appear to represent independent associations (r(2) = 0.09). Multiple additional polymorphisms in low linkage disequilibrium with these coding SNPs were also strongly associated. In summary, PLA2G7 represents an important, potentially functional candidate in the pathophysiology of CAD based on replicated associations using two independent datasets and multiple statistical approaches. Further functional studies involving a combination of risk alleles are warranted.
Title: Comprehensive evaluation of genetic and environmental factors influencing the plasma lipoprotein-associated phospholipase A2 activity in a Japanese population Zhang SY, Shibata H, Karino K, Wang BY, Kobayashi S, Masuda J, Nabika T Ref: Hypertens Res, 30:403, 2007 : PubMed
The lipoprotein-associated phospholipase A2 (Lp-PLA2) metabolizes oxidized phospholipids, generating lysophosphatidylcholine. The activity of the enzyme is known to be influenced largely by a single-nucleotide polymorphism, G994T, in the Lp-PLA2 gene. Interestingly, this polymorphism is much more prevalent in Japanese than Caucasians. The purpose of the current study was to evaluate the effects of the G994T, several environmental factors, and their interactions on the Lp-PLA2 activity in a large Japanese cohort. Participants (1,110 males and 908 females) of a health-screening examination were recruited for this study. Genotyping of the G994T was done using allele-specific polymerase chain reaction (PCR). The Lp-PLA2 activity was measured using commercial kits. The minor allele (994T) frequency of the polymorphism was 0.17 in this study, which was consistent with previous reports. According to the multivariate linear regression analysis, the G994T was the most potent factor influencing the enzyme activity (standardized beta=0.76), followed by the low-density lipoprotein cholesterol (LDL-C) level (standardized beta=0.32) and the sex (standardized beta=0.13). The LDL-C level showed a significant interaction with the G994T genotype. By contrast, no significant interaction was observed between the LDL-C level and the sex. These observations should provide useful information for future clinical and epidemiological evaluations of the Lp-PLA2 activity in cardiovascular diseases in Japanese.
CONTEXT AND OBJECTIVE: It is unclear whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) exerts a pro- or antiatherogenic effect on cardiovascular disease (CVD). We investigated the association between Lp-PLA(2) variant (V279F and A379V) and CVD in Korean men. DESIGN: CVD patients (n = 532) and healthy controls (n = 670) were genotyped for the Lp-PLA(2) polymorphism (V279F and A379V). MAIN OUTCOME MEASURES: We calculated odds ratio (OR) on CVD risk and measured anthropometries, lipid profiles, low-density lipoprotein (LDL) particle size, oxidized LDL, lipid peroxides, and Lp-PLA(2) activity. RESULTS: The presence of the 279F allele was associated with a lower risk of CVD [OR 0.646 (95% confidence interval 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% confidence interval 0.512-0.911), P = 0.009]. Lp-PLA(2) activity was lower in CVD patients taking a lipid-lowering drug (31%), those not taking a lipid-lowering drug (26%), and control subjects (23%) with the V/F genotype, compared with those with the V/V genotype. Subjects with the F/F genotype in controls and two CVD patients groups showed no appreciable enzymatic activity. Control subjects with the V/F genotype had larger LDL particle size than those with the V/V genotype. In addition, control subjects carrying the F allele showed lower malondialdehyde concentrations. On the other hand, we found no significant relationship between A379V genotype and CVD risk. CONCLUSIONS: The association of the F279 loss of function variant with the reduced risk of CVD supports the concept that Lp-PLA(2) plays a proatherogenic and causative role in CVD.
