SEARCH

SEARCH BY CITATION

Keywords:

  • Lipoprotein-associated phospholipase A2;
  • single-nucleotide polymorphism;
  • haplotype;
  • coronary artery disease

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  8. Supporting Information

The role of the lipoprotein-associated phospholipase A2 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.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  8. Supporting Information

Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase (PAF-AH), is a member of the phospholipase A2 superfamily. It is a Ca2+-independent phospholipase that specifically hydrolyses phospholipid substrates with short and/or oxidized chains located on the sn-2 of the glycerin skeleton (Yanoshita et al., 1988; Stafforini et al., 1991). Lp-PLA2 is mostly secreted by macrophagocytes and monocytes, and approximately 70% of Lp-PLA2 binds to low-density lipoprotein (LDL) particles; the residual 30% binds to high-density lipoprotein (HDL) particles (Stafforini et al., 2003). Lp-PLA2 exerts an antioxidative function by hydrolyzing oxidized lipid substrates generated from the oxidation or oxidative stress of PAF and LDL; it also regulates the potential proinflammatory and vasodilatory effect of PAF (Yanoshita et al., 1988). However, it was reported that Lp-PLA2 may also generate lyso-phosphatidylcholine (lyso-PC) and free-oxidative radicals, both of which have proatherosclerotic abilities, by inducing hydrolysis of oxidized phospholipids (MacPhee et al., 1999). Epidemiologic studies have revealed significant associations between Lp-PLA2 and the incidence of coronary artery disease (CAD) (Caslake et al., 2000; Packard et al., 2000; Blankenberg et al., 2003; Hou et al., 2009), equally for mass and activity (The Lp-PLA2 Studies Collaboration et al., 2010). However, whether the increase in the Lp-PLA2 level caused CAD was a response to inflammatory changes secondary to atherosclerosis, or was simply a marker of risk, remains to be clarified. Therefore, acquired or hereditary functional defects of the enzymes might result in alterations in the pro- or antiatherosclerotic function of Lp-PLA2.

Studies on the single-nucleotide polymorphisms (SNPs) of the gene encoding Lp-PLA2 (PLA2G7) revealed that the V279F variant (rs16874954) in exon 9 and the A379V variant (rs1051931) in exon 11 were functional. The missense mutation of G994[RIGHTWARDS ARROW]T in exon 9 causes Val-to-Phe substitution in the mature protein (Val279Phe). Individuals with the homozygous genotype of V279F, a rare allele, have reduced, or almost absent Lp-PLA2 activity (Stafforini et al., 1996; Hou et al., 2009; Paik et al., 2010). Additionally, the substitution of Ala by Val in A379V results in a twofold decrease in the affinity of Lp-PLA2 for its substrate, and thereby reduces the degradation of PAF (Kruse et al., 2000). These two sites of variation are adjacent to the amino acid residues His-351, Ser-273, and Asp-296 in Lp-PLA2, which represent a very important catalytic domain, and the activity of Lp-PLA2 may be impaired if any of the three amino acid residues are destroyed (Tjoelker et al., 1995a). The rs16874954 variant was first detected in the Japanese population, and the incidence of the FF homozygote was reported to be 4%; subsequently, this variant was reported in Korean and Chinese populations, but has not been reported in Caucasian populations thus far. Studies conducted in Japanese populations have revealed that carriers of the rare allele F have increased risk of CAD (Yamada et al., 1998; Shimokata et al., 2004). The opposite result was reported in the case of the Korean population (Jang et al., 2006). The results of studies on the rs1051931 variant in European populations and Taiwan Han Chinese populations are also conflicting in this regard (Abuzeid et al., 2003; Ninio et al., 2004; Liu et al., 2006; Casas et al., 2010).

Thus, we investigated the genetic polymorphisms of rs16874954 and rs1051931 in PLA2G7 and the distribution of these variants in Chinese Han people to further characterise the relationship of PLA2G7 polymorphisms and haplotypes with the risk and severity of CAD.

