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Journal of Lipid Research, Vol. 44, 2374-2381, December 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Apolipoprotein C-III, metabolic syndrome, and risk of coronary artery disease

Oliviero Olivieri^1,*, Antonella Bassi, Chiara Stranieri, Elisabetta Trabetti, Nicola Martinelli^*, Francesca Pizzolo^*, Domenico Girelli^*, Simonetta Friso^*, Pier Franco Pignatti and Roberto Corrocher^*

^* Unit of Internal Medicine, Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy
Institute of Clinical Chemistry, University of Verona, Verona, Italy
Section of Biology and Genetics, Department of Mother and Child and Biology–Genetics, University of Verona, Verona, Italy

Published, JLR Papers in Press, October 16, 2003. DOI 10.1194/jlr.M300253-JLR200

¹ To whom correspondence should be addressed. e-mail: oliviero.olivieri{at}univr.it

	ABSTRACT

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Apolipoprotein C-III (apoC-III) is a marker of triglyceride (TG)-rich lipoproteins, which are often increased in metabolic syndrome (MS). The T-455C polymorphism in the insulin-responsive element of the APOC3 gene influences TG and apoC-III levels. To evaluate the contribution of apoC-III levels and T-455C polymorphisms in the coronary artery disease (CAD) risk of MS patients, we studied 873 patients, 549 with CAD and 251 with normal coronary arteries. Patients were classified also as having or not having MS (MS, n = 270; MS-free, n = 603). Lipids, insulin, apolipoprotein levels, and APOC3 T-455C genotypes were evaluated. ApoC-III levels were significantly increased in MS patients, and the probability of having MS was correlated with increasing quartiles of apoC-III levels. MS patients with CAD had significantly higher apoC-III levels than did CAD-free MS patients. The carriership for the -455C variant multiplied the probability of CAD in MS in an allele-specific way and was associated with increased apoC-III and TG levels. Obesity was less frequent in MS carriers of the -455C allele than in MS noncarriers (21.6% vs. 34.8%, P < 0.05).

In conclusion, apoC-III-rich lipoprotein metabolism and the APOC3 polymorphism have relevant impacts on the CAD risk of MS patents.

Supplementary key words apolipoproteins • apoC-III • coronary disease • genes • lipids

	INTRODUCTION

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The metabolic syndrome (MS) is a clinical entity characterized by obesity, hypertension, hypertriglyceridemia, low serum HDL cholesterol, and either diabetes mellitus type 2 or glucose intolerance (1). The importance of this clinical clustering as a single pathological entity was recently defined (1), although the underlying etiological factors are as yet mostly unknown. Patients with MS have an enhanced propensity to develop premature arteriosclerosis and an increased cardiovascular disease mortality and morbidity rate (2), and they represent, depending on age, 24% to 42% of the US general population (3). Therefore, it is of paramount importance to identify causal and/or aggravating factors of MS, particularly in terms of cardiovascular disease prevention.

All of the key components of the syndrome have a genetic basis (4, 5). As a consequence, an interaction or multiplicative effects of polymorphisms in a number of different genes may potentially be involved in the pathogenesis (4). Gene mutations interfering with specific insulin or hormone-responsive elements in the regulatory regions have been regarded lately with particular attention (5).

In addition to the presence of hypertriglyceridemia and low serum HDL cholesterol, MS and/or insulin resistance are also characterized by an increase of small LDL particles and triglyceride (TG)-rich lipoproteins, features that also contribute to the cardiovascular disease risk (4–8). One of the most important and reliable markers of TG-rich lipoproteins levels is apolipoprotein C-III (apoC-III). ApoC-III is a 79-amino-acid protein synthesized by liver and intestine, which is an essential constituent of circulating particles rich in triacylglycerol, i.e., chylomicrons and VLDLs. ApoC-III inhibits the hydrolysis of TG-rich particles by the lipoprotein lipase and their hepatic uptake mediated by apoE (9, 10). Therefore, the overexpression of the APOC3 gene results in an overt hypertriglyceridemia [as reviewed in ref. (11)]. In spite of this important role of apoC-III in TG metabolism, relatively few data exist in the literature regarding the relationships between apoC-III and hypertriglyceridemia in MS patients (6–8). The atherogenetic role of apoC-III (12–17), as well as that of hypertriglyceridemia in MS for coronary artery disease (CAD) risk (3–6), is well recognized. However, it is still unclear whether elevated levels of TG-rich lipoproteins and apoC-III are highly coexpressed in MS and what their specific contribution is to the higher risk for cardiovascular disease in MS patients.