Title: Platelet-activating factor-acetylhydrolase A379V (exon 11) gene polymorphism is an independent and functional risk factor for premature myocardial infarction Liu PY, Li YH, Wu HL, Chao TH, Tsai LM, Lin LJ, Shi GY, Chen JH Ref: J Thromb Haemost, 4:1023, 2006 : PubMed
BACKGROUND: Oxidation of low density lipoproteins is an initial step of atherogenesis that generates pro-inflammatory phospholipids, including platelet-activating factor (PAF). PAF is degraded by PAF-acetylhydrolase (PAF-AH), which has been postulated to be a risk factor for myocardial infarction (MI). The role of PAF-AH for the onset of premature MI is unclear. METHODS: Polymorphisms located in putatively functional regions were investigated in a cohort of patients having premature MI onset prior to 46 years of age (n = 200) and a sex-age-matched control group (n = 200). The activity of PAF-AH and coronary angiograms were evaluated for the severity of coronary atherosclerosis. RESULTS: The V allele of A379V (exon 11) polymorphism on PAF-AH gene was more frequent in patients with premature MI (P = 0.001). This V allele polymorphism was also associated with a lower activity of plasma PAF-AH and a more complex coronary atherosclerosis (p Trends <0.05). Multiple logistic regression analysis showed that this polymorphism was an independent risk factor (Odds Ratio [OR] 1.66, 95% CI 1.14.1 to 5.80, P = 0.008) as well as smoking (OR 3.72, 95% CI 1.77 to 9.28, P = 0.001), diabetes mellitus (OR 2.25, 95% CI 1.40 to 5.32, P = 0.007) and hypertension (OR 1.88, 95% CI 1.25 to 5.36, P = 0.003) for the onset of premature MI. CONCLUSION: We conclude that a functional and significant association between the A379V polymorphism on exon 11 of PAF-AH gene and premature MI exists in this Taiwanese population. This polymorphism is significantly associated with the PAF-AH activity and the severity of coronary atherosclerosis.
Title: Association of platelet-activating factor acetylhydrolase gene polymorphism with premature coronary artery disease in Turkish patients Sekuri C, Cam FS, Tengiz I, Ercan E, Bayturan O, Berdeli A Ref: Anadolu Kardiyol Derg, 6:132, 2006 : PubMed
OBJECTIVE: Platelet-activating factor (PAF) is a phospholipid with multiple actions that is involved in inflammatory diseases as well as in atherogenesis. It is inactivated by a plasma enzyme, PAF-acetylhydrolase (PAF-AH). Deficiency of this enzyme in plasma is caused by a missense mutation in the gene (G994T). The aim of this study was to investigate association of this mutation with premature coronary artery disease (CAD). METHODS: One hundred and fifteen unrelated Turkish patients with a diagnosis of premature CAD and 128 unrelated healthy subjects were enrolled in this study. Genotyping was performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The prevalence of the G994T mutation in the patients was 2.60 % (heterozygote), and 0 % in the controls. There was no significant difference in allele frequency and genotype distribution among the study groups. CONCLUSION: The G9943T mutation in the plasma PAF acetylhydrolase gene is not associated with premature CAD in Turkish subjects.
Title: Vasospastic angina and microvascular angina are differentially influenced by PON1 A632G polymorphism in the Japanese Mashiba J, Koike G, Kamiunten H, Ikeda M, Sunagawa K Ref: Circ J, 69:1466, 2005 : PubMed
BACKGROUND: Ethnicity and smoking are well-known risk factors for the pathogenesis of coronary vasospasm. Oxidative stress induced by smoking plays a crucial role in coronary vasospasm, but is not enough to account for the pathogenesis of coronary vasospasm, indicating that genetic factors are strongly involved. METHODS AND RESULTS: The study group comprised 162 vasospastic angina patients (VSAs), 61 microvascular angina patients (MVAs) and 61 non-responders (NRs) diagnosed by acetylcholine provocation test. Four polymorphisms of the oxidative stress related genes, cytochrome b-245, alpha polypeptide gene (CYBA) C242T and A640G, paraoxonase 1 gene (PON1) A632G, phospholipase A2 group VII gene (PLA2G7) G994T were genotyped. Allele frequency of PON1 632-G was significantly higher in both the VSA with dominant fashion and the MVA with recessive fashion compared with NR. This association was strongly influenced by gender in the MVA only. There were no significant associations between the other polymorphisms and coronary vasospasm. In addition, the allele frequency of PON1 632-G in the Japanese was higher than in Caucasians. CONCLUSIONS: There was a significant association between PON1 A632G polymorphism and MVA as well as VSA, but the impact of this on VSA and MVA is different in the Japanese.
