Apolipoprotein C-III, metabolic syndrome, and risk of coronary artery disease
2003; Elsevier BV; Volume: 44; Issue: 12 Linguagem: Inglês
10.1194/jlr.m300253-jlr200
ISSN1539-7262
AutoresOliviero Olivieri, Antonella Bassi, Chiara Stranieri, Elisabetta Trabetti, Nicola Martinelli, Francesca Pizzolo, Domenico Girelli, Simonetta Friso, Pier Franco Pignatti, Roberto Corrocher,
Tópico(s)Lipoproteins and Cardiovascular Health
ResumoApolipoprotein 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. 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. 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 (1Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).J. Am. Med. Assoc. 2001; 285: 2497-2846Google Scholar). The importance of this clinical clustering as a single pathological entity was recently defined (1Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).J. Am. Med. 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All of the key components of the syndrome have a genetic basis (4Zimmet P. Boyko E.J. Collier G.R. de Courten M. Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players.Ann. N. Y. Acad. Sci. 1999; 892: 25-44Crossref PubMed Scopus (199) Google Scholar, 5Groop L. Orho-Melander M. The dysmetabolic syndrome.J. Intern. Med. 2001; 250: 105-120Crossref PubMed Scopus (189) Google Scholar). As a consequence, an interaction or multiplicative effects of polymorphisms in a number of different genes may potentially be involved in the pathogenesis (4Zimmet P. Boyko E.J. Collier G.R. de Courten M. Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players.Ann. N. Y. Acad. Sci. 1999; 892: 25-44Crossref PubMed Scopus (199) Google Scholar). 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Sci. 1999; 892: 25-44Crossref PubMed Scopus (199) Google Scholar, 5Groop L. Orho-Melander M. The dysmetabolic syndrome.J. Intern. Med. 2001; 250: 105-120Crossref PubMed Scopus (189) Google Scholar, 6Hulthe J. Bokemark L. Wikstrand J. Fagerberg B. The metabolic syndrome, LDL particle size, and atherosclerosis. The Atherosclerosis and Insulin Resistance (AIR) Study.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2140-2147Crossref PubMed Scopus (222) Google Scholar), 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 (18Chen M. Breslow J.L. Li W. Leff T. Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels.J. Lipid Res. 1994; 35: 1918-1924Abstract Full Text PDF PubMed Google Scholar), and sequences in the promoter region with high affinity for the nuclear transcription factors mediating the insulin response are highly polymorphic (19Dammeman M. Sandkuijl L.A. Halaas J.L. Chung W. Breslow J.L. An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3′ untranslated region polymorphisms.Proc. Natl. Acad. Sci. USA. 1993; 90: 4562-4566Crossref PubMed Scopus (206) Google Scholar). Variants at positions −455 and −482 have been shown to have a reduced affinity for the nuclear transcription factors mediating the insulin response (20Li W.W. Dammeman M. Smith J.D. Metzger S. Breslow J.L. Leff T. Common genetic variation in the promoter of the human apoCIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.J. Clin. Invest. 1995; 96: 2601-2605Crossref PubMed Scopus (239) Google Scholar), 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 (20Li W.W. Dammeman M. Smith J.D. Metzger S. Breslow J.L. Leff T. Common genetic variation in the promoter of the human apoCIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.J. Clin. Invest. 