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The Val279Phe Variant of the Lipoprotein-Associated Phospholipase A2 Gene Is Associated with Catalytic Activities and Cardiovascular Disease in Korean Men

Division of Cardiology (Y.J., Y.K.G.), Cardiovascular Genome Center, Yonsei Medical Institute, Yonsei University Research Institute of Science for Aging (Y.J., O.Y.K., S.J.K., J.S.C., Y.K.G., J.Y.K., H.C., J.H.L.), Brain Korea 21 Project for Medical Science (S.J.K.), National Research Laboratory of Clinical Nutrigenetics/Nutrigenomics (J.H.L.), Yonsei University, Seoul 120-749, Korea; DNA Link Ltd. (J.Y.K.), Seoul 120-110, Korea; National Research Laboratory of Lipid Metabolism and Atherosclerosis (T.-S.J., W.S.L.), Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Korea; and Nutrition and Genomics Laboratory (J.M.O.), Jean Mayer-U.S. Department of Agriculture-Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111

Address all correspondence and requests for reprints to: Jong Ho Lee, Department of Food and Nutrition, Yonsei University, 134 Shinchon-Ding, Sudaemun-Gu, Seoul 120-749, Korea. E-mail: jhleeb{at}yonsei.ac.kr.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context and Objective: It is unclear whether lipoprotein-associated phospholipase A₂ (Lp-PLA₂) exerts a pro- or antiatherogenic effect on cardiovascular disease (CVD). We investigated the association between Lp-PLA₂ variant (V279F and A379V) and CVD in Korean men.

Design: CVD patients (n = 532) and healthy controls (n = 670) were genotyped for the Lp-PLA₂ 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-PLA₂ 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-PLA₂ 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-PLA₂ plays a proatherogenic and causative role in CVD.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A SINGLE-NUCLEOTIDE polymorphism (SNP),Val279Phe (V279F) missense mutation in the lipoprotein-associated phospholipase A2 (Lp-PLA₂) gene, is found in approximately 30% of the Japanese population (3–4% homozygosity). This leads to loss of catalytic activity in subjects who are heterozygous for the allele and no appreciable enzyme activity in homozygotes (1, 2). The V279F variant in the Lp-PLA₂ gene indicating the loss of enzyme activity has been associated with an increased risk of stroke (3) and coronary artery disease (4) in Japanese volunteers. Yamada et al. (2) reported that the frequency of the V279F variation was significantly higher in individuals who had suffered a myocardial/cerebral infarction and thus suggested the concept that Lp-PLA₂ plays an antiatherogenic role. However, clinical data obtained from recent epidemiological studies of European populations (5) have consistently demonstrated the association of increased levels of Lp-PLA₂ with an increased risk of coronary heart disease, even though V279F variant has not been found in Caucasian populations (6).

A different SNP, Ala379Val (A379V), exists in Caucasians and is functional but may have reduced catalytic activity (6). Recently the V379 allele of the A379V polymorphism was found to be associated with a reduced risk of coronary artery disease in a large European case-control study (7). Interestingly, Abuzeid et al. (8) also found that subjects who are homozygous for the V379 allele (5% of Caucasians) have a reduced risk of coronary heart disease.

It is unclear whether Lp-PLA₂ exerts either a pro- or antiatherogenic effect in humans. Studies on the effects of Lp-PLA₂ genetic variation may provide support for a causal role of Lp-PLA₂ in cardiovascular disease (CVD). In this study, we examined the association of the Lp-PLA₂ V279F genetic variant with CVD through the Korean Cardiovascular Genome Center case-controlled study. We also determined the effects of this Lp-PLA₂ SNP on Lp-PLA₂ activity, low-density lipoprotein (LDL) particle size, and lipid peroxides.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study subjects

Male patients with CVD (n = 532) were recruited from the Cardiovascular Genome Center, Yonsei University Severance Hospital, Seoul, Korea. The inclusion criteria for the study required angiographic evidence with 50% or greater occlusion of one or more major coronary arteries, previous myocardial infarction, angina pectoris or other small vascular disease such as renal artery stenosis, and peripheral arterial disease, but any possible nonatherogenic occlusions such as osteal stenosis and spasm were excluded. Patients with orthopedic limitations, weight loss/gain over the previous 6 months, or any diagnosis of diabetes mellitus, liver disease, renal disease, or thyroid or pituitary disease were also excluded. Healthy male control subjects (n = 670) were recruited either from the Health Service Center during routine check-up visits or by newspaper advertisements briefly describing the study design. The inclusion criteria were age 30 yr or older; no history or diagnosis of atherosclerosis, vascular disease, diabetes mellitus, or cancer (clinically or by anamnesis); and no pathological electrocardiogram patterns. None of the subjects were taking medication. Written informed consent was obtained from all subjects, and the protocol was approved by the Institute of Review Board of Yonsei University.