The APOC3 gene is transcriptionally downregulated by insulin levels (18), and sequences in the promoter region with high affinity for the nuclear transcription factors mediating the insulin response are highly polymorphic (19). Variants at positions -455 and -482 have been shown to have a reduced affinity for the nuclear transcription factors mediating the insulin response (20), so that they appeared to be the first example of a genetic polymorphism in an insulin-responsive element and of "insulin resistance" at the gene level (20).

Recently, we reported that homozygosity for the APOC3 T-455C variant represents an independent factor for the susceptibility to CAD risk (21). Because homozygosity for the -455C allele is associated with increased levels of TG and apoC-III (21), we hypothesized a possible link between the -455C insulin-resistant variant and the MS phenotype, with a potential additive interaction for CAD risk. To this aim, in a large case-control study of subjects angiographically defined as either CAD or CAD-free, we analyzed TG and apoC-III levels according to the presence of both the MS phenotype and the -455C allele.

	METHODS

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Study population
We studied a total of 873 unrelated adult patients of both genders who were recruited consecutively from those referred to the Institute of Cardiovascular Surgery or to the Cardiovascular-Hypertension Unit of the Department of Internal Medicine of the University of Verona in Italy (the Verona Heart Project). Of these patients, 599 had angiographically documented, severe multivessel coronary atherosclerosis and were candidates for coronary artery bypass grafting (CAD group). As a control group, we considered 274 subjects with angiographically documented normal coronary arteries (CAD-free), examined for reasons other than possible CAD (in >90% of cases, valvular heart disease). The controls were required to have neither history nor evidence of atherosclerosis in other vascular beds. Because the primary aim of our selection was to provide an objective and clear-cut definition of the atherosclerotic phenotype, subjects with nonsignificant coronary stenosis (<50%) were not included in the study. At the time of blood sampling, a complete clinical and pharmacological history, including the presence or absence of the traditional cardiovascular disease risk factors, was obtained. According to these data, patients were classified as having MS (MS group) when at least three of the following elements were present: body mass index (BMI) 30 kg/m², clinically documented history of hypertension or blood pressure >140/90, fasting glucose >110 mg/dl, plasma TG >150 mg/dl, and HDL cholesterol <40 (50 for females) mg/dl. All the remaining patients (including those with only one or two of the above described clinical features) were considered to be MS-free subjects.

The study was approved by our institutional review boards. Either written or oral informed consent was obtained from all patients.

Biochemical analysis
Samples of venous blood were drawn from each subject in the free-living state after an overnight fast. Serum lipids and the other routine biochemical parameters were determined as previously described (21). Insulin was measured by an immunometric "sandwich" assay (Immulite 2000 Insulin) from Diagnostic Products Corporation, Los Angeles, CA; intra- and interassay variation coefficients of the method were <5%. To obtain an estimate of insulin resistance, we applied the homeostasis model assessment (HOMA) of insulin resistance using the following formula: HOMA = fasting insulin (µIU/ml) x fasting glucose (mmol/l)/22.5 (22). ApoA-I, apoB, and apoE were measured by commercially available nephelometric immunoassays; antisera, calibrators and BNII nephelometer were from Dade Behring, Marburg, Germany. Intra-asssay variation coefficient was calculated on 10 control replicates and interassay on duplicates over 10 days. Imprecision was within manufacturer specifications, i.e., the intra-assay variation coefficients were 2.1%, 1.6%, and 1.98%, and interassay variation coefficients were 3.2%, 2.36%, and 3.98% for apoA-I, apoB, and apoE, respectively.