Materials and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  8. Supporting Information

Subjects

We sequentially recruited unrelated Chinese Han patients with CAD who were managed at the Fuwai Hospital and the Peking Union Medical College Hospital. For this study, CAD was diagnosed if the patient had a history of typical angina pectoris and stenosis of major coronary arteries of 50% or more, detected in at least one site through percutaneous coronary angiography, or a history of myocardial infarction (MI). Patients with a history of malignant tumours were excluded. Subjects included in the control group were age-matched healthy Chinese Han individuals admitted to the two hospitals for routine health examinations. They did not show any clinical or electrocardiographic evidence of CAD. They also had no history of hyperlipidemia, diabetes mellitus, cerebrovascular disease, peripheral arterial disease, malignancy, or severe hepatic or renal disease. In all, 806 CAD patients and 482 controls were included in this study. Data on demographic characteristics of the study population and the frequency of conventional risk factors of CAD were collected. Informed consent was obtained from all subjects, and the study protocol was independently approved by the Research Committees of Fuwai Hospital and Peking Union Medical College Hospital.

Laboratory Methods

Peripheral venous blood samples were collected in the morning after the patients fasted overnight. Serum levels of total cholesterol (TC), triglycerides (TG), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C) were determined using commercially available kits (Sekisui Medical, Tokyo, Japan) on an autoanalyser (Olympus AU 5400 biochemistry analyzer, Olympus medical systems Corp., Tokyo, Japan). The results of coronary angiography, including data on sites of vessel stenosis and severity of disease, were obtained by visual analysis and were recorded.

Genotyping

Genomic DNA was extracted from peripheral blood leucocytes by a common salting-out procedure using peripheral blood samples anticoagulated with ethylenediaminetetraacetic acid (EDTA). Genotyping for the variants rs16874954 and rs1051931 was performed in the case of all subjects by using the Taqman® probe allelic discrimination method (Taqman® fluorescence-labelling probe was synthesized by U.S. Applied Biosystems Inc., Carlsbad, CA). Briefly, amplification of DNA was performed in 96-well microplates with ABI PCR 7300 according to the manufacturer's instructions. Fluorescence was measured and autoanalysed using an ABI PCR 7300 sequence detection system with ABI PCR 7300 SDS software version 1.0. The forward and reverse amplification primers were designed using primer version 5 and were synthesized by U.S. Applied Biosystems. For rs16874954, the sense primer was 5′-CTT ATT TTC TTA CCT GAA TCT CTG ATC TTC ACT-3′, while the antisense primer was 5′-GGG AAA AAA TAG CAG TAA TTG GAC ATT CTT-3′. For rs1051931, the sense primer was 5′-GCT TTT GTA AGA ATG CTA ATG AAG CTT TGT-3′, while the antisense primer was 5′-ACA CAT GCT CAA ATT AAA GGG AGA CA-3′. Genotyping was repeated randomly in a subset of the subjects to confirm concordance.

Statistical Analysis

The statistical analysis of data was performed using SPSS version 13 (SPSS Inc., Chicago, IL). Demographic and clinical characteristics were compared between CAD patients and controls by t testing for independent sample. Associations between categorical variables were examined by χ2 testing. Departure from the Hardy–Weinberg (H–W) equilibrium was assessed using χ2 goodness-of-fit test. Genetic haplotypes were analysed using SHEsis developed by Bio-X Life Science Research Center, Shanghai, China (Shi et al., 2005). Multiple logistic regression analysis was used to determine the association between the variants and the case–control status, while taking into account common risk factors. In this study, a P value of <0.05 was considered to be statistically significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  8. Supporting Information

The demographic characteristics and baseline data for the CAD patients and controls are presented in Table 1. The prevalence of diabetes was 36.6% among the CAD patients. The mean level of HDL-C was significantly lower in CAD patients than in the controls, while the serum TG level, body mass index (BMI), and the frequency of smoking status and positive family history were significantly higher in the CAD patients. However, the results indicated that the mean levels of TC and LDL-C in the CAD group were significantly lower than those in the control group; this was attributed to the fact that most of the CAD patients were taking statins before admission. The demographic characteristics of the CAD patients with or without a history of MI are also presented in Table 1. The CAD patients with a history of MI had significant increased frequency of smoking than those without a history of MI. However, the mean level of TC and LDL-C was significantly higher in CAD patients without a history of MI, which might be the result of taking statins.