1995; 96: 2601-2605Crossref PubMed Scopus (239) Google Scholar). Recently, we reported that homozygosity for the APOC3 T−455C variant represents an independent factor for the susceptibility to CAD risk (21Olivieri O. Stranieri C. Bassi A. Zaia B. Girelli D. Pizzolo F. Trabetti E. Cheng S. Grow M.A. Pignatti P.F. Corrocher R. Apolipoprotein CIII gene polymorphisms and risk of coronary artery disease.J. Lipid Res. 2002; 43: 1450-1457Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Because homozygosity for the −455C allele is associated with increased levels of TG and apoC-III (21Olivieri O. Stranieri C. Bassi A. Zaia B. Girelli D. Pizzolo F. Trabetti E. Cheng S. Grow M.A. Pignatti P.F. Corrocher R. Apolipoprotein CIII gene polymorphisms and risk of coronary artery disease.J. Lipid Res. 2002; 43: 1450-1457Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar), 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. 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 ( 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. 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 (21Olivieri O. Stranieri C. Bassi A. Zaia B. Girelli D. Pizzolo F. Trabetti E. Cheng S. Grow M.A. Pignatti P.F. Corrocher R. Apolipoprotein CIII gene polymorphisms and risk of coronary artery disease.J. Lipid Res. 2002; 43: 1450-1457Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). 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) × fasting glucose (mmol/l)/22.5 (22Matthews D.R. Hosker J.P. Rudenski A.S. Naylor G.A. Treacher D.F. Turner R.L. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia. 1985; 28: 412-419Crossref PubMed Scopus (24799) Google Scholar). 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. 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 (21Olivieri O. Stranieri C. Bassi A. Zaia B. Girelli D. Pizzolo F. Trabetti E. Cheng S. Grow M.A. Pignatti P.F. Corrocher R. Apolipoprotein CIII gene polymorphisms and risk of coronary artery disease.J. Lipid Res. 2002; 43: 1450-1457Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). 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 χ2 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 χ2 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. 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).TABLE 1Characteristics of patients with or without coronary artery diseasea± Values are means ± SD.ParametersCAD Patients (n = 599)CAD-Free (n = 274)PAge (years)60.3 ± 9.457.9 ± 12.4<0.01Male sex (%)81.166.4<0.001BMI (kg/height2)bAge- and sex-adjusted values.26.6 ± 3.425.3 ± 3.5<0.001CholesterolbAge- and sex-adjusted values. Total (mmol/l)5.83 ± 1.115.52 ± 1.04<0.001 LDL (mmol/l)3.89 ± 0.983.55 ± 0.92<0.001 HDL (mmol/l)1.21 ± 0.321.44 ± 0.42<0.001TGs (mmol/l)bAge- and sex-adjusted values.2.01 ± 1.121.47 ± 0.67<0.001ApoA-I (g/l)bAge- and sex-adjusted values.1.30 ± 0.241.43 ± 0.30<0.001ApoB (g/l)bAge- and sex-adjusted values.1.22 ± 0.291.06 ± 0.25<0.001ApoC-III (mg/dl)bAge- and sex-adjusted values.12.34 ± 4.510.65 ± 3.17<0.001ApoE (mg/dl)bAge- and sex-adjusted values.4.80 ± 3.704.33 ± 3.87NSInsulin (μIU/ml)bAge- and sex-adjusted values.15.80 ± 24.215.24 ± 11.6NSUric acid (mmol/l)bAge- and sex-adjusted values.0.36 ± 0.080.37 ± 0.1NSCurrent smoking (%)68.741.5<0.001Hypertension (%)58.331<0.001Diabetes (%)20.79.8<0.01MS patients22842<0.001(%)38.115.3−455C allele frequency0.4030.341<0.02(95% CI)0.375–0.4310.30–0.38T−455C genotypes −455 TT (%)222 (37.1) 115 (42) −455 TC (%)271 (45.2) 131 (47.8) −455 CC (%)106 (17.7) 28 (10.2) 10.58 mg/dl (values corresponding to the third or fourth quartile), and was confirmed even after adjustment for age, sex, total