ApoC-III was measured by a fully automated turbidimetric immunoassay. The reagents were obtained from Wako Pure Chemical Industries (Osaka, Japan), and the procedure recommended by the manufacturer was implemented on an RXL Dimension Analyzer (Dade International Inc., Newark, DE). Imprecision was assessed on three pools of control sera with low, medium, and high concentrations of apoC-III; intra-assay variation coefficients were 1.84%, 2.02%, and 1.98%, and interassay variation coefficients were 4.4%, 3.4%, and 2.29% for low, medium, and high concentration, respectively. In a subgroup of patients (CAD, n = 80; CAD-free, n = 36), apoC-III was measured in whole serum as well as heparin-Mn⁺⁺ supernatants and heparin-Mn⁺⁺ precipitates. In this way, apoC-III associated with HDL or with LDL+VLDL fractions was separately quantified.

Genotype analysis
Genomic DNA was extracted from whole blood samples by the phenol-chloroform procedure, and all subjects were genotyped for the APOC3 T-455C polymorphism as previously described (21).

Statistical analysis
All computations were performed using the SPSS 10.0 statistical package (SPSS Inc., Chicago, IL). Distributions of continuous variables were expressed as means ± SD. Logarithmic transformation was performed for skewed variables, i.e., for apoC-III and TG, and the statistical differences concerning these parameters were also computed on the corresponding log-transformed values, although, for the sake of simplicity and clearness, nontransformed data are reported in the Results. Statistical significance for differences in quantitative variables was assessed by Student's unpaired t-test, and it was also tested by one-way ANOVA adjusted for age and/or sex (General Linear Model procedure). Qualitative data were analyzed by the ² test. Correlation between log-transformed total apoC-III (measured in whole serum) and log-transformed apoC-III associated with HDL or associated with LDL-VLDL was evaluated by Pearson coefficient.

The T-455C allele and genotype frequencies were compared, by ² analysis, with the values predicted on the basis of the Hardy-Weinberg equilibrium. Lipid variables were compared among patients with different genotypes by ANOVA, using the Tukey procedure for post hoc multivariate comparison of the means. Odds ratio (OR) and 95% confidence interval (95% CI) for CAD or MS were calculated by logistic regression analysis. In particular, to assess the extent to which APOC3 genotypes and MS were associated with CAD, the population was stratified in six patient groups (TT, TC, and CC genotypes, with or without MS) and OR with 95% CI was estimated by logistic-regression analysis. To provide separate ORs for each genotype, dummy variables were used, considering MS-free TT genotype as the reference group. Adjustment for the risk factors conventionally not associated with MS (age, gender, smoking status, and total cholesterol) was performed by including these covariates in a second set of multivariate logistic regression models. A regression model for formal interaction between MS and the T-455C genotype was also built to estimate the CAD risk proportion associated with the MS genotype term.

	RESULTS

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The clinical characteristics and the T-455C genotype frequencies of CAD and CAD-free patients are summarized in Table 1. CAD patients had more conventional risk factors and significantly higher apoC-III levels than did CAD-free patients (Table 1). Age (OR for CAD = 1.033; 95% CI, 1.016–1.05), male gender (OR = 1.96; 95% CI, 1.22–3.15), LDL cholesterol (OR = 1.456; 95% CI, 1.216–1.74), and smoking (OR = 2.62; 95% CI, 1.64–3.72) were the main predictors of CAD risk. Interestingly, the T-455C polymorphism and MS were also significantly associated with CAD risk. Both the -455C allele (0.403 vs. 0.341; OR for CAD = 1.304; 95% CI, 1.056–1.61) and genotype frequency (OR for CAD = 1.96; 95% CI, 1.22–3.15) were significantly higher in CAD than in CAD-free individuals (Table 1).