Oxidation of low density lipoproteins is an initial step of atherogenesis that generates pro-inflammatory phospholipids, including platelet-activating factor (PAF) and its analogs. PAF is degraded by PAF-acetylhydrolase (PAF-AH), a circulating enzyme having both pro- and anti-inflammatory activities. PAF-AH activity has been postulated to be a risk factor for coronary artery disease (CAD); however, whether PAF-AH has a causal role or is simply a marker of risk is unclear. The aim of this study was to relate the variability of the genes encoding PAF-AH (PLA2G7) and the PAF-receptor (PTAFR) to the risk of CAD and its complications. All polymorphisms located in putatively functional regions were investigated in a prospective cohort of CAD patients (n = 1314) and a group of healthy controls (n = 485). The whole gene variability was investigated in relation to case-control status, prospective cardiovascular outcome and plasma PAF-AH levels by means of haplotype analyses. All analyses indicated an effect of the PLA2G7/A379V polymorphism independent of the other polymorphisms. The V379 allele was less frequent in CAD patients than in controls and was associated with a lower risk of future cardiovascular events, suggesting that this allele might be protective against the development of CAD. The V379 allele was also associated with a weak increase of plasma PAF-AH activity that was unlikely to explain the protective effect of the allele on risk. A more likely interpretation is that the A379V polymorphism might modify the enzyme function towards a more anti-atherogenic form. Polymorphisms of the PTAFR gene were not related to any phenotype.
Title: Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe Abuzeid AM, Hawe E, Humphries SE, Talmud PJ Ref: Atherosclerosis, 168:283, 2003 : PubMed
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been identified as a coronary heart disease (CHD) risk predictor. Both its anti-inflammatory role by hydrolysing platelet activating factor, and pro-inflammatory generation of atherogenic mediators may influence CHD risk. We investigated the association of the activity-reducing A379V variant with risk of myocardial infarction (MI) in a large European case-control study, which compared 527 post-MI men with 566 age-matched controls from north and south Europe. Overall, the frequency of the V379 allele was 0.24 (95%CI 0.21-0.26), with no evidence for differences between centres. Homozygosity for the V379 allele was associated with lower risk of MI, (Odds Ratio (OR) 0.56, 95%CI 0.32-0.98), maintained after adjustment for lifestyle factors and levels of inflammatory risk factors (C-reactive protein, fibrinogen, IL-6) (OR 0.46, 0.22-0.93). There was no evidence of heterogeneity of effect between the centres in the north and south of Europe (P-value for interaction=0.80). Since homozygosity for V379 occurs in only 5-6% of subjects, this genotype is not a major determinant of population genetic risk of CHD, but the association of this genotype with low levels of Lp-PLA(2), strongly support the pro-inflammatory causative, and not consequential, role of Lp-PLA(2) in CHD.
