Biological and genetic determinants of serum apoC-III concentration: reference limits from the Stanislas Cohort
2003; Elsevier BV; Volume: 44; Issue: 2 Linguagem: Inglês
10.1194/jlr.m200006-jlr200
ISSN1539-7262
AutoresPeggy Tilly, Catherine Sass, Monique Vincent‐Viry, Dominique Aguillon, Gérard Siest, Sophie Visvikis‐Siest,
Tópico(s)Genetic Associations and Epidemiology
ResumoApolipoprotein C-III (apoC-III) is involved in triglycerides metabolism, and is therefore important for the pathogenesis of coronary heart diseases. However, to our knowledge serum apoC-III variation factors and reference limits have never been determined, so the aim of this study was to establish them and facilitate clinical usefulness. We measured serum apoC-III concentration of apparently healthy subjects of the Stanislas Cohort by an immunoturbidimetric method. Genetic polymorphisms within the APOC3, APOE, APOAIV, and LPL genes were determined by a multiplex PCR. Serum apoC-III concentration varied from 28.2 mg/l to 225.8 mg/l in the overall sample and between subjects variability was about 30%. Factors influencing apoC-III concentration were age, BMI in adult men, alcohol consumption in adults, oral contraceptive intake in women, the post-pubescent status in boys.The APOC3 1100T allele in adult men and the APOC3 −455C allele in boys were associated with increased apoC-III concentration. The APOA4 360His allele was associated with decreased apoC-III concentration in women. We also established reference limits of serum apoC-III concentration according to age and gender. Apolipoprotein C-III (apoC-III) is involved in triglycerides metabolism, and is therefore important for the pathogenesis of coronary heart diseases. However, to our knowledge serum apoC-III variation factors and reference limits have never been determined, so the aim of this study was to establish them and facilitate clinical usefulness. We measured serum apoC-III concentration of apparently healthy subjects of the Stanislas Cohort by an immunoturbidimetric method. Genetic polymorphisms within the APOC3, APOE, APOAIV, and LPL genes were determined by a multiplex PCR. Serum apoC-III concentration varied from 28.2 mg/l to 225.8 mg/l in the overall sample and between subjects variability was about 30%. Factors influencing apoC-III concentration were age, BMI in adult men, alcohol consumption in adults, oral contraceptive intake in women, the post-pubescent status in boys. The APOC3 1100T allele in adult men and the APOC3 −455C allele in boys were associated with increased apoC-III concentration. The APOA4 360His allele was associated with decreased apoC-III concentration in women. We also established reference limits of serum apoC-III concentration according to age and gender. Apolipoprotein C-III (apoC-III), a major component of HDL, triglyceride-rich lipoproteins (TRL) (i.e., VLDL and chylomicrons), and, to a lesser extent LDL, plays an important role in the metabolism of these TRLs (1Shachter N.S. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism.Curr. Opin. Lipidol. 2001; 12: 297-304Google Scholar). Therefore, apoC-III concentration is highly and positively correlated to triglyceride concentrations (1Shachter N.S. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism.Curr. Opin. Lipidol. 2001; 12: 297-304Google Scholar). Over-expression of human apoC-III in the plasma of transgenic mice results in hypertriglyceridemia (2Ito Y. Azrolan N. O'Connell A. Walsh A. Breslow J.L. Hypertriglyceridemia as a result of human apo C-III gene expression in transgenic mice.Science. 1990; 249: 790-793Google Scholar, 3Jong M.C. Havekes L.M. Insights into apolipoprotein C metabolism from transgenic and gene-targeted mice.Int. J. Tissue React. 2000; 22: 59-66Google Scholar) and an increase of atherosclerosis (3Jong M.C. Havekes L.M. Insights into apolipoprotein C metabolism from transgenic and gene-targeted mice.Int. J. Tissue React. 2000; 22: 59-66Google Scholar). In contrast, apoC-III-deficient mice are protected from postprandial hypertriglyceridemia and show reduced triglyceride concentrations (3Jong M.C. Havekes L.M. Insights into apolipoprotein C metabolism from transgenic and gene-targeted mice.Int. J. Tissue React. 