View larger version (14K): [in this window] [in a new window]   Fig. 1. Odds ratio for metabolic syndrome (MS) in relation to the percentiles distribution of apolipoprotein C-III in the whole population. 95% CI, 95% confidence interval.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Odds ratio for coronary artery disease in different genotype groups of patients with or without MS.

	DISCUSSION

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The results of the present study suggest that increased apoC-III levels are a common feature of the MS phenotype. ApoC-III levels were, indeed, significantly increased in the majority of MS patients, and the probability of having MS was directly correlated with apoC-III levels divided into quartiles (Fig. 1). Moreover, a relevant interaction able to modulate CAD risk was observed between MS phenotype and the carriership of an APOC3 variant, predisposing to an insulin resistant, abnormal apoC-III production.

Genetic and/or acquired mechanism(s) leading to the development of MS may, directly or indirectly, imply an increased apoC-III synthesis, due either to gene activation and/or to stabilization of its transcript, or to a decreased catabolism of the protein. The former mechanism may reasonably be invoked in the case of carriership of the -455C genetic variant. It has been shown that the most frequent promoter variant, -455T, is associated with a 40–50% insulin-mediated downregulation of APOC3 gene expression (20). In contrast, the less common -455C variant seems associated with the complete loss of the insulin-mediated suppression of APOC3 gene transcription (20). Based on these findings, -455C carriership should lead, in vivo, to an increased synthesis of apoC-III in a proportion ranging from 25% to 50%, depending on the presence of the variant in heterozygosis and homozygosis, even in the presence of an effective cell insulin action. A recent study reported for the first time the reference limits for apoC-III in a large, healthy, French Caucasian population, in which the level corresponding to the 50th percentile for middle-aged men was 10 mg/dl (23). Considering the French values as a reference, our MS Italian Caucasians with either the -455TC or -455CC genotype had apoC-III levels 29% and 53% higher, respectively. Patients with the same genotypes but without MS showed, however, increments of apoC-III by 7% and 11.3%, respectively. Using the apoC-III mean values observed for -455TT MS-free subjects in our population as a reference (10.6 mg/dl, see Table 4), we observed that percent increases of apoC-III for MS patients were substantially similar to those reported in the French study (22% and 44% of increment for heterozygous and homozygous, respectively). There were none or only marginal differences (6.6%) in comparison with the corresponding genotype groups of MS-free patients. Therefore, the comparison of the data predicted by in vitro gene expression studies with those obtained in our human study suggests that the apoC-III-raising effect inherent in the genetic variant cannot be expressed in the absence of MS and becomes detectable only with the coexistence of MS. The opposite situation does not necessarily occur. In fact, increased apoC-III levels in MS do not require the presence of the -455C variant. Indeed, apoC-III was increased also in noncarriers with MS (Table 6), and no difference in distribution of T-455C genotypes was observed between MS and MS-free patients (Table 2). This observation excludes an etiologic role for the gene variant in MS and implies that other independent apoC-III-raising mechanisms, such as a reduced protein catabolic rate, also have to be activated in MS (8). In this context, it should be interesting to verify the role of other recently discovered TG-raising genetic variants on the same apoA3/A4/A5 genes cluster (24–26). Similarly, we cannot exclude the possibility that the -455C mutation is in linkage disequilibrium with these new variants, resulting in being merely a marker for some of them. Our findings indicate, however, that the interaction between the insulin-resistant T-455C gene polymorphism and MS seems to play a synergic role in the expression of MS-associated lipid abnormality and in its impact on CAD risk.

In our study, MS patients affected or not by CAD differed exclusively in lipid metabolism parameters, i.e., total and LDL cholesterol, apoB, apoC-III, and apoE levels (Table 3), suggesting a primary role for lipid abnormalities in CAD risk associated with MS. Furthermore, no differences were observed in apoA-I and HDL cholesterol levels between the two groups. Increased apoB and cholesterol in circulating lipid particles is a well-known feature in CAD patients, but the notion of increased apoC-III and apoE levels in MS patients with CAD is not generally accepted. Sparse information concerning the different MS elements, such as obesity (7, 8, 27) or type II diabetes (28, 29), exist, generally confirming the relation between hypertriglyceridemia and increase of apoC-III and apoE, but there are no specific studies reporting on MS as a unique complex. To the best of our knowledge, there are no studies evaluating the CAD risk of MS patients in relation to the extent of apoC-III increase. Several reports have independently confirmed the role of apoC-III in increasing CAD risk without distinguishing between patients with or without MS (12–17).