Table 1.  The characteristics of traditional risk factors in the CAD and control groups.
 CAD group (n= 806)Control group (n= 482)CAD patients with MI (n= 307)CAD patients without MI (n= 499)
  1. Data are presented as mean ± SD or number (%) of patients.

  2. 1Compared by t testing.

  3. 2Compared by χ2 testing.

  4. *P < 0.05, **P < 0.01, ***P < 0.001.

Age (years)161.51 ± 10.7461.63 ± 8.4160.84 ± 11.5561.92 ± 10.20
Gender (M/F)2 580/170 264/220*** 257/50 363/136***
BMI (kg/m2)125.99 ± 3.5924.54 ± 3.53***25.78 ± 3.5026.10 ± 3.64
TC (mmol/l)1 4.39 ± 1.05 4.59 ± 0.60*** 4.25 ± 1.01 4.47 ± 1.07**
TG (mmol/l)1 1.74 ± 1.03 1.09 ± 0.37*** 1.68 ± 0.92 1.79 ± 1.09
HDL-C (mmol/l)1 1.14 ± 0.29 1.46 ± 0.34*** 1.11 ± 0.29 1.15 ± 0.29
LDL-C (mmol/l)1 2.53 ± 0.86 2.82 ± 0.53*** 2.45 ± 0.84 2.58 ± 0.87*
Diabetes (%)2 295 (36.6) 0*** 117 (38.1) 178 (35.7)
Smoking (%)2 459 (56.9) 114 (23.7)*** 195 (63.5) 264 (52.9)**
Positive family history (%)2 153 (19.0)  32 (6.6)***  51 (16.6) 102  (20.4)***

Distribution of PLA2G7 Genotypes among CAD Patients and Controls

The distribution of the two variants of PLA2G7 among CAD patients and controls is presented in Table 2; no deviation from the H–W balance was noted in either group. The VF and FF genotypes of rs16874954 were combined together for analysis since the frequency of FF homozygotes was extremely low, at 0.2% and 0.4% for CAD patients and controls, respectively. For the rs16874954 mutation, a significantly higher prevalence of VF and FF genotypes was noted in the CAD patients than in the controls (13.5% vs. 9.3%, P= 0.024). For rs1051931, there was no significant difference among any alleles between the CAD patients and the controls. However, in CAD patients who have a history of MI, the frequency of the V379 alleles was significantly higher than in patients without a history of MI (18.7% vs. 14.8%, P= 0.038). The distribution of rs1051931 genotypes in CAD patients with or without a history of MI is shown in Table 3.

Table 2.  Distribution of PLA2G7 rs16874954 and rs1051931 genotypes in CAD patients and control.
PLA2G7 genotypesCAD group (n= 806)Control group (n= 482)P-value
  1. 1Data on three patients were unavailable.

  2. 2Data on two patients were unavailable.

  3. *The VF and FF genotypes of rs16874954 were combined together for analysis because of the extremely low frequency of FF genotypes.

Exon 9/rs168749541
 VV694 (86.4)437 (90.7)0.024*
 VF107 (13.3)43 (8.9) 
 FF2 (0.2)2 (0.4) 
Exon 11/rs10519312
 AA558 (69.4)321 (66.5)0.480
 AV230 (28.6)148 (30.8) 
 VV16 (2.0)13 (2.7) 
Table 3.  Distribution of PLA2G7 rs1051931 genotypes in CAD patients with or without a history of MI.
 MI subgroup (n= 307)Non-MI subgroup (n= 497)P-value
rs1051931 genotype
 AA202 (65.8)356 (71.6)0.053
 AV95 (30.9)135 (27.2) 
 VV10 (3.3)6 (1.2) 
rs1051931 alleles
 A499 (81.3)847 (85.2)0.038
 V115 (18.7)147 (14.8) 

Haplotype analysis for the variants rs16874954 and rs1051931 was performed using SHEsis (Table 4), in which the FV haplotype was excluded from the analysis because its frequency in our study population was extremely low (less than 3%). The analysis showed that, compared with the VA haplotype that had the highest frequency in both CAD group and control group, the FA haplotype was associated with a high risk of developing CAD (OR = 1.449; 95% CI [1.019–2.061]; P= 0.038).

