Phytosterol plasma concentrations and coronary heart disease in the prospective Spanish EPIC cohort
2009; Elsevier BV; Volume: 51; Issue: 3 Linguagem: Inglês
10.1194/jlr.p000471
ISSN1539-7262
AutoresVerónica Escurriol, Montserrat Cofán, Concepción Moreno-Iribas, Nerea Larrañaga, Carmen Martínez, Carmen Navarro, Laudina Rodríguez, Carlos A. González, Dolores Corella, Emilio Ros,
Tópico(s)Hormonal Regulation and Hypertension
ResumoPhytosterol intake with natural foods, a measure of healthy dietary choices, increases plasma levels, but increased plasma phytosterols are believed to be a coronary heart disease (CHD) risk factor. To address this paradox, we evaluated baseline risk factors, phytosterol intake, and plasma noncholesterol sterol levels in participants of a case control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) Spanish cohort who developed CHD (n = 299) and matched controls (n = 584) who remained free of CHD after a 10 year follow-up. Sitosterol-to-cholesterol ratios increased across tertiles of phytosterol intake (P = 0.026). HDL-cholesterol level increased, and adiposity measures, cholesterol/HDL ratios, and levels of glucose, triglycerides, and lathosterol, a cholesterol synthesis marker, decreased across plasma sitosterol tertiles (P < 0.02; all). Compared with controls, cases had nonsignificantly lower median levels of phytosterol intake and plasma sitosterol. The multivariable-adjusted odds ratio for CHD across the lowest to highest plasma sitosterol tertile was 0.59 (95% confidence interval, 0.36–0.97). Associations were weaker for plasma campesterol. The apolipoprotein E genotype was unrelated to CHD risk or plasma phytosterols. The data suggest that plasma sitosterol levels are associated with a lower CHD risk while being markers of a lower cardiometabolic risk in the EPIC-Spain cohort, a population with a high phytosterol intake. Phytosterol intake with natural foods, a measure of healthy dietary choices, increases plasma levels, but increased plasma phytosterols are believed to be a coronary heart disease (CHD) risk factor. To address this paradox, we evaluated baseline risk factors, phytosterol intake, and plasma noncholesterol sterol levels in participants of a case control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) Spanish cohort who developed CHD (n = 299) and matched controls (n = 584) who remained free of CHD after a 10 year follow-up. Sitosterol-to-cholesterol ratios increased across tertiles of phytosterol intake (P = 0.026). HDL-cholesterol level increased, and adiposity measures, cholesterol/HDL ratios, and levels of glucose, triglycerides, and lathosterol, a cholesterol synthesis marker, decreased across plasma sitosterol tertiles (P < 0.02; all). Compared with controls, cases had nonsignificantly lower median levels of phytosterol intake and plasma sitosterol. The multivariable-adjusted odds ratio for CHD across the lowest to highest plasma sitosterol tertile was 0.59 (95% confidence interval, 0.36–0.97). Associations were weaker for plasma campesterol. The apolipoprotein E genotype was unrelated to CHD risk or plasma phytosterols. The data suggest that plasma sitosterol levels are associated with a lower CHD risk while being markers of a lower cardiometabolic risk in the EPIC-Spain cohort, a population with a high phytosterol intake. Dietary sterols consist of animal-derived cholesterol and plant-derived noncholesterol sterols or phytosterols. Phytosterols are important components of a vegetable-based diet and are particularly abundant in whole grains, nuts, seeds, and oils derived from them. The principal molecular forms are sitosterol and campesterol (1Moreau R.A. Whitaker B.D. Hicks K.B. Phytosterols, phytostanols, and their conjugates in foods: structural diversity, quantitative analysis, and health-promoting uses.Prog. Lipid Res. 2002; 41: 457-500Crossref PubMed Scopus (865) Google Scholar). These compounds are structurally related to cholesterol but have bulkier and more hydrophobic molecules, which confer them a higher affinity for intestinal micelles than has cholesterol. Consequently, cholesterol is displaced from micelles, and the amount available for absorption is limited. The phytosterol content of usual diets is similar to that of cholesterol (150 to 450 mg/day), but their intestinal absorption is much less efficient (see review in Ref. 2von Bergmann K. Sudhop T. Lütjohann D. Cholesterol and plant sterol absorption: recent insights.Am. J. Cardiol. 