cholesterol, apoA-I, apoB, apoE, TG, and the other MS elements. In the patient samples analyzed by means of heparin-Mn++ centrifugation, total apoC-III was strongly correlated with non-HDL apoC-III concentration (R = 0.93; P < 0.0001) and much more weakly correlated with HDL-associated apoC-III (R = 0.38; P < 0.001).TABLE 2Characteristics of patients with or without MSa± Values are means ± SD.ParametersMS Patients (n = 270)MS-Free (n = 603)PAge (years)58.7 ± 9.659.9 ± 10.8NSMale sex (%)80.774.6<0.05BMI (kg/height2)bSex-adjusted values.28.4 ± 3.024.8 ± 3.1<0.001Glucose (mmol/l)bSex-adjusted values.7.95 ± 6.45.3 ± 0.95<0.05CholesterolbSex-adjusted values. Total (mmol/l)5.81 ± 1.175.76 ± 1.06NS LDL (mmol/l)3.84 ± 1.033.75 ± 0.94NS HDL (mmol/l)1.09 ± 0.261.45 ± 0.36<0.001TG (mmol/l)bSex-adjusted values.2.41 ± 1.231.53 ± 0.76<0.001ApoA-I (g/l)bSex-adjusted values.1.27 ± 0.221.43 ± 0.27<0.001ApoB (g/l)bSex-adjusted values.1.24 ± 0.311.13 ± 0.27<0.001ApoC-III (mg/dl)bSex-adjusted values.13.6 ± 5.12 11 ± 3.40<0.001ApoE (mg/dl)bSex-adjusted values.4.93 ± 3.654.79 ± 3.79<0.05Insulin (μIU/ml)bSex-adjusted values.17.57 ± 35.214.4 ± 8.96 0.01Uric acid (mmol/l)bSex-adjusted values.0.37 ± 0.090.35 ± 0.09<0.001HOMA, upper quartile (%)39.818.8<0.001Current smoking (%)66.757<0.01Hypertension (%)76.137.7<0.001−455C allele frequency0.3800.381NS(95% CI)(0.33–0.42)(0.35–0.41)T−455C genotypes −455 TT (%) 99 (36.7) 238 (39.5) −455 TC (%) 130 (48.1) 272 (45.1) −455 CC (%) 41 (15.2) 93 (15.4)NSHOMA, homeostasis model assessment. Statistical significance for differences was tested by Student's unpaired t-test or by χ2 test when appropriate. P value was considered significant when <0.05.a ± Values are means ± SD.b Sex-adjusted values. Open table in a new tab HOMA, homeostasis model assessment. Statistical significance for differences was tested by Student's unpaired t-test or by χ2 test when appropriate. P value was considered significant when <0.05. There was no difference in T−455C genotype distribution between MS and MS-free patients, and no increase of MS risk was associated with the mutant allele (Table 2). Differences between MS patients with or without CAD were also analyzed (Table 3). The two groups of MS patients were well matched for most parameters, including apoA-I and HDL cholesterol levels, but differed for lipid variables such as total cholesterol, TG, apoC-III, apoB, and apoE levels (Table 3).TABLE 3Characteristics of MS patients, separated into two groups according to the angiographic evidence of CADParametersCAD Patients (n = 228)CAD-Free (n = 42)PAge (years)58.7 ± 9.459.1 ± 10.6NSMale sex (%)8273.8NSBMI (kg/height2)a± Values are means ± SD.28.5 ± 3.128.9 ± 2.4NSCholesterola± Values are means ± SD. Total (mmol/l)5.90 ± 1.175.21 ± 1.05<0.001 LDL (mmol/l)3.92 ± 1.033.49 ± 0.97<0.02 HDL (mmol/l)1.03 ± 0.251.09 ± 0.32NSTGs (mmol/l)a± Values are means ± SD.2.59 ± 1.282.01 ± 0.69 0.001ApoA-I (g/l)a± Values are means ± SD.1.22 ± 0.211.26 ± 0.26NSApoB (g/l)a± Values are means ± SD.1.27 ± 0.311.07 ± 0.26<0.001ApoC-III (mg/dl)a± Values are means ± SD.14.03 ± 5.212.2 ± 4.2<0.02ApoE (mg/dl)a± Values are means ± SD.5.23 ± 3.864.24 ± 1.86<0.01HOMA, upper quartile (%)40.139.5NSUric acid (mmol/l)a± Values are means ± SD.0.37 ± 0.090.40 ± 0.1NSCurrent smoking (%)68.557.1NSHypertension (%)7669.2NS Diabetes (%)4135.1NSStatistical significance for differences was tested by Student's unpaired t-test or by χ2 test when appropriate. P value was considered significant when <0.05.a ± Values are mean
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