It is possible that more accurate information on CAD risk could be obtained by evaluation of non-HDL apoC-III fraction (17), and the lack of availability of these parameters for analysis in our study is certainly a limitation of the present work. However, in a subgroup of patients, total apoC-III concentration was much more strongly correlated with non-HDL fraction (R = 0.93) than with HDL apoC-III (R = 0.38), suggesting that the informative power of the total concentration of the apolipoprotein should be similar to that given by the fraction not associated with HDL.

In our population, MS was associated per se with an odds ratio for CAD of 3.39 (95% CI, 2.35–4.90). Consistent with our previous report (21), -455C homozygosity was also associated with CAD per se, regardless of coexisting MS (see Fig. 2, -455CC no MS group). The new and interesting finding was that a graded, strong interaction in determining CAD risk emerged when both MS and carriership of the -455C gene variant coexist in the same individual (Fig. 2, Table 5). This result is important for at least two reasons: i) it strongly supports the preeminent role of apoC-III-rich lipoproteins in increasing CAD risk in MS patients, because the mathematical relation (a factor 2) we observed between the graded ORs for CAD risk and -455C heterozygosity or homozygosity is difficult to explain without accepting the apoC-III-raising effect of the gene variant on an allelic basis; and ii) a strong interaction was also demonstrated in the cases of heterozygosis for the -455C allele, thus extending the potential impact of the gene variant in terms of general population risk. Because in the general population, 50–70% of individuals are -455C carriers (30–33), the risk deriving from the interaction of this polymorphism with acquired or life-style factors favoring the development of MS is potentially very relevant.

Among all factors, one of the most important is probably obesity (34) or, more generally, a condition of increased calorie availability derived from excess alimentary intake. Its role has been particularly stressed in the case of the association of hyperlipidemia with MS and insulin resistance, in which a liver abundance of free fatty acids flux stimulates the assembly and secretion of TG-rich lipoproteins (35). Recently, obese men with insulin resistance (mean BMI, 33.6 ± 4.1 kg/m²) were demonstrated to have higher plasma apoC-III and TG-rich lipoprotein levels and a lower estimated fractional catabolic rate of these particles (8). Both increased synthesis and reduced catabolic rate of apoC-III rich particles seem, therefore, to be involved in hyperlipidemia observed in MS patients, although the relative contribution of each mechanism remains to be specified. In the case of our MS patients, obese individuals (BMI 30 kg/m²) were significantly less numerous in -455C carriers than in noncarriers (21.6% vs. 34.8%), and carriers had significantly lower BMIs than did noncarriers. There was no apparent reason for this difference (particularly considering that it is the result of a post hoc analysis) unless a causal effect is attributed to -455C carriership. If a reduced catabolic rate of apoC-III-rich lipoproteins is the prevailing mechanism leading to hyperlipidemia in obesity (8), then obese individuals should be preferentially found in the group of -455C noncarriers rather than in the -455C carriers. Another reasonable interpretation is that in -455C carriers, a relatively smaller BMI increase and liver fatty acid flux are required to trigger the cascade of metabolic events peculiar to MS, i.e., an increased synthesis of TG and apoC-III. As a consequence, a generally lower threshold of risk for MS (and, in turn, for CAD) may be hypothesized for -455C carriers, with all the obvious results in terms of cardiovascular disease prevention.

	ACKNOWLEDGMENTS

 
This work was supported by grants from the Ministry of the University and Scientific and Technological Research, the Veneto Region Department of Health, and CNR Target Project Biotechnology.

Manuscript received June 11, 2003 and in revised form September 3, 2003.

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