2000; 22: 59-66Google Scholar). Serum concentration of apoC-III, especially non-HDL apoC-III present on TRL, has been found to be associated with coronary heart disease (CHD) (4Krauss R.M. Atherogenicity of triglyceride-rich lipoproteins.Am. J. Cardiol. 1998; 81: 13B-17BGoogle Scholar, 5Sacks F.M. Alaupovic P. Moye L.A. Cole T.G. Sussex B. Stampfer M.J. Pfeffer M.A. Braunwald E. VLDL, Apolipoproteins B, C-III, and E, and Risk of Recurrent Coronary Events in the Cholesterol and Recurrent Events (CARE) Trial.Circulation. 2000; 102: 1886-1892Google Scholar). It has been proposed that apolipoprotein composition of lipoproteins is more closely linked to CHD than the conventional measurement of lipid content (6Alaupovic P. Significance of apolipoproteins for structure, function, and classification of plasma lipoproteins.Methods Enzymol. 1996; 263: 32-60Google Scholar). Serum apoC-III concentration has been found at higher level in several pathological situations such as type 2 diabetes (7Attia N. Durlach V. Cambilleau M. Roche D. Girard Globa A. Postprandial concentrations and distribution of apo C-III in type 2 diabetic patients. Effect of bezafibrate treatment.Atherosclerosis. 2000; 149: 427-433Google Scholar), hyperbilirubinemia (8Davit-Spraul A. Pourci M.L. Atger V. Cambillau M. Hadchouel M. Moatti N. Legrand A. Abnormal lipoprotein pattern in patients with Alagille syndrome depends on Icterus severity.Gastroenterology. 1996; 111: 1023-1032Google Scholar), kidney deficiency (9Moberly J.B. Attman P.O. Samuelsson O. Johansson A.C. Knight-Gibson C. Alaupovic P. Apolipoprotein C-III, hypertriglyceridemia and triglyceride-rich lipoproteins in uremia.Miner. Electrolyte Metab. 1999; 25: 258-262Google Scholar), and decreased in thyroid dysfunction (10Tada H. Irie Y. Yagoro A. Ohya H. Hayashi S. Fushimi R. Tamaki H. Amino N. Serum concentrations of apolipoproteins in patients with thyroid dysfunction.Thyroidology. 1994; 6: 93-97Google Scholar). Factors reported to influence apoC-III levels in healthy individuals are gender (11Rifai N. Silverman L.M. Immunoturbidimetric techniques for quantifying apolipoproteins CII and C-III.Clin. Chem. 1986; 32: 1969-1972Google Scholar), age, menopause status (12Noma A. Hata Y. Goto Y. Quantitation of serum apolipoprotein A-I, A-II, B, C-II, C-III and E in healthy Japanese by turbidimetric immunoassay: reference values, and age- and sex-related differences.Clin. Chim. Acta. 1991; 199: 147-157Google Scholar), and genetic polymorphisms in the APOC3 gene (13Dallongeville J. Meirhaeghe A. Cottel D. Fruchart J.C. Amouyel P. Helbecque N. Gender related association between genetic variations of APOC-III gene and lipid and lipoprotein variables in northern France.Atherosclerosis. 2000; 150: 149-157Google Scholar, 14Peacock R.E. Temple A. Gudnason V. Rosseneu M. Humphries S.E. Variation at the lipoprotein lipase and apolipoprotein AI-C-III gene loci are associated with fasting lipid and lipoprotein traits in a population sample from Iceland: interaction between genotype, gender, and smoking status.Genet. Epidemiol. 1997; 14: 265-282Google Scholar, 15Dallinga-Thie G.M. Linde-Sibenius T.M. Rotter J.I. Cantor R.M. Bu X. Lusis A.J. de Bruin T.W. Complex genetic contribution of the Apo AI-C-III-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.J. Clin. Invest. 1997; 99: 953-961Google Scholar, 16Groenendijk M. Cantor R.M. Blom N.H. Rotter J.I. de Bruin T.W. Dallinga-Thie G.M. Association of plasma lipids and apolipoproteins with the insulin response element in the apoC-III promoter region in familial combined hyperlipidemia.J. Lipid Res. 1999; 40: 1036-1044Google Scholar). Genetic variants in the APOE, APOA4, and LPL genes are also potential determinants of apoC-III concentration. LPL and apoE are both involved in TRL metabolism (17Weinstock P.H. Bisgaier C.L. Aalto-Setala K. Radner H. Ramakrishnan R. Levak-Frank S. Essenburg A.D. Zechner R. Breslow J.L. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.J. Clin. Invest. 1995; 96: 2555-2568Google Scholar, 18Zhao S.P. Verhoeven M.H. Vink J. Hollaar L. van Der L.A. de Knijff P. 