Table 4.  The haplotype analysis using SHEsis for rs16874954 and rs1051931 of PLA2G7.*
Haplotypes**CAD (frequency)Control (frequency)OR95% CIP-value
  1. *Global result: Global χ2= 5.183, df = 2, P= 0.075 (frequency <0.01 in both control and case has been dropped).

  2. **For the four haplotypes constructed, the first allele of a haplotype was from rs16874954 and the second allele from rs1051931.

VA0.7690.7710.9870.816–1.1940.893
VV0.1620.1800.8810.713–1.0890.241
FA0.0690.0481.4491.019–2.0610.038
FV0.0000.000---

The results of logistic regression analysis suggested that there was an association between the VF and FF genotype of rs16874954 and CAD compared with the VV genotype (OR = 1.525; 95% CI [1.056–2.202]; P= 0.024). This association remains even after adjustment for age, gender, BMI, smoking status, history of diabetes, positive family history of CAD, serum HDL-C level, and serum TG level (OR = 1.922; 95% CI [1.146–3.224]; P= 0.013) (Table 5). Considering the risk of developing MI, the results show a significantly higher risk in VV homozygotes of rs1051931 compared with AA homozygotes (OR = 1.714; 95% CI [1.026–2.864]; P= 0.040). Even after adjustment for age, gender, BMI, smoking status, history of diabetes, positive family history of CAD, serum HDL-C level, and serum TG level, the VV homozygotes still had a higher risk of developing MI than the AA homozygotes (OR = 1.790; 95% CI [1. 048–3.058]; P= 0.033) (Table 5).

Table 5.  Multiple logistic regression analysis of the association of PLA2G7 rs16874954 and the risk of CAD, rs1051931 and the risk of MI in CAD patients.
VariantOR (95% CI)P-value
  1. 1Compared between variant rs16874954 and the risk of CAD.

  2. 2Compared between variant rs1051931 and the risk of MI in CAD patients.

  3. *Adjusted for age, gender, BMI, smoking status, the history of diabetes, serum HDL-C level, serum TG level, and positive family history of CAD.

rs168749541
 VF + FF vs. VV1.525 (1.056–2.202)0.024
 VF + FF vs. VV adjusted*1.922 (1.146–3.224)0.013
rs10519312
 AV vs. AA1.240 (0.906–1.698)0.179
 VV vs. AA1.714 (1.026–2.864)0.040
 VV vs. AA adjusted*1.790 (1. 048–3.058)0.033

Clinical Phenotypes of CAD Associated with the rs16874954 and rs1051931 Genotypes

A total of 774 patients underwent coronary angiography or interventional treatment; 438 (68.2%) of them had multiple coronary lesions and 246 (31.8%) had single coronary lesions. The frequency of the VF and FF genotype in rs16874954 was significantly greater in patients with multiple coronary lesions (15.2%) than in the controls (9.3%, P= 0.005) and in patients with a single coronary lesion (9.4%, P= 0.027). The frequency of the VF and FF genotype among the 718 patients who had coronary artery stenosis of ≥70% in at least one site was significantly greater than that in the controls (14.1% vs. 9.3%, P= 0.013).

The lipid levels and the risk factors adjusted in logistic regression were studied by comparing genotypes of rs16874954 and rs1051931 for the control and CAD group. For the variant rs1051931 in the CAD patients, the serum TC and LDL-C levels of individuals with the AV and VV genotype were significantly greater than those of individuals with the AA genotype (for TC, 4.50 ± 1.02 vs. 4.34 ± 1.06, P= 0.050; for LDL-C, 2.63 ± 0.85 vs. 2.48 ± 0.86, P= 0.030). There was no association between rs16874954 and the levels of the measured lipids, neither was there any association between the genotypes of either variant and risk factors adjusted in logistic regression, including age, gender, BMI, smoking status, history of diabetes, and positive family history in the CAD patients and the controls.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  8. Supporting Information