Anthropometric and blood pressure measurements and blood collection

Body weight and height were measured unclothed and without shoes in the morning. Body mass index (BMI) was calculated as body weight in kilograms divided by height in square meters. Body fat percentages were measured with a TBF-105 body fat analyzer (Tanita Corp., Tokyo, Japan). Waist circumferences were measured with paper tape horizontally at the umbilicus in the standing position after normal expiration. Blood pressure was read from the left arm of seated patients with an automatic blood pressure monitor (TM-2654; A&D, Tokyo, Japan) after 20 min of rest. The average of three measurements was recorded for each subject.

Venous blood specimens were collected in EDTA-treated and plain tubes after a 12-h fast. The tubes were immediately covered with aluminum foil and placed on ice until they arrived at the laboratory room (within 1–3 h) and were stored at –70 C until analysis.

Genotyping of V279F and A379V

Genomic DNA was prepared from peripheral blood samples using a Puregene DNA purification kit (Gentra, Minneapolis, MN), following the manufacturer’s protocol. We genotyped two Lp-PLA₂ SNPs [Val279Phe (V279F) and Ala379Val (A379V)] in 532 CVD male patients and 670 male control subjects. V279F genotyping was performed by a single-base primer extension assay using the SNaPShot assay kit (Applied Biosystems Inc., Foster City, CA) according to the manufacturer’s recommendation. A379V genotyping was performed by using SNP-IT assays with single primer extension technology (SNPstream 25K system; Orchid Biosystems, Princeton, NJ).

Serum lipid profile

Fasting serum concentrations of total cholesterol and triglycerides were measured using commercially available kits on a Hitachi 7150 autoanalyzer (Hitachi Ltd., Tokyo, Japan). After using dextran sulfate magnesium to precipitate serum chylomicron, LDL, and very low-density lipoprotein, the remaining high-density lipoprotein (HDL) cholesterol from the supernatant was measured by an enzymatic method. LDL cholesterol was indirectly estimated in subjects with serum triglyceride concentrations less than 4.52 mol/liter (400 mg/ml) by using the Friedewald formula. In subjects with serum triglyceride concentration 4.52 mol/liter or greater, LDL cholesterol was measured directly. Serum apolipoprotein A-I and B were determined by turbidometry at 340 nm using a specific antiserum (Roche, Basel, Switzerland).

Plasma LDL particle size determination

The particle size distribution of LDL (d = 1.019–1.063 g/ml) was isolated by sequential flotation ultracentrifugation and examined by a pore-gradient lipoprotein system (CBS Scientific, Del Mar, CA) using commercially available nondenaturing polyacrylamide 2–16% gradient slab gels (Alamo Gels Inc., San Antonio, TX). The relative migration rates of each band were estimated using the following standards: latex beads, 34 nm; thyroglobulin, 17 nm; apoferritin, 12.2 nm; and catalase, 10.4 nm. The gels were scanned with a GS-800 calibrated imaging densitometer (Bio-Rad Laboratories, Graz, Austria). LDL particle size was calculated using the relative migration values of the standards as a reference.

Measurement of Lp-PLA₂ activity and plasma oxidized LDL levels

The activity of Lp-PLA₂, which is also known as platelet-activating factor acetylhydrolase (PAF-AH), was measured using a previously described modified method (9). Plasma oxidized LDL was measured using an enzyme immunoassay (Mercodia, Uppsala, Sweden). The resultant color reaction was read at 450 nm with a Victor² (PerkinElmer Life Sciences, Turku, Finland).

Measurements of urinary 8-epiprostaglandin F₂ (8-epi-PGF₂) and plasma malondialdehyde

Urine was collected in polyethylene bottles containing 1% butylated hydroxytoluene after 12 h of fasting. The tubes were immediately covered with aluminum foil and stored at –70 C until analysis. 8-Epi-PGF₂ was measured using an enzyme immunoassay (BIOXYTECH urinary 8-epi-PGF₂ assay kit, OXIS International Inc., Portland, OR). The resulting color reaction from the enzyme immunoassay was read at 650 nm using a Victor² (PerkinElmer Life Sciences). Urinary creatinine was determined by the alkaline picrated (Jeffe) reaction. Urinary 8-epi-PGF₂ concentrations were expressed as picomoles per millimole of creatinine. Plasma malondialdehyde (MDA) was assayed according to the fluorometric method described by Buckingum (10).