The aim of this study was to investigate association of a missense mutation in plasma PAF acetylhydrolase (G994T) with intima media thickness (IMT) of the carotid arteries. One hundred and forty Japanese type 2 diabetic patients aged from 40 to 79 years without severe nephropathy were enrolled in this study. The genotype of the patients was determined by allele specific PCR. IMT of the carotid arteries of the subjects was recorded by B-mode ultrasound imaging. The patients were divided into two groups by genotyping, one carrying two wild alleles (wild group), and another carrying one or two mutant alleles (mutant group). Each group was further divided into two subgroups according to age; one subgroup consisted of 40s or 50s, and another consisted of 60s or 70s. The prevalence of the G994T mutation in the subjects was 28.6% (24.3% heterozygote, and 4.3% homozygote). IMT of the elderly patients of the mutant group was significantly greater (0.98 +/- 0.22 mm, n = 26) than of the elderly patients of the wild group (0.87 +/- 0.20 mm, n = 50, P = 0.0292). There was no significant difference in clinical characteristics between the two subgroups. The results of this study indicate that the missense mutation in plasma PAF acetylhydrolase is associated with development of atherosclerosis in the elderly.
Title: Evidence for the existence of the PAF acetylhydrolase mutation (Val279Phe) in non-Japanese populations: a preliminary study in Turkey, Azerbaijan, and Kyrgyzstan Balta G, Gurgey A, Kudayarov DK, Tunc B, Altay C Ref: Thromb Res, 101:231, 2001 : PubMed
Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase resulting from a missense mutation (Val279Phe) in exon 9 of the gene has been described exclusively in the Japanese population with a very high frequency. This study describes the distribution of the mutation in Turkey and two other Turkic nations, Kyrgyzstan in central Asia and Azerbaijan bordering the Caspian Sea. Among 358 unrelated healthy subjects studied from Turkish population, only 3 had the mutation in heterozygous state (0.84%). Family studies also revealed the presence of homozygous individuals in close relatives of one of these subjects. Among 143 healthy subjects studied from Kyrgyzstan, 12 were heterozygous for the mutation (8.4%). No mutation was detected among 100 healthy individuals studied from Azerbaijan. However, it was suggested that the number of subjects was not enough to draw any conclusion about the prevalence of the mutation in the populations studied. Contrary to the previous notions, identification of the mutation in Turkey and Kyrgyzstan shows the existence of the mutation in non-Japanese populations as well.
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.
BACKGROUND: Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events. METHODS: A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-associated phospholipase A2, C-reactive protein, and fibrinogen levels, and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles. RESULTS: Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile. CONCLUSIONS: Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.
Platelet-activating factor (PAF) may be involved in the pathogenesis of Escherichia coli O157-associated hemolytic uremic syndrome (HUS). PAF is degraded to inactive products by PAF acetylhydrolase. In this study, we investigated whether a PAF acetylhydrolase gene mutation (G-->T transversion at position 994) is involved in HUS in Japanese children. A point mutation in the PAF acetylhydrolase gene (G994T) was identified using polymerase chain reaction in 50 Japanese children with E coli O157-associated HUS and 100 healthy Japanese. We then determined the relationship between the PAF acetylhydrolase G994T gene mutation and clinical features of HUS. There was no difference in genotype and allele frequencies between patients with HUS and healthy controls. The mean duration of oligoanuria was significantly longer in patients with the GT genotype than in those with the GG genotype (P = 0.012). Although 11 of 15 patients (73%) heterozygous for the mutant allele (GT) required dialysis, only 13 of the 35 wild-type homozygotes (GG; 37%) required dialysis (P = 0. 030). Mean plasma PAF acetylhydrolase activity was significantly less in patients with the GT genotype than in those with the GG genotype (P < 0.0001). In conclusion, we have shown an association between the G994T PAF acetylhydrolase gene mutation and the severity of renal damage in E coli O157-associated HUS. Our study suggests that analysis of the PAF acetylhydrolase gene mutation in Japanese children with E coli O157-associated HUS may allow the prediction of the severity of HUS.
Asthma, a family of airway disorders characterized by airway inflammation, has an increasing incidence worldwide. Platelet-activating factor (PAF) may play a role in the pathophysiology of asthma. Its proinflammatory actions are antagonized by PAF acetylhydrolase. A missense mutation (V279F) in the PAF acetylhydrolase gene results in the complete loss of activity, which occurs in 4% of the Japanese population. We asked if PAF acetylhydrolase deficiency correlates with the incidence and severity of asthma in Japan. We found that the prevalence of PAF acetylhydrolase deficiency is higher in Japanese asthmatics than healthy subjects and that the severity of this syndrome is highest in homozygous-deficient subjects. We conclude that the PAF acetylhydrolase gene is a modulating locus for the severity of asthma.