The characterization of the role of Lp-PLA2 in the pathogenesis of CAD is particularly challenging because it exhibits both pro- and antiatherosclerotic activities. On one hand, Lp-PLA2 can hydrolyze PAF and oxidized lipid metabolites produced by LDL oxidation and oxidative stress (Yanoshita et al., 1988), thereby exhibiting antiatherosclerotic activity. On the other hand, Lp-PLA2 can also generate lyso-PC and free-oxidized fatty acids that play an important role in promoting atherosclerosis by facilitating hydrolysis of oxidized phospholipids (MacPhee et al., 1999). A previous study showing that recombinant Lp-PLA2 exerted an anti-inflammatory effect in animal models provided evidence for the antiatherosclerotic activity of Lp-PLA2 (Tjoelker et al., 1995b). Furthermore, adenovirus-mediated gene transfer of PLA2G7 in atherosclerosis-prone apoE–/– mice inhibited injury-induced neointima formation and spontaneous atherosclerosis (Quarck et al., 2001). The overexpression of Lp-PLA2 in apoE–/– mice might substantially diminish the chemotaxis of macrophages to aortic roots and inhibit the development of spontaneous atherosclerosis (Noto et al., 2003). Evidence in favour of its proatherogenic function was obtained in a study which revealed that atherosclerotic aorta of the rabbits with hypercholesterolemia showed increased expression of PLA2G7 mRNA and activity of plasma Lp-PLA2 and that administration of an Lp-PLA2 inhibitor led to decreased formation of atherosclerotic lesions (Carpenter et al., 2001). The results of several epidemiological studies conducted in European countries suggest that the mass and the activity of Lp-PLA2 were elevated in CAD patients and the increase is associated with a high risk of developing CAD (Caslake et al., 2000; Packard et al., 2000; Blankenberg et al., 2003; The Lp-PLA2 Studies Collaboration, 2010). A study of darapladib, which produces sustained inhibition of Lp-PLA2 plasma activity, showed that intervention with this drug in the presence of intensive statin therapy might result in additional systemic anti-inflammatory effects (Mohler et al., 2008). Patients receiving the drug had detectable reductions in the area of the necrotic core of atheromatous plaques in coronary arteries (Serruys et al., 2008). Further studies on the effect of Lp-PLA2 inhibitors on CAD are being conducted.

The results of our study on the rs16874954 SNP in exon 9 of the PLA2G7 gene, suggest that the frequency of the FF genotype of rs16874954 is extremely low in Chinese populations, at 0.2% and 0.4% in CAD patients and controls, respectively, which is lower than that reported (4%) in the Japanese population. The missense mutation of this variant leads to a reduced and almost absent Lp-PLA2 activity in East Asian populations (Stafforini et al., 1996; Paik et al., 2010), including the Chinese Han population (Hou et al., 2009), which is partially similar to the intended effect induced by the Lp-PLA2 inhibitor. F allele carriers are reportedly prone to CAD and stroke, and this variant might be an independent risk factor of CAD (Yamada et al., 2000) and stroke (Satoh et al., 1992). In our study, the frequency of the VF and FF genotypes of rs16874954 was significantly greater in the CAD patients than in the controls, and the severity of atherosclerosis (multiple coronary lesions or severe stenosis) was greater in F allele carriers. The results of our study agreed with those of a study conducted in the Japanese population, which showed that the expression of this variant was associated with a high risk of developing CAD (Yamada et al., 1998, 2000). However, Yangsoo Jang and his co-workers observed the opposite in a Korean population (Jang et al., 2006). Although they attributed the discrepancy between their results and those in the Japanese studies to differences in ethnicity or phenotypes, we believe the latter were more predominant. This is because the Korean study included patients with coronary artery stenosis of ≥50% or MI and those with other vascular diseases (e.g., renal artery stenosis and peripheral arterial disease), and all the patients enrolled were male. The results of this loss-of-function mutation in East Asian populations are in contrast with the effect of darapladib on CAD patients, which could indicate that this drug might not have the same effect on East Asians.

