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Clinical Chemistry 50: 2077-2082, 2004. First published September 13, 2004; 10.1373/clinchem.2004.036863
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Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
(Clinical Chemistry. 2004;50:2077-2082.)
© 2004 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Platelet-Activating Factor Acetylhydrolase Is Not Associated with Carotid Intima-Media Thickness in Hypercholesterolemic Sicilian Individuals

Salvatore Campo1, Maria A. Sardo1, Alessandra Bitto1, Antonio Bonaiuto1, Giuseppe Trimarchi2, Michele Bonaiuto1, Maria Castaldo1, Carlo Saitta1, Simona Cristadoro1 and Antonino Saitta1,a

1 Department of Internal Medicine and2 Institute of Statistical Science, School of Medicine, University of Messina, Messina, Italy.

aAddress correspondence to this author at: Department of Internal Medicine, Via Camiciotti, 82, 98123 Messina, Italy. Fax 39-090-2213900; e-mail asaitta{at}unime.it.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Atherosclerosis is a complex, chronic disease that usually arises from the converging action of several pathogenic processes, including hypertension, hyperlipidemia, obesity, and the accumulation of oxidized LDL. Platelet-activating factor acetylhydrolase (PAF-AH) is a LDL- and HDL-bound enzyme that hydrolyzes and inactivates PAF and prevents LDL-cholesterol oxidation, thus delaying the onset of atherosclerotic disease.

Methods: We evaluated the relationship between variants of the PAF-AH gene polymorphisms Arg92His, Ile198Thr, and Ala379Val and the presence of carotid atherosclerosis in 190 hypercholesterolemic Sicilian individuals. Carotid artery intima-media wall thickness (IMT) was measured as an indicator of early atherosclerotic disease. The participants were classified according to having normal (≤1 mm) or abnormal (≥1 mm) IMT and were also investigated for physical characteristics and biochemical indices, including PAF-AH activity.

Results: PAF-AH activity and LDL concentrations were significantly correlated in hypercholesterolemic patients, but plasma PAF-AH activity and HDL were not significantly correlated in either IMT group. No significant differences were detected among the PAF-AH gene polymorphisms in both groups after correction for age, sex, body mass index, plasma glucose and lipid concentrations, PAF-AH activity, blood pressure, and smoking habits. The analysis of PAF-AH genotype distribution showed no significant differences in percentage of 92, 198, and 379 genotypes in both IMT groups.

Conclusion: Our data provided no evidence that PAF-AH polymorphisms influence PAF-AH activity and atherosclerosis in hypercholesterolemic Sicilian patients.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction and lipid and macrophage accumulation in the arterial wall. In hypercholesterolemia, the atherosclerotic process is triggered by increased concentrations of LDL-cholesterol (LDL-C)1 that lead to the retention and accumulation of oxidized bioactive lipids in the subendothelial space, inducing a proinflammatory reaction by vascular cells(1)(2). Thus, LDL oxidation is considered one of the first steps in the early stages of atherosclerosis(3).

Platelet-activating factor acetylhydrolase (PAF-AH) is a hydrophobic enzyme associated with LDL and HDL that inactivates PAF and also plays an important role in preventing LDL oxidation by hydrolyzing oxidized phospholipids(4)(5). PAF has already been described as a potent proinflammatory substance suggested to be a mediator involved in several diseases as well as allergy and atherosclerosis.

In contrast to the antioxidant role of PAF-AH, other studies have shown that lysophosphatidylcholine and oxidized fatty acids exhibiting proatherogenic activities are released during hydrolysis of oxidized phospholipids by PAF-AH(6). It thus is not fully clear whether this enzyme is anti- or proatherogenic in humans.