Platelet-activating factor (PAF) is a potent mediator of inflammatory injury in renal diseases. PAF is degraded to inactive products by PAF acetylhydrolase. Recently, a point mutation (G to T transversion) of the PAF acetylhydrolase gene was observed at position 994, and this mutation was found to contribute to the variability in plasma PAF levels, with undetectable plasma PAF acetylhydrolase activity occurring in homozygous patients (TT genotype) and reduced levels of activity in heterozygous patients (GT genotype). Therefore, we investigated the effect of the PAF acetylhydrolase gene mutation on the pathogenesis and progression of immunoglobulin A (IgA) nephropathy. Genomic DNA was obtained from 89 children with IgA nephropathy and 100 controls. We identified the PAF acetylhydrolase gene mutation (G994T) by polymerase chain reaction. There was no significant difference in genotypic frequency between patients and controls. However, urinary protein excretion at the time of biopsy was significantly greater in patients with the GT/TT genotypes than in those with the GG genotype. The percentage of glomeruli with mesangial cell proliferation was significantly greater in patients with the GT/TT genotypes than in those with the GG genotype. These results indicate the PAF acetylhydrolase gene mutation may influence the degree of proteinuria and the extent of mesangial proliferation in the early stage of childhood IgA nephropathy.
Asthma is among the most frequent chronic diseases in childhood. Although numerous environmental risk factors have already been identified, the basis for familial occurrence of asthma remains unclear. Previous genome screens for atopy in British/Australian families and for asthma in different American populations showed inconsistent results. We report a sib pair study of a sample of 97 families, including 415 persons and 156 sib pairs. Following an extensive clinical evaluation, all participants were genotyped for 351 polymorphic dinucleotide markers. Linkage analysis for asthma identified four chromosomal regions that could to be linked to asthma: chromosome 2 (at marker D2S2298, P = 0.007), chromosome 6 (around D6S291, lowest P = 0.008), chromosome 9 (proximal to D9S1784, P = 0.007), and chromosome 12 (D12S351, P = 0.010). These linkage regions could be reproduced for all loci by analysis of total or specific immunoglobulin E (minimum P values at these regions were 0. 003, 0.001, 0.010, and 0.015, respectively).
Founder populations offer many advantages for mapping genetic traits, particularly complex traits that are likely to be genetically heterogeneous. To identify genes that influence asthma and asthma-associated phenotypes, we conducted a genome-wide screen in the Hutterites, a religious isolate of European ancestry. A primary sample of 361 individuals and a replication sample of 292 individuals were evaluated for asthma phenotypes according to a standardized protocol. A genome-wide screen has been completed using 292 autosomal and three X-Y pseudoautosomal markers. Using the semi-parametric likelihood ratio chi2 test and the transmission-disequilibrium test, we identified 12 markers in 10 regions that showed possible linkage to asthma or an associated phenotype (likelihood ratio P < 0.01). Markers in four regions (5q23-31, 12q15-24.1, 19q13 and 21q21) showed possible linkage in both the primary and replication samples and have also shown linkage to asthma phenotypes in other samples; two adjacent markers in one additional region (3p24.2-22) showing possible linkage is reported for the first time in the Hutterites. The results suggest that even in founder populations with a relatively small number of independent genomes, susceptibility alleles at many loci may influence asthma phenotypes and that these susceptibility alleles are likely to be common polymorphisms in the population.