In our study, there was no significant difference in the frequency of any rs1051931 genotype between the CAD patients and the controls. However, the frequency of the V379 allele of the rs1051931 polymorphism was significantly greater in the CAD patients with a history of MI than in those without a history of MI. The variant rs1051931 was associated with a higher risk of MI in CAD patients. This result suggests that Lp-PLA2 might play a protective role against the development of CAD and that functional enzyme defects caused by the variation of the rs1051931 site in the Chinese Han population exerted a proatherosclerotic effect, as shown in a study on Taiwanese people by Liu (Liu et al., 2006). In his study, Liu found that polymorphisms of the V379 allele were more frequent in patients with premature MI than in those without premature MI and that the severity of atherosclerosis was greater in V379 allele carriers (Liu et al., 2006). However, studies conducted in European Caucasians furnished completely opposite results. Ninio et al. found that polymorphism of the V379 allele is less frequent in CAD patients than in the controls and was associated with a lower risk of subsequent cardiovascular events (Ninio et al., 2004). A multicentre controlled study conducted in Europe, which compared CAD patients with a history of MI and healthy individuals, revealed that homozygosity for the V379 allele is associated with low risk of MI (Abuzeid et al., 2003). A recent meta-analysis, including 12 studies conducted in European populations, revealed that there was no clear association between the rs1051931 variant and the risk of CAD, although the variant is associated with a modest difference in Lp-PLA2 activity (Casas et al., 2010). We believe that the discrepancies in the results discussed above can be attributed mainly to the ethnicity of the study populations and partly to phenotypes. For example, CAD patients with >30% stenosis in at least one major coronary artery were included in the study by Ninio, whereas post-MI patients aged <60 years were included in the Europe multicentre study. Furthermore, we observed that the LDL-C level was significantly greater in individuals with the AV and VV genotype than in those with the AA genotype in CAD patients. This may reflect the effect of the Lp-PLA2 functional defect on serum LDL level because 70% of Lp-PLA2 binds to LDL. In addition, this effect might aggravate CAD progression in individuals with the AV and VV genotype, rendering them prone to MI; however, the mechanism underlying this effect remains unclear.

An analysis of the association between the rs16874954 and rs1051931 haplotypes and the risk of developing CAD suggests that the FA haplotype is associated with CAD. These results suggest that Lp-PLA2 might be involved in CAD development because the association between haplotype and the disease is more specific and has greater statistical power than that between any individual SNP and CAD.