Statistical analysis

Statistical analyses were performed with SPSS (version 12.0 for Windows; Statistical Package for the Social Science, SPSS Inc., Chicago, IL). Hardy Weinberg equilibrium was examined using the Executive SNP analyzer version 1.0 (http://www.istech.info/SilicoSNP/index.html). To compare the differences in baseline characteristics between control subjects and CVD patients [taking or not taking lipid-lowering drug (LLD)], we performed an independent t test, one way-ANOVA, or general linear model test followed by Bonferroni method with adjustment of anthropometries and lifestyle factors. Also, we compared the differences in biomarkers according to genotype in control subjects and CVD patients, respectively. To find correlation between Lp-PLA₂ and common CVD risk like anthropometric parameters and lipid profile, we performed Pearson correlation test. The association between CVD and genotype was calculated by odds ratio (OR) [95% confidence intervals (CIs)] using ² test and logistic regression adjusting for anthropometries and lifestyle factors. Each variable was examined for normal distribution patterns. Significantly skewed variables were log transformed. For descriptive purposes, mean values are presented using untransformed and unadjusted values. Results are expressed as mean ± SE. A two-tailed value of P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical features of control subjects and CVD patients are shown in Table 1. CVD patients were treated with antidyslipidemic (40.0%), antihypertensive (58.3%), or antiplatelet drugs (57.3%); thus, we subdivided CVD patients into two groups: those not treated with LLD and those treated with LLD. Compared with control subjects, both CVD groups were older and had higher waist circumference and waist to hip ratio (WHR). However, BMI was significantly highest in CVD men taking LLD. The proportion of cigarette smoking and alcohol consumption was significantly different between control and CVD patients (P < 0.001). The mean plasma Lp-PLA₂ activities were lower in control (18.3 ± 0.4 nmol/ml·min) compared with CVD patients, particularly those not taking LLD (20.0 ± 0.5 nmol/ml·min; P < 0.05), which still remained after adjustment for age, BMI, waist circumference, WHR, cigarette smoking, and alcohol consumption (P < 0.01). CVD patients showed lower levels of LDL cholesterol and smaller LDL particle size than control subjects before (P < 0.001, P < 0.05, respectively) and after the adjustment (P < 0.001, P < 0.001, respectively) (Table 1).

Genotype distributions were within the Hardy-Weinberg equilibrium in the population as a whole and in cases and controls separated. Significant difference in the genotypic distribution of the V279F SNP (P = 0.005) was observed (Table 2). Men homozygous for the common V alleles were less frequent in controls, compared with CVD patients. In contrast, CVD and control subjects had a similar genotypic distribution of the A379V SNP.

Clinical characteristics and Lp-PLA₂ activity associated with the V279F genotype

There were no significant genotype-related differences among control subjects having the V279F SNP genotype with respect to age, BMI, smoking, alcohol consumption, calorie intake, or total energy expenditure (data not shown). Similarly, in CVD patients differences among genotype groups were not found with regard to age, BMI, smoking, alcohol consumption, calorie intake, energy expenditure, or pharmacological interventions (data not shown). Figure 1 shows the influence of V279F genotype on Lp-PLA₂ activity in controls and CVD patients. There was a significant association between the Lp-PLA₂ activity and the V279F genotype in controls (P < 0.001), CVD patients with LLD (P < 0.001), and those without LLD (P < 0.001). In addition, Lp-PLA₂ activity was 31.3, 25.7, and 23.1% lower in CVD patients with LLD and those without LLD and controls, respectively. Controls and all CVD patients with the F/F genotype showed no appreciable enzymatic activity.

View larger version (16K): [in this window] [in a new window]   FIG. 1. Influence of V279F genotypes on Lp-PLA2 activity and LDL particle size in control subjects and CVD patients (, VV; , VF; , FF). Mean ± SE. Means not sharing a common superscript letter are significantly different at P < 0.05 based on one-way ANOVA with Kruskal-Wallis test in control subjects, CVD patients taking LLD, and CVD patients not taking LLD, respectively.