't Hooft F.M. Relationship between apolipoprotein E and low density lipoprotein particle size.Atherosclerosis. 1993; 102: 147-154Google Scholar) and common APOE polymorphisms, and several polymorphisms in the LPL gene have been related to triglyceride concentration (19Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Google Scholar, 20Siest G. Schlenck A. Starck M. Vincent-Viry M. Schiele F. Visvikis S. Apolipoprotein E: Laboratory determinations and clinical significance.in: Rifai N. Warnick G.R. Dominiczak M.H. Handbook of lipoprotein testing. AACC, Washington, DC2000: 401-440Google Scholar). The APOA4 gene is located in the 15 kb APOA4-C3-A1 gene cluster (21Groenendijk M. Cantor R.M. de Bruin T.W. Dallinga-Thie G.M. The apoAI-C-III-AIV gene cluster.Atherosclerosis. 2001; 157: 1-11Google Scholar) and is involved in triglyceride metabolism. Polymorphisms in the APOA4 gene have been related to triglyceride concentrations (22Fisher R.M. Burke H. Nicaud V. Ehnholm C. Humphries S.E. Effect of variation in the apo A-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II.J. Lipid Res. 1999; 40: 287-294Google Scholar). ApoC-III is not frequently measured in clinical investigations, whereas apoA-I and apoB are well tested. Due to the important role of apoC-III in TRL metabolism and the increasing evidence of the implication of these particles in the pathogenesis of cardiovascular diseases, we judged it useful to determine both biological and genetic factors influencing serum apoC-III concentration and establish its reference limits for a Caucasian population coming from the Eastern part of France. Indeed, current values of apoC-III concentration have been evaluated through an immunoturbidimetric method on only a small sample of 100 individuals (11Rifai N. Silverman L.M. Immunoturbidimetric techniques for quantifying apolipoproteins CII and C-III.Clin. Chem. 1986; 32: 1969-1972Google Scholar) or on a larger population composed of non-Caucasian people (12Noma A. Hata Y. Goto Y. Quantitation of serum apolipoprotein A-I, A-II, B, C-II, C-III and E in healthy Japanese by turbidimetric immunoassay: reference values, and age- and sex-related differences.Clin. Chim. Acta. 1991; 199: 147-157Google Scholar). To our knowledge, serum apoC-III concentration reference limits had never been established in Caucasian populations. The studied population has been taken from the Stanislas cohort, a longitudinal familial study that has been previously described (23Siest G. Visvikis S. Herbeth B. Gueguen R. Vincent-Viry M. Sass C. Beaud B. Lecomte E. Steinmetz J. Locuty J. Chevrier P. Objectives, design and recruitment of a familial and longitudinal cohort for studying gene-environment interactions in the field of cardiovascular risk: the Stanislas cohort.Clin. Chem. Lab. Med. 1998; 36: 35-42Google Scholar). The sample population is composed of volunteers for a free 5-year periodic health examination. Subjects were Caucasian and came from the Vosges and the South of Meurthe et Moselle (Eastern part of France). All the individuals were apparently healthy: they were free from serious and/or chronic illnesses known and declared by them, none demonstrated clinical, biochemical or haematological evidence of cardiovascular, hepatic, or renal failures. Each subject gave written informed consent for participating in this study, which was approved by the Local Ethics Committee of Nancy. For this study, the sample population included 865 individuals coming for the second health examination. These subjects did not take any cardiovascular medication. We excluded four subjects for abnormal liver metabolism with γ-glutamyltransferase (GGT) values higher than 300 U/l, alanine aminotransferase values greater than 200 U/l, aspartate aminotransferase greater than 200 U/l, and triglycerides and cholesterol concentrations higher than 10 mmol/l, and a pregnant woman. We also excluded two women with outliers values for apoC-III concentration (lower than 22 mg/l and greater than 240 mg/l) as these values are clearly outliers that do not belong to the reference distribution. The resulting sample contained 858 individuals aged 4 to 58 years old with complete biochemical and physical parameters. For genetic parameters, only 839 individuals among the 858 had complete data. After an overnight fast, venous blood was collected in Vacutainer tubes containing either EDTA for DNA preparation or a gel for serum separation (Becton Dickinson). Puberty was determined using Tanner stages (24Marshall W.A. Tanner J.M. Variations in pattern of pubertal changes in girls.Arch. Dis. Child. 