In summary, we found a significant association between the rs16874954 mutation in PLA2G7 and CAD in the Chinese Han population. Patients with the VF and FF genotype have a higher risk of developing CAD and more severe coronary artery stenosis than others. The rs1051931 variant in CAD patients is associated with a high risk of MI. Further functional studies on these variants are warranted.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  8. Supporting Information
  • Abuzeid, A. M., Hawe, E., Humphries, S. E., Talmud, P. J.; HIFMECH Study Group. (2003) Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe. Atherosclerosis 168, 283288.
  • Blankenberg, S., Stengel, D., Rupprecht, H. J., Bickel, C., Meyer, J., Cambien, F., Tiret, L. & Ninio, E. (2003) Plasma PAF-acetylhydrolase in patients with coronary artery disease. Results of a cross-sectional analysis. J Lipid Res 44, 13811386.
  • Carpenter, K. L., Dennis, I. F., Challis, I. R., Osborn, D. P., Macphee, C. H., Leake, D. S., Arends, M. J. & Mitchinson, M. J. (2001) Inhibition of lipoprotein-associated phospholipase A2 diminishes the death-inducing effects of oxidized LDL on human monocyte-macrophages. FEBS Lett 505, 357363.
  • Casas, J. P., Ninio, E., Panayiotou, A., Palmen, J., Cooper, J. A., Ricketts, S. L., Sofat, R., Nicolaides, A. N., Corsetti, J. P., Fowkes, F. G., Tzoulaki, I., Kumari, M., Brunner, E. J., Kivimaki, M., Marmot, M. G., Hoffmann, M. M., Winkler, K., Marz, W., Ye, S., Stirnadel, H. A., Boekholdt, S. M., Khaw, K. T., Humphries, S. E., Sandhu, M. S., Hingorani, A. D. & Talmud, P. J. (2010) PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10494 cases and 15624 controls of European ancestry. Circulation 121, 22842293.
  • Caslake, M. J., Packard, C. J., Suckling, K. E., Holmes, S. D., Chamberlain, P. & Macphee, C. H. (2000) Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase: A potential new risk factor for coronary artery disease. Atherosclerosis 150, 413419.
  • Hou, L., Chen, S., Yu, H., Lu, X., Chen, J., Wang, L., Huang, J., Fan, Z. & Gu, D. (2009) 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. Hum genet 125, 1120.
  • Jang, Y., Kim, O. Y., Koh, S. J., Chae, J. S., Ko, Y. G., Kim, J. Y., Cho, H., Jeong, T. S., Lee, W. S., Ordovas, J. M. & Lee, J. H. (2006) The Val279Phe variant of the lipoprotein-associated phospholipase A2 gene is associated with catalytic activities and cardiovascular disease in Korean men. J Clin Endocrinol Metab 91, 35213527.
  • Kruse, S., Mao, X. Q., Heinzmann, A., Blattmann, S., Roberts, M. H., Braun, S., Gao, P. S., Forster, J., Kuehr, J., Hopkin, J. M., Shirakawa, T. & Deichmann, K. A. (2000) The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am J Hum Genet 66, 15221530.
  • Liu, P. Y., Li, Y. H., Wu, H. L., Chao, T. H., Tsai, L. M., Lin, L. J., Shi, G. Y. & Chen, J. H. (2006) Platelet-activating factor-acetylhydrolase A379V (exon 11) gene polymorphism is an independent and functional risk factor for premature myocardial infarction. J Thromb Haemost 4, 10231028.
  • MacPhee, C. H., Moores, K. E., Boyd, H. E., Dhanak, D., Ife, R. J., Leach, C. A., Leake, D. S., Milliner, K. J., Patterson, R. A., Suckling, K. E., Tew, D. G. & Hickey, D. M. (1999) Lipoprotein-associated phospholipase A2, platelet-activating factor Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: Use of a novel inhibitor. Biochem J 338(Pt 2), 479487.
  • Mohler, E. R., 3rd, Ballantyne C. M., Davidson, M. H., Hanefeld, M., Ruilope, L. M., Johnson, J. L., Zalewski, A.; Darapladib Investigators. (2008) The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: The results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 51, 16321641.
  • Ninio, E., Tregouet, D., Carrier, J. L., Stengel, D., Bickel, C., Perret, C., Rupprecht, H. J., Cambien, F., Blankenberg, S. & Tiret, L. (2004) Platelet-activating factor-acetylhydrolase and PAF-receptor gene haplotypes in relation to future cardiovascular event in patients with coronary artery disease. Hum Mol Genet 13, 13411351.
  • Noto, H., Hara, M., Karasawa, K., Iso-O, N., Satoh, H., Togo, M., Hashimoto, Y., Yamada, Y., Kosaka, T., Kawamura, M., Kimura, S. & Tsukamoto, K. (2003) Human plasma platelet-activating factor acetylhydrolase binds to all the murine lipoproteins, conferring protection against oxidative stress. Arterioscler Thromb Vasc Biol 23, 829835.