In control subjects, the V279F Lp-PLA₂ gene polymorphism was associated with LDL particle size (P < 0.05) (Fig. 1) and the circulating concentrations of LDL-cholesterol (P < 0.05) (Table 4) and MDA (P < 0.01) (Fig. 2). Control subjects with the V/F genotype had a significantly larger LDL particle size than those with the V/V genotype. LDL particle size was significantly smaller in CVD patients than control subjects of the same genotype (Fig. 1). Control subjects with the F/F genotype had lower LDL cholesterol concentrations than subjects with the V/V or V/F genotype (Table 4). Control subjects carrying the F allele showed significantly lower plasma concentrations of MDA than those with the V/V genotype (Fig. 2). However, none of these associations was observed in CVD patients. Subjects carrying the F allele showed slightly, but not significantly, lower urinary excretion of PGF₂ than those with the V/V genotype (Fig. 2).

View larger version (18K): [in this window] [in a new window]   FIG. 2. Influence of V279F genotypes on MDA and PGF2 in control subjects and CVD patients (, VV; , VF; , FF). Mean ± SE. Means not sharing a common superscript letter are significantly different at P < 0.05 based on one-way ANOVA with Kruskal-Wallis test in control subjects, CVD patients taking LLD, and CVD patients not taking LLD, respectively.

By Pearson correlation analysis, we found that Lp-PLA₂ was positively correlated with LDL cholesterol (control: r = 0.124, P < 0.01; CVD total: r = 0.095, P < 0.05; CVD patients with LLD: r = 0.174, P < 0.05) and negatively correlated with HDL cholesterol (control: r = –0.159, P < 0.001; CVD patients with LLD: r = –0.145, P < 0.05). However, we could not find any statistically significant correlation between Lp-PLA₂ activity and anthropometric parameters or smoking status.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The major finding of this study is that the frequency of a Lp-PLA₂ loss-of-function variant, V279F, was significantly lower in individuals with CVD. This finding supports the concept that Lp-PLA₂ may play a proatherogenic and causative role in CVD. The V279F variant led to significant loss (23% in control subjects, 27% in CVD patients) of enzyme in heterozygous subjects and no appreciable enzyme activity in homozygous subjects. This loss of activity from a V279F substitution is supported by several previous reports including Miwa et al. (11), Naoki et al. (12), and Yamada et al. (2, 4). According to Karasawa et al. (13), the deficiencies of plasma PAF-AH activity are due to a loss-of-function mutation (Val279Phe, exon 9, position 994; GT) in the plasma PAF-AH gene because Val-279 conserved in plasma PAF-AH lies between the active site Ser-273 and Asp-296 residues in a region that is critical for proper folding of the enzyme. Stafforini et al. (14) performed immunoreactivity to observe whether PAF-AH protein could be expressed to the same level by bacteria transformed with mutant constructs (Phe²⁷⁹) as well as with the normal constructs and found that the normal construct yielded a protein with enzymatic activity, whereas the Phe²⁷⁹ construct resulted in inactive protein. This result indicates that the Val²⁷⁹Phe mutation abolishes the enzymatic activity of PAF-AH. In addition, Ishihara et al. (1) reported that complete absence of Lp-PLA₂ in subjects with F/F (279) was caused by a defect in enzyme secretion. Kim and Arvan (16) and Zhang and Kaufman (17) also reported that misfolded Val279Phe protein is not secreted.

Overall, the lower activity of the F279 allele in Korean men was associated with a significantly lower risk (32%) of CVD after the results were adjusted for age, WHR, and lifestyle factors. However, the proatherogenic role for Lp-PLA₂ observed in this study contrasts with a previous study of the Japanese population, which found an antiinflammatory and antiatherogenic role for Lp-PLA₂ (2, 4, 18). This discrepancy might be explained by either ethnic specificity of the genetic variations present in Korean and Japanese populations or the difference in the phenotypes (i.e. myocardial/cerebral infarct vs. CVD, including approximately 80% coronary angiography-defined atherosclerosis).

The present finding of elevated Lp-PLA₂ activity in men with CVD agrees with the results of European population studies (7, 19, 20, 21, 22) that found a positive association between enzyme activity and susceptibility to atherosclerosis. The most recent evidence from epidemiological studies in Caucasian populations (19, 21, 23, 24, 25) suggests that Lp-PLA₂ is a potential novel risk factor for CVD. In these studies, Lp-PLA₂ predicts risk independently of other inflammatory markers, such as C-reactive protein and fibrinogen as well as classic risk factors such as smoking and LDL cholesterol. In addition, Lp-PLA₂ inhibition in Watanabe heritable hyperlipidemic rabbits showed a significant reduction of atherogenesis (26). Furthermore, Naoki et al. (12) found that healthy individuals homozygous for the V279F mutation and without appreciable Lp-PLA₂ activity did not show an expected inflammatory response to inhaled platelet-activating factor (12).