1969; 44: 291-303Google Scholar, 25Marshall W.A. Tanner J.M. Variations in the pattern of pubertal changes in boys.Arch. Dis. Child. 1970; 45: 13-23Google Scholar): pubic hair and sexual maturation were scored by visual assessment (stage 1 represents pre-puberty, stage 2 represents early-puberty, stages 3 and 4 represent mid-puberty, and stage 5 represents late-puberty). Score used in this study is the addition of both sexual and pubic hair maturation scores. Alcohol, tobacco, and drug consumption were collected during the blood sampling by a self-administered questionnaire. Current number of cigarettes, cigars, and pipes smoked daily were recorded. Cigars and pipes tobacco consumption was converted into equivalent cigarette tobacco consumption. Daily wine and beer consumption and weekly spirit consumption have been recorded. Beverages consumption has been convert in grams of alcohol daily consumed. BMI was calculated according to the Quetelet's formula: weight /height 2 (kg/m 2). DNA extraction was performed according to the salting out method described by Miller et al. (26Miller S.A. Dykes D.D. Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 161215Google Scholar). APOC3 (−641T/C, −482C/T, −455T/C, 1100C/T, 3175C/G, and 3206T/G), APOE (Arg 112Cys and Arg158Cys), APOA4 (Thr347Ser and Glu360His), and LPL Ser447Ter were determined by a PCR multilocus genotyping assay, essentially as previously described (27Cheng S. Grow M.A. Pallaud C. Klitz W. Erlich H.A. Visvikis S. Chen J.J. Pullinger C.R. Malloy M.J. Siest G. Kane J.P. A multilocus genotyping assay for candidate markers of cardiovascular disease risk.Genome Res. 1999; 9: 936-949Google Scholar). Concentrations of serum apoC-III were determined by immunoturbidimetry, without any pre-treatment, using COBAS-Mira analyser (Roche Diagnostics) and Daiichi's kits (apoC-III AutoN "Daiichi", reference 241871) and calibrator (Apoauto N "Daiichi" High Calibrator). Antihuman apoC-III polyclonal antibodies from goat were used according to the manufacturer's recommendations. The performance of these assays was examined in control serum samples provided by the manufacturer with assigned values. Data from our assays were included when the values of the control serum samples were within the control ranges established for the control samples. The detection limits for the method used to test apoC-III were 4.38 mg/l for the smallest and 270 mg/l for the largest. The within-series imprecision of apoC-III measurements was estimated to be 2.5% on a serum pool made at the Centre for Preventive Medicine (mean apoC-III concentration of 77.6 mg/l). The day-to-day reproducibility was tested with the same serum pool and was 2.3%. Statistical analyses were performed using BMDP® statistical software (University of California, Los Angeles, CA). Log-transformed values of apoC-III were used as the distribution was skewed. Data were stratified by gender and age with a cut-off value of 20 years for age in order to established reference limits according to age and gender as biological and genetic factors of variation can be different according to gender and age. Analyses were performed separately for four groups: adult men (called men group), adult women (called women group), boys, and girls. Twenty-two sons (21 to 30 years) and 20 daughters (21 to 28 years) were pooled together with fathers and mothers, respectively. Performing analysis without including the oldest children in these groups did not change the results, especially the genetic data. Pearson correlation coefficients between apoC-III concentrations and biological, clinical, and lifestyle variables were calculated. Factors significantly correlated to apoC-III concentration were next introduced in a stepwise multiple regression analysis that was