  • Packard, C. J., O’Reilly, D. S., Caslake, M. J., McMahon, A. D., Ford, I., Cooney, J., Macphee, C. H., Suckling, K. E., Krishna, M., Wilkinson, F. E., Rumley, A. & Lowe, G. D. (2000) Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med 343, 114811455.
  • Paik, J. K., Chae, J. S., Jang, Y., Kim, J. Y., Kim, O. Y., Jeong, T. S., Lee, S. H. & Lee, J. H. (2010) Effects of V279F in the Lp-PLA(2) gene on markers of oxidative stress and inflammation in Koreans. Clin Chim Acta 411, 486493.
  • Quarck, R., De Geest, B., Stengel, D., Mertens, A., Lox, M., Theilmeier, G., Michiels, C., Raes, M., Bult, H., Collen, D., Van Veldhoven, P., Ninio, E. & Holvoet, P. (2001) Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice. Circulation 103, 24952500.
  • Satoh, K., Yoshida, H., Imaizumi, T., Takamatsu, S. & Mizuno, S. (1992) Platelet-activating factor acetylhydrolase in plasma lipoproteins from patients with ischemic stroke. Stroke 23, 10901092.
  • Serruys, P. W., Garcia-Garcia, H. M., Buszman, P., Erne, P., Verheye, S., Aschermann, M., Duckers, H., Bleie, O., Dudek, D., Botker, H. E., von Birgelen, C., D’Amico, D., Hutchinson, T., Zambanini, A., Mastik, F., van Es, G. A., van der Steen, A. F., Vince, D. G., Ganz, P., Hamm, C. W., Wijns, W., Zalewski, A.; Integrated Biomarker and Imaging Study-2 Investigators. (2008) Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118, 11721182.
  • Shi, Y. Y. & He, L. (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15, 9798.
  • Shimokata, K., Yamada, Y., Kondo, T., Ichihara, S., Izaws, H., Nagata, K., Murohara, T., Ohno, M. & Yokota, M. (2004) Association of gene polymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. Atherosclerosis 172, 167173.
  • Stafforini, D. M., McIntyre, T. M., Zimmerman, G. A. & Prescott, S. M. (2003) Platelet-activating factor, a pleiotrophic mediator of physiological and pathological processes. Crit Rev Clin Lab Sci 40, 643672.
  • Stafforini, D. M., Prescott, S. M., Zimmerman, G. A. & McIntyre, T. M. (1991) Platelet-activating factor acetylhydrolase activity in human tissues and blood cells. Lipids 26, 979985.
  • Stafforini, D. M., Satoh, K., Atkinson, D. L., Tjoelker, L. W., Eberhardt, C., Yoshida, H., Imaizumi, T., Takamatsu, S., Zimmerman, G. A., McIntyre, T. M., Gray, P. W. & Prescott, S. M. (1996) Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase. J Clin Invest 97, 27842791.
  • The Lp-PLA2 Studies Collaboration, Thompson, A., Gao, P., Orfei, L., Watson, S., Di Angelantonio, E., Kaptoge, S., Ballantyne, C., Cannon, C. P., Criqui, M., Cushman, M., Hofman, A., Pachard, C., Thompson, S. G., Collins, R. & Danesh, J. (2010) Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: Collaborative analysis of 32 prospective studies. Lancet 375, 15361544.
  • Tjoelker, L. W., Eberhardt, C., Unger, J., Trong, H. L., Zimmerman, G. A., McIntyre, T. M., Stafforini, D. M., Prescott, S. M. & Gray, P. W. (1995a) Plasma plateletactivating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad. J Biol Chem 270, 2548125487.
  • Tjoelker, L. W., Wilder, C., Eberhardt, C., Stafforini, D. M., Dietsch, G., Schimpf, B., Hooper, S., Le Trong, H., Cousens, L. S. & Zimmerman, G. A. (1995b) Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature 374, 549553.
  • Yamada, Y., Ichihara, S., Fujimura, T. & Yokota, M. (1998) Identification of the G994/T missense mutation in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men. Metabolism 47, 177181.
  • Yamada, Y., Yoshida, H., Ichihara, S., Imaizumi, T., Satoh, K. & Yokota, M. (2000) Correlations between plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and PAF-AH genotype, age and atherosclerosis in a Japanese population. Atherosclerosis 150, 209216.
  • Yanoshita, R., Kudo, I., Ikizawa, K., Chang, H.W., Kobayashi, S., Ohno, M., Nojima, S. & Inoue, K. (1988) Hydrolysis of platelet-activating factor and its methylated analogs by acetylhydrolases. J Biochem 103, 815819.

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
  8. Supporting Information

Table S1 Multiple logistic regression for the association of PLA2G7 rs16874954 and the risk of CAD, rs1051931 and the risk of MI in CAD patients, using different models

Table S2 Comparisons of the lipids levels and the risk factors by genotypes of rs16874954 for control group

FilenameFormatSizeDescription
AHG_666_sm_SuppMat.doc58KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.