Our study shows an association between the V279F genotype and LDL particle size in control subjects. These results may support the previous findings that Lp-PLA₂ is enriched and has increased activity in the highly atherogenic small dense LDL (27). A study by Guerra et al. (28) also suggested that elevated Lp-PLA₂ levels reflect the presence of small LDL particles that are slowly cleared from the circulation system. The preferential binding of Lp-PLA₂ to smaller, denser LDL species is possible because of the distinctive conformation apolipoprotein B adopts in small LDL, compared with large LDL (27, 29). In addition, the high enzymatic activity, small LDL particle size, and low LDL cholesterol level we found in patients with CVD could support an association among the Lp-PLA₂ genotype, Lp-PLA₂ levels, small dense LDL species, and CVD risk.

In contrast to control subjects, CVD patients did not show the genotypic effects of V279F on LDL particle size and circulating levels of MDA. This difference may reflect that the CVD progression is related to small LDL particle size and lipid peroxidation (30, 31) regardless of the V279F genotype. For example, the treatment of CVD patients with lipid-lowering drugs may also account for the lack of a V279F genotypic effect on LDL particle size, MDA, and LDL cholesterol. In fact, LLDs are found to influence LDL cholesterol, dense LDL concentrations, and Lp-PLA₂ activity (32, 33). However, we cannot draw definitive conclusions from our observations of the F/F genotype because of the small number of control subjects (n = 8) with this genotype in our study.

The key role of Lp-PLA₂ in atherogenesis is the hydrolysis of oxidized LDL and the production of the proinflammatory, atherogenic byproducts, lysophosphatidyl choline, and oxidized free fatty acid (5). In addition, Lp-PLA₂ in LDL particles may release arachidonic acid, a precursor of eicosanoids such as prostaglandins and leukotrienes (15). This concept indicates that Lp-PLA₂ may have an active role in atherogenesis rather than simply being a risk factor (32). The lower levels of lipid peroxides, such as circulating MDA, found in the F279 allele control subjects may be related to lower Lp-PLA₂ activity rather than oxidized LDL because oxidized LDL concentrations between the F279 and V/V genotypic groups were not significantly different.

Several points should be considered when interpreting our findings. First, one of our study limitations is the measurement of Lp-PLA₂ activity rather than the Lp-PLA₂ mass, despite the previously found correlation (0.86) between Lp-PLA₂ mass and activity (18). Second, our results share the limitations of cross-sectional, observational studies. We evaluated association, not prospective prediction. Third, the frequency of F/F homozygous subjects was similar between healthy male controls (1.2%) and CVD male patients (1.3%), but the frequency of heterozygous subjects was significantly lower in CVD men (17.8%) than the control population (25.7%). Finally, because the male sex is an important risk factor for CVD, in our study we specifically focused on a representative group of Korean men. Therefore, our data cannot be generalized to other ethnic groups, women, or other populations.

Despite these limitations, our results show an association between the loss of function F279 variant and a reduced risk of CVD. This finding supports a proinflammatory and causal role of Lp-PLA₂ in CVD. Therefore, we suggest that Lp-PLA₂ V279F genotype determination or plasma enzyme activity assays may identify subjects who are at greater risk of CVD, especially in men who lack conventional risk factors. These indicators could be used to specifically target these subjects for preventive programs that help reduce CVD later in life.

	Footnotes

 
This work was supported by the National Research Laboratory Project (2005-01572), Ministry of Science and Technology, Seoul, Korea; Korea Science and Engineering Foundation, Seoul, Korea (R01-2003-0000-11709-0); Korea Health 21 R&D Projects (00-PJ3-PG6-GN-01-0001), Ministry of Health and Welfare, Seoul, Korea; National Institutes of Health/National Heart, Lung, and Blood Institute (HL54776) and contracts 53-K06-5-10 and 58-1950-9-001 from the U.S. Department of Agriculture Research Service, Beltsville, MD.

First Published Online June 20, 2006

¹ Y.J. and O.Y.K. contributed equally to this work.

Abbreviations: BMI, Body mass index; CI, confidence interval; CVD, cardiovascular disease; 8-epi-PGF₂, 8-epiprostaglandin F₂; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LLD, lipid-lowering drug; Lp-PLA₂, lipoprotein-associated phospholipase A2; MDA, malondialdehyde; OR, odds ratio; PAF-AH, platelet-activating factor acetylhydrolase; SNP, single-nucleotide polymorphism; WHR, waist to hip ratio.

Received January 19, 2006.

Accepted June 13, 2006.

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