used to determine the most important parameters of apoC-III variability and to quantify the relationships between the apoC-III concentration and these variables. These factors were also used for apoC-III adjustment before the estimation of apoC-III reference limits. We estimated the 2.5th, 5th, 50th, 95th, and 97.5th percentiles in men and women separately. Associations between genetic polymorphisms were investigated by analysis of variance after adjustment for the significant biological covariates. Multiple pairwise comparisons were also performed using a Student's t-test with Bonferroni corrections for multiple comparisons to determine difference between genotypic means. Polymorphisms showing significant relationship with apoC-III concentration were entered in a stepwise multiple regression analysis together with covariates to determine the most important genetic factors of apoC-III variation. Interactions between genetic polymorphisms and environmental factors (gender, age, BMI, or alcohol consumption) were also assessed in multiple regression analysis or in two-way ANOVA after adjustment for covariates. For APOE common polymorphism, three variables, APOE4, APOE3, and APOE2 were generated. The APOE4 group was composed of subjects carrying the ε3/ε4 and ε4/ε4 genotypes; the APOE2 group included ε2/ε2, ε2/ε3 and ε2/ε4 genotypes. We decided to include subjects carrying the ε2/ε4 genotype in the APOE2 group because of the previously observed dominant effect of the ε2 allele on apoB and apoE in this genotype (28Bohnet K. Regis-Bailly A. Vincent-Viry M. Schlenck A. Gueguen R. Siest G. Visvikis S. Apolipoprotein E genotype epsilon 4/epsilon 2 in the STANISLAS Cohort Study—dominance of the epsilon 2 allele?.Ann. Hum. Genet. 1996; 60: 509-516Google Scholar); the results were similar with or without the ε2/ε4 subjects in the APOE2 group. The APOE3 group included only subjects carrying the ε3/ε3 genotype. For studying APOC3 3175 C/G, APOA4 Thr347Ser and Glu360His, and LPL Ser447Ter polymorphisms, individuals homozygous and heterozygous for the less frequent allele were pooled together due to the small number of homozygous subjects. Statistical significance was set at P < 0.05. Characteristics of the sample population are presented in Table 1. They were in agreement with the recruitment of apparently healthy subjects (29Siest G. Henny J. Schiele F. Références en biologie clinique. Elsevier, Paris, Collection BIO1990Google Scholar). Most of the adults were middle-aged. Alcohol and tobacco consumption, as well as drug intake were moderate. All biological parameters had values within reference ranges and BMI values were almost within the reference ranges. Table 2 indicates the allelic frequencies for all the studied polymorphisms, the genotype distribution for each polymorphism being in Hardy-Weinberg equilibrium.TABLE 1Characteristics of the sample populationaMen (n = 219)Women (n = 214)Boys (n = 218)Girls (n = 207)Age (years)42.4 (8.0)40.8 (7.3)15.2 (3.3)15.2 (3.2)BMI (kg/m2)25.2 (3.3)23.8 (4.0)20.1 (2.9)20.3 (3.1)Post puberty stage (%)——38.534.3Menopause status (%)—5.1——Season of recruitmentWinter (%)26.026.228.023.7Spring (%)27.429.928.427.0Summer (%)24.724.322.026.6Autumn (%)21.919.621.622.7Alcohol consumption (g/day)24.4 (27.0)7.1 (13.1)1.7 (5.3)0.7 (2.8)Tobacco consumption (cig/day)5.2 (10.2)2.4 (6.5)1.7 (4.5)1.3 (3.8)Oral contraceptive use (%)—26.6—18.4Anti-inflammatory drug use (%)6.85.10.54.3Bilirubin (μmol/l)13.6 (6.8)10.6 (5.2)13.5 (8.1)10.7 (5.9)Triglyceride (mmol/l)1.37 (0.76)1.02 (0.45)0.87 (0.40)0.92 (0.49)Total Cholesterol (mmol/l)5.71 (1.06)5.58 (0.86)4.27 (0.71)4.63 (0.83)HDL-Cholesterol (mmol/l)1.44 (0.42)1.80 (0.45)1.44 (0.34)1.58 (0.38)ApoC-III (mg/l)100.7 (35.6)88.8 (26.4)70.1 (18.4)76.2 (24.8)Median of ApoCIII (mg/l)93.383.967.872.1a Mean (SD) or percent. Open table in a new tab TABLE 2Allelic frequencies in the population of the studied polymorphismsAlleleAllelic FrequencyAPOC3 −641 C0.414APOC3 −482 T0.297APOC3 −455 C0.399APOC3 1100 T0.277APOC3 3206 G0.354APOC3 3175 G0.101APOA4 347Ser0.213APOA4 360His0.100APOE 20.106APOE 30.769APOE 40.125LPL 447Ter0.125 Open table in a new tab a Mean (SD) or