BACKGROUND: Platelet-activating factor (PAF) may be involved in the pathogenesis of steroid-responsive nephrotic syndrome (SRNS). PAF is degraded to inactive products by PAF acetylhydrolase. We have investigated whether PAF acetylhydrolase gene mutation is involved in SRNS in Japanese children. METHODS: We identified a point mutation in the PAF acetylhydrolase gene (G994T) using the polymerase chain reaction in 101 Japanese children with SRNS and 100 healthy Japanese. RESULTS: There was no difference in the genotype and allele frequencies between patients with SRNS and normal controls. The mean number of relapses during the first year after onset was significantly higher in the 26 patients who were heterozygous for the mutant allele (GT) than in 75 wild-type homozygotes (GG) (2.61 +/- 1.98 vs. 1.33 +/- 1.35; P = 0.0019). CONCLUSIONS: We conclude that analysis of the PAF acetylhydrolase gene mutation at position 994 in Japanese children with SRNS allows the identification of patients who are more likely to have a disease relapse.
Systematic scans of the genome using microsatellite markers have identified chromosome 6p21.1 as a putative locus for schizophrenia in multiply affected families. There is also evidence from a series of studies for a role of abnormal phospholipid metabolism in schizophrenia. In light of these findings, and the role of platelet activating factor in neurotransmission and neurodevelopment, we have examined the LDL-PLA2 (plasma PAF acetylhydrolase, PAF-AH) gene, a serine dependent phospholipase that has been mapped by hybrid mapping to chromosome 6p21.1, as a positional candidate gene for schizophrenia. The gene was systematically screened using SSCP/HD analysis for polymorphisms associated with the disease. Four polymorphic variants were found within the gene and studied in a group of 200 schizophrenic patients and 100 controls. The variant in exon 7 (Iso195Thr) was found to be weakly associated with schizophrenia (p = 0.04) and the variant in exon 11 (Val379Ala) almost reached significance (p = 0.057). After correcting for multiple testing no significant associations were detected. Haplotype analysis combining pairs of polymorphisms also provided no evidence for association of this gene with schizophrenia in our sample of patients.
Title: A mutation in plasma platelet-activating factor acetylhydrolase (Val279-->Phe) is a genetic risk factor for stroke Hiramoto M, Yoshida H, Imaizumi T, Yoshimizu N, Satoh K Ref: Stroke, 28:2417, 1997 : PubMed
BACKGROUND AND PURPOSE: Platelet-activating factor (PAF) is a phospholipid with multiple actions that include thrombosis and inflammation. It is inactivated by a plasma enzyme, PAF acetylhydrolase. Deficiency of this enzyme in plasma is caused by a missense mutation in the gene (Val279-->Phe). We have studied a possible association of this mutation with the risk of stroke. SUBJECTS AND METHODS: We studied 120 consecutive patients with cerebral thrombosis. The control group consisted of 134 patients matched for age and sex with minor complaints but without stroke. Genomic DNA was analyzed for the mutant allele by a specific polymerase-chain reaction. Plasma PAF acetylhydrolase activity was determined by the method of Stafforini et al. RESULTS: The prevalence of the mutant gene was 43.4% in stroke patients (39.2% heterozygotes and 4.2% homozygotes), which was significantly higher than the 25.4% in control subjects (22.4% heterozygotes and 3.0% homozygotes) (chi 2 = 9.22, P < .01). The prevalence was slightly higher in stroke patients without hypertension than those with hypertension, but the difference was not significant. The patients with family histories of stroke had a slightly higher but not a significant prevalence of the mutant gene as compared with those without family histories of stroke. Plasma PAF acetylhydrolase activity was higher in patients than in control subjects, in normal subjects, or patients with a heterozygous genotype. CONCLUSIONS: These results suggest that plasma PAF acetylhydrolase deficiency may be a risk factor for stroke. This may explain the relatively high prevalence of stroke in Japan, as the mutation is more common among Japanese than Caucasians.