The PAF-AH gene is located in the 6 q21.2-p12 chromosome. Polymorphisms of this gene have been detected. Two, described only in Japanese populations (Val279Phe and Gln281Arg in exon 9), lead to a complete loss of enzyme activity(7)(8). Other genetic mutations [Arg92His (exon 4, position 275; G>A), Ile198Thr (exon 7, position 593; T>C), and Ala379Val (exon 11, position 1136; T>C)] have been described in European populations(9)(10). In Japanese, several investigations have shown that PAF-AH gene polymorphisms are associated with an increased risk for developing inflammatory diseases such as asthma, stroke, and cardiovascular disease(7)(11)(12)(13)(14). By contrast, in Caucasian populations, no clinical studies have been carried out to examine the possible involvement of the PAF-AH gene in the pathogenesis of atherosclerosis; therefore, the contribution of the PAF-AH gene to the development of atherosclerosis remains unknown in European populations. Carotid artery intima-media wall thickness (IMT) is a clinical sign of early atherosclerotic disease and is regarded as an early marker of morphologic alterations of the vessel wall(15). Vascular remodeling of the carotid artery with IMT is an important predictive factor for cardiovascular disease. IMT has been shown to be strongly associated with an enhanced cardiovascular risk(16).

The aim of the present study was to evaluate the possible relationship between PAF-AH gene Arg92His, Ile198Thr, and Ala379Val polymorphisms and IMT as an early sign of endothelial dysfunction in a sample of hypercholesterolemic Sicilian patients.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study design
The study population was composed of 190 individuals with primary hypercholesterolemia [99 men and 91 women; mean (SD) age, 57:2 (10) years; Table 1 ] recruited from a total of 934 individuals referred to our lipid center from October 2003 through January 2004. Every participant gave informed consent, and the study was approved by the Ethics Committee of University of Messina. All participants were unrelated individuals of Sicilian origin. During the study, all patients were on an isocaloric diet and did not receive any lipid-lowering treatment.


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  		Table 1. Characteristics of patients with normal and abnormal carotid artery IMT.1

Inclusion criteria for study population were a normal electrocardiographic pattern and no history or clinical signs of arterial disease, including coronary artery disease, stroke, or peripheral arterial disease. Individuals with thyroid, liver, or kidney disease or infectious or autoimmune diseases were excluded from the study.

The characteristics of the study population are given in Table 1Up . In all patients, blood pressure, height, and weight were measured by routine methods, and venous blood for clinical chemistry and DNA analysis was collected after overnight fasting.

Hypertension was defined as a blood pressure ≥140/90 mmHg or current use of antihypertensive medications. Diabetes mellitus was defined according to the American Diabetes Association(17) or if the participant was taking insulin or oral hypoglycemic agents. Current smokers were defined as individuals smoking >5 cigarettes/day. After 3 months of pharmacologic wash-out and isocaloric diet, hypercholesterolemia was defined on the basis of total cholesterol concentrations ≥6 mmol/L and triglyceride concentrations <2.5 mmol/L.

All study participants underwent carotid Doppler ultrasonography and laboratory testing, including lipid traits, PAF-AH activity, and DNA isolation. Patients were then classified on the basis of a normal (≤1 mm) or an abnormal (>1 mm) IMT.

The hypercholesterolemic patients divided in the two IMT groups had the same percentages of risk factors, which would provide better evidence on the role of PAF-AH gene polymorphisms and activity on the assessment of carotid atherosclerosis.

lipids and paf-ah determination
Plasma cholesterol, triglycerides, and blood glucose were measured by routine enzymatic methods. HDL-cholesterol was determined after precipitation of the apolipoprotein B-containing lipoproteins with magnesium phosphotungstate. LDL-C was calculated using the Friedewald formula.