percent. Figure 1showed apoC-III distribution among men, women, boys, and girls. Mean values and medians of serum apoC-III concentration are shown in Table 1. In the total sample, serum apoC-III concentration varied between 28.1 mg/l and 225.8 mg/l. Serum apoC-III concentration was significantly higher in men than in women (P < 0.01), and adults had higher serum apoC-III concentration than children (P < 0.01). There was no difference among children according to gender. The between-subjects variabilities were 35% for men, 30% for women, 26% in boys, and 32% for girls. No influence of tobacco consumption, bilirubin concentration, anti-inflammatory treatment, or the season during which the blood collection had been done was found (P > 0.10) (data not shown). In contrast, both men and boys serum apoC-III concentration was significantly correlated with age and BMI (Table 3). Serum apoC-III concentration was significantly linked to alcohol consumption in adults. The post-pubescent status was related to serum apoC-III concentration in boys and oral contraceptive intake was significantly related to increased serum apoC-III concentration in females. Menopausal status seemed to have no significant influence on serum apoC-III concentration (P = 0.082).TABLE 3Correlations between biological variables and apoCIII concentrationaOnly variables presenting correlation with P value <0.10 in at least one group are presented.Correlation CoefficientMen (n = 219)Women (n = 214)Boys (n = 218)Girls (n = 207)Age0.237bP < 0.001.0.0450.134dP < 0.05.0.133eP < 0.10.BMI0.270bP < 0.001.0.0470.173dP < 0.05.0.085Post puberty——0.200cP < 0.01.−0.008Menopause—0.119eP < 0.10.——Alcohol consumption0.227bP < 0.001.0.225bP < 0.001.0.0850.100Oral contraceptive intake—0.188cP < 0.01.—0.232bP < 0.001.a Only variables presenting correlation with P value <0.10 in at least one group are presented.b P < 0.001.c P < 0.01.d P < 0.05.e P < 0.10. Open table in a new tab The main biological factors of serum apoC-III concentration, determined by stepwise multiple regression analysis, were age (β = 0.0028, P = 0.022), BMI (β = 0.0086, P = 0.004), and alcohol consumption (β = 0.77 10−3, P = 0.035) in men. In women, they were alcohol consumption, oral contraceptive intake, and age (β = 0.0025, P < 0.001; β = 0.092, P < 0.001 and β = 0.0029, P = 0.030 respectively). The main factor of serum apoC-III variation in boys was the post-pubescent status (β = 0.046, P = 0.003) and in girls it was the oral contraceptive intake (β = 0.083, P = 0.001). Reference limits for serum apoC-III concentration were obtained after adjustment for significant biological covariates in each group. Table 4 presents percentiles of serum apoC-III concentration according to age and gender used as partition criteria. Subjects aged 4 to 20 years were pooled together as apoC-III medians were not found significantly different in (4Krauss R.M. Atherogenicity of triglyceride-rich lipoproteins.Am. J. Cardiol. 1998; 81: 13B-17BGoogle Scholar, 5Sacks F.M. Alaupovic P. Moye L.A. Cole T.G. Sussex B. Stampfer M.J. Pfeffer M.A. Braunwald E. VLDL, Apolipoproteins B, C-III, and E, and Risk of Recurrent Coronary Events in the Cholesterol and Recurrent Events (CARE) Trial.Circulation. 2000; 102: 1886-1892Google Scholar, 6Alaupovic P. Significance of apolipoproteins for structure, function, and classification of plasma lipoproteins.Methods Enzymol. 1996; 263: 32-60Google Scholar, 7Attia N. Durlach V. Cambilleau M. Roche D. Girard Globa A. Postprandial concentrations and distribution of apo C-III in type 2 diabetic patients. Effect of bezafibrate treatment.Atherosclerosis. 2000; 149: 427-433Google Scholar, 8Davit-Spraul A. Pourci M.L. Atger V. Cambillau M. Hadchouel M. Moatti N. Legrand A. Abnormal lipoprotein pattern in patients with Alagille syndrome depends on Icterus severity.Gastroenterology. 1996; 111: 1023-1032Google Scholar, 9Moberly J.B. Attman P.O. Samuelsson O. Johansson A.C. Knight-Gibson C. Alaupovic P. Apolipoprotein C-III, hypertriglyceridemia and triglyceride-rich lipoproteins in uremia.Miner. Electrolyte Metab. 