Title: Genetics reveals importance of platelet activating factor in asthma and possibly other inflammatory states Nadel JA Ref: J Clinical Investigation, 97:2689, 1996 : PubMed
Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase is an autosomal recessive syndrome that has been associated with severe asthma in Japanese children. Acquired deficiency has been described in several human diseases usually associated with severe inflammation. PAF acetylhydrolase catalyzes the degradation of PAF and related phospholipids, which have proinflammatory, allergic, and prothrombotic properties. Thus, a deficiency in the degradation of these lipids should increase the susceptibility to inflammatory and allergic disorders. Miwa et al. reported that PAF acetylhydrolase activity is absent in 4% of the Japanese population, which suggests that it could be a common factor in such disorders, but the molecular basis of the defect is unknown. We show that inherited deficiency of PAF acetylhydrolase is the result of a point mutation in exon 9 and that this mutation completely abolishes enzymatic activity. This mutation is the cause of the lack of enzymatic activity as expression in E. coli of a construct harboring the mutation results in an inactive protein. This mutation as a heterozygous trait is present in 27% in the Japanese population. This finding will allow rapid identification of subjects predisposed to severe asthma and other PAF-mediated disorders.
Platelet-activating factor (PAF) is a potent pro-inflammatory phospholipid that activates cells involved in inflammation. The biological activity of PAF depends on its structural features, namely an ether linkage at the sn-1 position and an acetate group at the sn-2 position. The actions of PAF are abolished by hydrolysis of the acetyl residue, a reaction catalysed by PAF acetylhydrolase. There are at least two forms of this enzyme--one intracellular and another that circulates in plasma and is likely to regulate inflammation. Here we report the molecular cloning and characterization of the human plasma PAF acetylhydrolase. The unique sequence contains a Gly-Xaa-Ser-Xaa-Gly motif commonly found in lipases. Recombinant PAF acetylhydrolase has the substrate specificity and lipoprotein association of the native enzyme, and blocks inflammation in vivo: it markedly decreases vascular leakage in pleurisy and paw oedema, suggesting that PAF acetylhydrolase might be a useful therapy for severe acute inflammation.
Title: Characterization of serum platelet-activating factor (PAF) acetylhydrolase. Correlation between deficiency of serum PAF acetylhydrolase and respiratory symptoms in asthmatic children Miwa M, Miyake T, Yamanaka T, Sugatani J, Suzuki Y, Sakata S, Araki Y, Matsumoto M Ref: J Clinical Investigation, 82:1983, 1988 : PubMed
Platelet-activating factor (PAF) acetylhydrolase has been recognized as an enzyme that inactivates PAF. We developed a convenient and reproducible method for determining human serum PAF acetylhydrolase activity. The assay was based on measurement of [14C]acetate produced from 1-O-alkyl-2-[14C]-acetyl-sn-glycero-3-phosphocholine upon precipitation of the complex of radioactive substrate and albumin with TCA. The apparent Km value of PAF acetylhydrolase (near the physiological concentration of serum protein) was 1.5 X 10(-4) M PAF. 32 subjects with serum PAF acetylhydrolase deficiency were found among 816 healthy Japanese adults. The low PAF acetylhydrolase activity in the deficient serum might not be due to the presence of enzyme inhibitor. Both the sensitivity to PAF and the metabolism of PAF in platelets from PAF acetylhydrolase-deficient subjects were almost the same as those of normal subjects. Deficiency in serum PAF acetylhydrolase appeared to be transmitted by autosomal recessive heredity among five Japanese families. Among healthy adults, healthy children, and asthmatic children, who were grouped into five classes on the basis of respiratory symptoms (remission, wheezy, mild, moderate, and severe groups), the probability of PAF acetylhydrolase deficiency was significantly higher in groups with severe symptoms (moderate and severe) (P less than 0.01). These results suggest that deficiency of serum PAF acetylhydrolase might be one of the factors leading to severe respiratory symptoms in asthmatic children.