PAF-AH activity was measured by a spectrophotometric assay, with detection at 405 nm (Auto PAF-AH-AZ-01; kindly provided by R & D Division, Nesco Company, Azwel Inc., Osaka, Japan)(18).

ultrasound scanning procedure
High-resolution B-mode ultrasound images (Vingmed CFM 750) with a 7.0 MHz linear array transducer were used to measure IMT. The carotid arteries were examined bilaterally in the areas of the common carotid (1 cm proximal to the carotid bulb), the carotid bifurcation (1 cm proximal to the flow divider), and the internal carotid artery (1 cm distal to the flow divider). All measurements were performed manually in longitudinal and transverse planes with anterior, lateral, and posterior approaches. From the B-mode images, single video frames were selected for IMT measurements.

IMT was defined as the distance between the lumen/intima and the media/adventitia interfaces. The mean wall thickness of the common carotid, bulb, and internal carotid artery was used as the key variable for statistical analysis because of its strong association with cardiovascular risk factors(16). Patients were classified according to having a normal (≤1 mm) or an abnormal (>1 mm) maximum IMT.

For each variable, the mean value of measurements performed by the two readers was used. The interobserver variability was evaluated on the measurements obtained from all patients participating in the study. The mean (SD) interobserver variability of IMT measurements, as evaluated by comparing values obtained by two sets of scans evaluated by each reader, was 0.05 (0.03) mm (CV = 2.1%). The interobserver variability was 0.05 (0.02) mm (CV = 3.5%).

paf-ah genotyping
The DNA was extracted from blood according to standard procedures. PAF-AH genotypes were determined by PCR amplification and restriction analysis. PCRs (total volume, 25 µL) contained 150 ng of DNA template, 200 µM each of the deoxynucleotide triphosphates, 400 nM each primer, 1.5 mM MgCl2, and 0.6 U of Taq polymerase (Perkin-Elmer Cetus). PCR included 35 cycles of amplification (3 min at 94 °C followed by 30 s at 95 °C, 20 s at primer-specific annealing temperatures, and 50 s at 72 °C) with a final extension of 10 min at 72 °C.

PCR amplification of the PAF-AH 379T>C polymorphism was performed with the primers 5'-TGACTTTTAAATGTCTTGTT-3' (forward) and 5'-CTGGTTTAGGTCATGAAAAA-3' (reverse; annealing temperature, 58 °C). PCR products were digested with Fnu4h1 (New England Biolabs), and the digestion produced 85- and 126-bp fragments for the 379C allele and a nondigested 211-bp fragment for the 379T allele.

The PAF-AH 198T>C polymorphism was analyzed using the primers 5'-TTCAAGGACCAATCTGCTGCAGAAc-3' (forward) and 5'-TCACCAACCACCTCTCCTTT3-' (reverse; annealing temperature, 60 °C). The lowercase base in the PAF-AH 198 upstream primer indicates a mismatch, introducing a restriction site for Bfa1 (New England Biolabs) After digestion, the 198T allele was identified by 26- and 103-bp fragments, whereas the 198C allele gave a nondigested 129-bp fragment.

PCR amplification of the PAF-AH 92G>A polymorphism was performed with the following primers: 5'-TCTAAAGTGCATTAATTTC3-' (forward); and 5'-ATACATGCAAGACCCTACAA-3' (reverse; annealing temperature, 50 °C). PCR products were digested with Bcl1 (New England Biolabs), and the digestion yielded 74- and 145-bp fragments for the 92A allele and in a nondigested 219-bp fragment for the 92G allele. DNA fragments were separated by electrophoresis on 4% high-resolution agarose gels (agarose HR 3:1; Euro Clone), and PAF-AH genotypes were confirmed by direct sequencing (377 DNA Sequencer; Applied Biosystems).

statistical analysis
Categorical variables among PAF-AH genotypes were compared by the {chi}2 test. Allele frequencies were calculated by the gene-counting method. Hardy–Weinberg equilibrium was assessed by the {chi}2 test. The assumption of gaussian distribution for continuous variables was tested by the Kolmogorov–Smirnov test. Non-gaussian-distributed variables were compared by the Kruskal–Wallis test, the NPC test, and multiple comparisons. Multiple logistic regression analysis was used to assess the contribution of PAF-AH genotypes to the presence of normal or abnormal carotid IMT. The carotid score (dependent variable) was dichotomized into normal (grade 1) or abnormal (grade 2) IMT. Forward stepwise selection was used for model building, and Wald’s statistics were used to determine variables to be removed from the model. Odds ratios and 95% confidences intervals were calculated from the regression ß-coefficients and their SE. P values were calculated by two-sided test; P <0.05 indicated statistical significance.


