p.V279F Val279Phe c.G994T in PAFAD; loss of function; risk factor for coronary arthery disease and stroke. rs76863441
Kinetic parameters
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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: 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: Correlations Between LP-PLA2 Gene Polymorphisms and Susceptibility and Severity of Acute Pancreatitis in a Chinese Population Ma M, Zhai CX, Sun CX Ref: Genet Test Mol Biomarkers, 21:206, 2017 : PubMed
OBJECTIVE: This case-control study explored correlations between LP-PLA2 gene polymorphisms (A379V, V279F, and R92H) and susceptibility and severity of acute pancreatitis (AP) in a Chinese population. MATERIALS AND METHODS: From October 2013 to October 2015, 94 AP patients were chosen as the case group. According to the Acute Physiology and Chronic Health Evaluation (APACHE) II score standard, AP patients were divided into a mild AP (MAP) group (n = 46) and severe AP (SAP) group (n = 48). The 48 SAP patients were further divided into an SAP with multiple organ dysfunction syndrome (MODS) group (n = 42) and SAP without MODS group (n = 6). Meanwhile, 96 healthy subjects who received physical examinations at the study hospitals were selected as the control group. Serum lipoprotein-associated phospholipase A2 (LP-PLA2) levels were detected by an enzyme-linked immunosorbent assay (ELISA). The A379V (s1051931), V279F (rs16874954), and R92H (rs13989) polymorphisms of the LP-PLA2 gene were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: There were significant differences in the frequencies of the LP-PLA2 gene polymorphisms between the AP group and the control group. The distribution of V279F-AA+AC genotype and R92H-AA+AG genotype in the AP group was higher than that in the control group, whereas the SAP group and SAP with MODS group distributions were higher than those in the MAP group and SAP without MODS group (both p < 0.05). G-C-A, G-A-G, and G-C-G haploids formed by A379V, V279F, and R92H may be associated with AP susceptibility. LP-PLA2 gene polymorphisms could affect serum LP-PLA2 level, whereas the V279F-A allele gene, the R92H-A allele gene, serum LP-PLA2 level, and serum amylase may be independent risk factors for AP (all p < 0.05). CONCLUSION: These results demonstrated that the LP-PLA2 gene polymorphisms, V279F and R92H, may be associated with susceptibility to and severity of AP.
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.
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: 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: Nonsynonymous polymorphisms in PLA2G7 gene are associated with the risk of coronary heart disease in a southern Chinese population Hong M, Zhang M, Lu X Ref: Mamm Genome, 26:191, 2015 : PubMed
Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an important role in coronary heart disease (CHD). This study was aimed to investigate the associations of polymorphisms (R92H, V279F, I198T, and A379V) in PLA2G7 with CHD. A total of 322 patients with CHD and 414 CHD-free controls were included in the study. Polymorphisms in PLA2G7 were sequenced by DNA Sequencer and statistical analyses were performed to study the associations between polymorphisms and CHD. RH + HH genotype, RH genotype, and H allele of R92H were significantly associated with an increased risk of CHD (P = 0.005, P = 0.009, and P = 0.003, respectively), while no associations were observed between V279F and I198T and CHD (A379V was not analyzed because of deviation from Hardy-Weinberg equilibrium). Correlations between R92H and CHD still existed after adjustment for confounding risk factors of CHD (P = 0.001). Furthermore, stratified analyses showed subgroups of the senior, hypertension, non-smoking, non-diabetics, and male subjects brought a higher risk for CHD (P = 0.015, P = 0.001, P = 0.001, P = 0.002, and P = 0.004, respectively). We also observed a lower level of protective factor HDL-C in CHD patients carrying genotype RH + HH than patients with RR (P = 0.047). Furthermore, we conducted haplotype analysis and detected more harmful effects of haplotypes HVI and RVT as compared with other haplotypes (P = 2.538 x 10(-3) and P = 0.031). These findings indicated that R92H variant in PLA2G7 gene might contribute to CHD susceptibility in a southern Chinese population.
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.
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.
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.
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.
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.
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.
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.
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.
Title: Identification of the G994--> T missense in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men Yamada Y, Ichihara S, Fujimura T, Yokota M Ref: Metabolism, 47:177, 1998 : PubMed
Platelet-activating factor (PAF) acetylhydrolase may play important roles in the pathophysiology of thrombosis and atherosclerosis related to its catalytic action in the degradation of PAF and oxidized phospholipids. A missense mutation (G--> T transversion at nucleotide 994) in the plasma PAF acetylhydrolase gene results in a Val--> Phe substitution at amino acid 279 of the mature protein and a consequent loss of catalytic activity. However, the role of a deficiency or low activity of this enzyme caused by the missense mutation in the etiology of coronary artery disease (CAD) has not been determined. The relation between this mutation and the incidence of CAD in the Japanese population is investigated herein. The genotype of plasma PAF acetylhydrolase (MM, normal; Mm, heterozygote; and mm, deficient homozygote) was determined with a polymerase chain reaction (PCR) assay for 454 patients with myocardial infarction (MI) and 602 control subjects. The frequency of the m allele was significantly higher in male patients with MI (odds ratio, 1.8) than in controls, an association that was more marked in a low-risk subgroup (odds ratio, 2.3). In contrast, the m allele was not associated with MI in women. These results indicate that the G994--> T missense mutation in exon 9 of the plasma PAF acetylhydrolase gene is an independent risk factor for CAD in Japanese men, especially low-risk individuals, but not in women.
Platelet-activating factor (PAF) acetylhydrolase is an enzyme that inactivates PAF. Deficiency of this enzyme is caused by a missense mutation in the gene. We previously found a higher prevalence of this mutation in patients with ischemic stroke. This fact suggests that the mutation might enhance the risk for stroke through its association with hypertension. We have addressed this hypothesis by analyzing the prevalence of the mutation in hypertension. We studied 138 patients with essential hypertension, 99 patients with brain hemorrhage, and 270 healthy controls. Genomic DNA was analyzed for the mutant allele by the polymerase-chain reaction. The prevalence of the mutation was 29.3% (27.4% heterozygotes and 1.9% homozygotes) in controls and 36.2% in hypertensives and the difference was not significant. The prevalence in patients with brain hemorrhage was significantly higher than the control: 32.6% heterozygotes and 6.1% homozygotes (p <0.05). PAF acetylhydrolase deficiency may be a genetic risk factor for vascular diseases.
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.
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.