1999; 25: 258-262Google Scholar, 10Tada H. Irie Y. Yagoro A. Ohya H. Hayashi S. Fushimi R. Tamaki H. Amino N. Serum concentrations of apolipoproteins in patients with thyroid dysfunction.Thyroidology. 1994; 6: 93-97Google Scholar, 11Rifai N. Silverman L.M. Immunoturbidimetric techniques for quantifying apolipoproteins CII and C-III.Clin. Chem. 1986; 32: 1969-1972Google Scholar, 12Noma A. Hata Y. Goto Y. Quantitation of serum apolipoprotein A-I, A-II, B, C-II, C-III and E in healthy Japanese by turbidimetric immunoassay: reference values, and age- and sex-related differences.Clin. Chim. Acta. 1991; 199: 147-157Google Scholar, 13Dallongeville J. Meirhaeghe A. Cottel D. Fruchart J.C. Amouyel P. Helbecque N. Gender related association between genetic variations of APOC-III gene and lipid and lipoprotein variables in northern France.Atherosclerosis. 2000; 150: 149-157Google Scholar), (14Peacock R.E. Temple A. Gudnason V. Rosseneu M. Humphries S.E. Variation at the lipoprotein lipase and apolipoprotein AI-C-III gene loci are associated with fasting lipid and lipoprotein traits in a population sample from Iceland: interaction between genotype, gender, and smoking status.Genet. Epidemiol. 1997; 14: 265-282Google Scholar, 15Dallinga-Thie G.M. Linde-Sibenius T.M. Rotter J.I. Cantor R.M. Bu X. Lusis A.J. de Bruin T.W. Complex genetic contribution of the Apo AI-C-III-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.J. Clin. Invest. 1997; 99: 953-961Google Scholar, 16Groenendijk M. Cantor R.M. Blom N.H. Rotter J.I. de Bruin T.W. Dallinga-Thie G.M. Association of plasma lipids and apolipoproteins with the insulin response element in the apoC-III promoter region in familial combined hyperlipidemia.J. Lipid Res. 1999; 40: 1036-1044Google Scholar, 17Weinstock P.H. Bisgaier C.L. Aalto-Setala K. Radner H. Ramakrishnan R. Levak-Frank S. Essenburg A.D. Zechner R. Breslow J.L. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.J. Clin. Invest. 1995; 96: 2555-2568Google Scholar), and (18Zhao S.P. Verhoeven M.H. Vink J. Hollaar L. van Der L.A. de Knijff P. 't Hooft F.M. Relationship between apolipoprotein E and low density lipoprotein particle size.Atherosclerosis. 1993; 102: 147-154Google Scholar, 19Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Google Scholar, 20Siest G. Schlenck A. Starck M. Vincent-Viry M. Schiele F. Visvikis S. Apolipoprotein E: Laboratory determinations and clinical significance.in: Rifai N. Warnick G.R. Dominiczak M.H. Handbook of lipoprotein testing. AACC, Washington, DC2000: 401-440Google Scholar) age groups. Concerning the 50th percentile, values of serum apoC-III concentration increased regularly with age in both males and females.TABLE 4Reference limits of apoC-III concentrationAgePercentilesNumber2.55509597.5MenWomenMenWomenMenWomenMenWomenMenWomenMenWomen4–2021820741.039.444.543.568.572.4103.3120.8111.9133.421–4513816850.048.055.352.588.182.8157.4133.0173.8145.546–55aFor women 46–53.794652.754.558.259.0100.091.4161.8134.6178.6145.9Apolipoprotein C-III values were adjusted on all biological covariables affecting apoC-III concentration (alcohol consumption and BMI for men and puberty for boys, alcohol consumption for women and oral contraceptive intake for females) as followed: in boys (4–20) y = Log apoC-III − 0.046 × (puberty status −0.385) with puberty status = 1 if after puberty, else puberty status = 0; in men (21–55) y = Log apoC-III − 0.0099 × (BMI −25.2) − 0.923 10−3 × (alcohol −24.4); in girls (4–20) y = Log apoC-III – 0.083 × (oral contraceptive intake −0.184) with oral contraceptive intake = 1 if use, else = 0; in women (21−53) y = Log apoC-III – 0.068 × (oral contraceptive intake −0.266) − 0.0026 × (alcohol −7.11).a For women 46–53. Open table in a new tab Apolipoprotein C-III values were adjusted on all biological covariables affecting apoC-III concentration (alcohol consumption and BMI for men and puberty for boys, alcohol consumption for women and oral contraceptive intake for females) as followed: in boys (4–20) y = Log apoC-III − 0.046 × (puberty status −0.385) with puberty status = 1 if after puberty, else puberty status = 0; in men (21–55) y = Log apoC-III − 0.0099 × (BMI −25.2) − 0.923 10−3 × (alcohol −24.4);
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