   Results
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 Materials and Methods
 Results
Discussion
 References
 
The mean (SD) differences in the study variables between normal and abnormal IMT groups [0.73 (0.21) mm (range, 0.5–1 mm) and 1.74 (0.62) mm (range, 1.1–3.7 mm), respectively] are shown in Table 1Up .

We found no significant differences in age, mean body mass index, blood pressure, total cholesterol, HDL-cholesterol, and LDL-C values between the two groups. Total plasma PAF-AH activity [463.71 (110.32) and 471.3 (100.1) U/L, respectively; not significantly different] and PAF-AH activity in HDL-rich plasma [45.62 (14.40) and 49.17 (13.22) U/L, respectively; difference not significant] were comparable in individuals with normal and abnormal IMT. There was a strong correlation between total plasma PAF-AH activity and LDL-C concentrations (r = 0.32; P <0.01).

The PAF-AH genotypes and allele distribution are reported in Table 2 . The frequencies of PAF-AH genotypes were comparable to those reported previously in Caucasian populations(9)(10). The genotype frequencies were in Hardy–Weinberg equilibrium in both the normal and abnormal IMT groups. Linkage disequilibrium was observed between the PAF-AH gene Ile198Thr and Ala379Val polymorphisms ({chi}2 = 14.65; P <0.005). We found no association between Ile198Thr and Arg92His and Ala379Val and Arg92His polymorphisms. The Ala379Val, Ile198Thr, and Arg92His genotype frequencies in both the normal and abnormal IMT groups showed no significant difference in the percentage of each allele, indicating a lack of association between the PAF-AH gene polymorphisms and carotid abnormalities (Table 2 ).


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  		Table 2. Genotype distributions of PAF-AH gene Ala379Val, Ile198Thr, and Arg92His polymorphisms.

We found no significant differences among the PAF-AH polymorphism genotypes relating to PAF-AH activity in plasma (Table 3 ) and in HDL-rich plasma (Table 4 ), age, sex, body mass index, and plasma lipids in either group of patients.


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  		Table 3. Plasma PAF-AH activity and PAF-AH gene Ala379Val, Ile198Thr, and Arg92His polymorphisms.


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  		Table 4. HDL-associated PAF-AH activity and PAF-AH gene Ala379Val, Ile198Thr, and Arg92His polymorphisms.

The data were further confirmed by stepwise forward logistic regression analysis, which showed that no variables entered significantly into the model (data not shown).


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study we showed that in hypercholesterolemic individuals from Sicily, the PAF-AH gene polymorphisms Ala379Val, Ile198Thr, and Arg92His were not associated with the presence of early carotid atherosclerosis. We found that the Arg92His, Ile198Thr, and Ala379Val polymorphisms were not associated with carotid atherosclerosis or with changes in plasma PAF-AH activity in hypercholesterolemic Sicilian patients; thus, these polymorphisms might not be of functional importance in the development of atherosclerosis in these individuals. For example, the polymorphisms could be not causally related to atherosclerosis, but rather appeared to be in linkage disequilibrium with other functional PAF-AH gene variants. Furthermore, the ability of the PAF-AH enzyme to protect against atherosclerosis may be mediated through a mechanism that is at least partially independent of its polymorphic activity.

Some potential biases have been taken into consideration; to limit the inclusion of genetically nonhomogeneous populations, we enrolled only unrelated individuals of Sicilian origin. Moreover, in our sample the distributions of PAF-AH alleles and genotypes were comparable to those reported previously in other Caucasian populations, indicating no segregation of PAF-AH gene variants. Another common bias of allelic association studies is the lack of appropriate control groups; therefore, in the present study, hypercholesterolemic individuals with normal IMT values in each segment examined were used as the control group. Finally, the number of patients may be a potential limitation of this study; however, it should be underlined that the participants of the study were clinically well defined and strictly selected.

Plasma PAF-AH activity was comparable in the normal and abnormal IMT groups. Patients with hypercholesterolemia exhibit premature atherosclerosis mainly as a result of high plasma LDL-C concentrations(19). An increase in plasma PAF-AH activity, reflecting LDL-C values, has been shown in these patients(18)(20)(21); thus, plasma PAF-AH has been proposed as a marker of atherosclerosis. Data from clinical studies, however, have revealed inconsistent findings regarding plasma PAF-AH activity in atherosclerotic disease(22)(23)(24)(25)(26)(27)(28). Moreover, a proatherogenic role of PAF-AH has been hypothesized, based on the fact that, during hydrolysis of oxidized phospholipids, PAF-AH also produces lysophosphatidylcholine and oxidized fatty acids, inflammatory mediators that could promote atherogenesis(6). Recent data suggest that plasma of PAF-AH mass values, which are proportional to the PAF-AH activity and mainly reflect the LDL-associated enzyme, represent an independent risk factor for coronary artery disease(29). By contrast, it has been also reported that in healthy middle-aged women, PAF-AH mass is not a strong predictor of future cardiovascular risk(30). Thus, the role of this enzyme in predicting the risk of cardiovascular disease remains unclear.

The PAF-AH present in HDL has been suggested to act as a reservoir of excess plasma PAF-AH(31). Alternatively, HDL-associated PAF-AH may be related to the protective role of HDL in atherosclerosis, together with other HDL-associated enzymes, including paraoxonase (PON1)(32). Thus, it was speculated that increased HDL-associated PAF-AH activity may contribute to the potential antiinflammatory and antioxidative roles of HDL and thereby to the protection conferred by HDL against atherosclerosis.

Recently, it has been reported that the HDL-associated PON1 can hydrolyze PAF and is primarily responsible for the HDL-associated PAF-AH activity(33). In normo- and dyslypidemic populations, the PON1 gene Leu55Met polymorphism but not the PAF-AH gene Ala379Val polymorphism has been found to be associated with HDL-associated PAF-AH activity(33). It is therefore possible that the lack of changes in HDL-associated PAF-AH activity between individuals with normal and abnormal IMT may depend on the PON1 activity, which was not measured in the present study.

We enrolled hypercholesterolemic patients showing the same percentages of risk factors to better illustrate the role of PAF-AH gene polymorphisms and activity on the assessment of carotid atherosclerosis.

Finally, we hypothesize that Sicilian dietary habits may have influenced our results; in fact, this antioxidant-rich diet may provide better protection against oxidative stress(34)(35). In this case, the relative contribution of the PAF-AH gene polymorphism-dependent alterations may be small compared with those provided by dietary habits. Nevertheless, further investigations taking these factors into consideration should be performed to clarify this assumption.

In conclusion, our data provide no evidence of a significant association between the PAF-AH gene Arg92His, Ile198Thr, and Ala379Val polymorphisms and early carotid atherosclerosis, although we cannot exclude a potential role of the PAF-AH gene in modulating later steps of atherosclerosis.


   Acknowledgments
 
This work was supported in part by grants from the University of Messina (Fondo d’Ateneo).


   Footnotes
 
1 Nonstandard abbreviations: LDL-C, LDL-cholesterol; PAF-AH, platelet-activating factor acetylhydrolase; IMT, intima-media wall thickness; and PON1, paraoxonase.


   References
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 Abstract
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Right arrow Articles by Campo, S.
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Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors

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