2005; 96: 10D-14DAbstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Because of low absorption and rapid biliary elimination, physiological plasma concentrations of phytosterols are in the order of 10−3 those of cholesterol. Their ratios to cholesterol are accepted as surrogate markers for the efficiency of cholesterol absorption, while those of the cholesterol precursor lathosterol are a reliable index of cholesterol synthesis (3Miettinen T.A. Tilvis R.S. Kesäniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Crossref PubMed Scopus (558) Google Scholar). The lower absorption of phytosterols compared with cholesterol is attributable to active resecretion back into the intestinal lumen, a process that is mediated by the half-transporters ABCG5 and ABCG8. Genetic defects in these transporters (4Berge K.E. Tian H. Graf G.A. Yu L. Grishin N.V. Schultz J. Kwiterovich P. Shan B. Barnes R. Hobbs H.H. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.Science. 2000; 290: 1771-1775Crossref PubMed Scopus (1348) Google Scholar, 5Lee M.H. Lu K. Hazard S. Yu H. Shulenin S. Hidaka H. Kojima H. Allikmets R. Sakuma N. Pegoraro R. et al.Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.Nat. Genet. 2001; 27: 79-83Crossref PubMed Scopus (0) Google Scholar, 6Lu K. Lee M.H. Hazard S. Brooks-Wilson A. Hidaka H. Kojima H. Ose L. Stalenhoef A.F. Mietinnen T. Bjorkhem I. et al.Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.Am. J. Hum. Genet. 2001; 69: 278-290Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar) cause sitosterolemia, a rare autosomal recessive disorder characterized by intestinal sterol hyperabsorption, raised plasma phytosterol levels, xanthomas, and accelerated atherosclerosis. Because of the presumed pathogenic role of elevated plasma phytosterols in sitosterolemia, the question whether high levels of circulating phytosterols might also be atherogenic in nonsitosterolemic individuals has been much debated (7Chan Y.M. Varady K.A. Lin Y. Trautwein E. Mensink R.P. Plat J. Jones P.J. Plasma concentrations of plant sterols: physiology and relationship with coronary heart disease.Nutr. Rev. 2006; 64: 385-402Crossref PubMed Google Scholar, 8Katan M.B. Grundy S.M. Jones P. Law M. Miettinen T. Paoletti R. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels.Mayo Clin. Proc. 2003; 78: 965-978Abstract Full Text Full Text PDF PubMed Google Scholar). This is a substantial concern, given that inhibition of cholesterol absorption by gram doses of phytosterols incorporated into various foods is widely used as a nonpharmacological strategy for cholesterol lowering but is associated with increased serum phytosterol concentrations (8Katan M.B. Grundy S.M. Jones P. Law M. Miettinen T. Paoletti R. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels.Mayo Clin. Proc. 2003; 78: 965-978Abstract Full Text Full Text PDF PubMed Google Scholar). Results of epidemiological studies have suggested either a direct association between plasma phytosterols and coronary heart disease (CHD) risk (9Glueck C.J. Speirs J. Tracy T. Streicher P. Illig E. Vandegrift J. Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives.Metabolism. 1991; 40: 842-848Abstract Full Text PDF PubMed Scopus (178) Google Scholar, 10Rajaratnam R.A. Gylling H. Miettinen T.A. Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women.J. Am. Coll. Cardiol. 2000; 35: 1185-1191Crossref PubMed Scopus (143) Google Scholar, 11Sudhop T. Gottwald B.M. von Bergmann K. Serum plant sterols as a potential risk factor for coronary heart disease.Metabolism. 2002; 51: 1519-1521Abstract Full Text PDF PubMed Scopus (185) Google Scholar, 12Assmann G. Cullen P. Erbey J. Ramey D.R. Kannenberg F. Schulte H. Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: results of a nested case-control analysis of the Prospective Cardiovascular Munster (PROCAM) study.Nutr. Metab. Cardiovasc. Dis. 2006; 16: 13-21Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar) or a null (13Pinedo S. Vissers M.N. von Bergmann K. Elharchaoui K. Lutjohann D. Luben R. Wareham N.J. Kastelein J.J. Khaw K.T. Boekholdt S.M. Plasma levels of plant sterols and the risk of coronary artery disease: the prospective EPIC-Norfolk Population Study.J. Lipid Res. 2007; 48: 139-144Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 14Windler E. Zyriax B.C. Kuipers F. Linseisen J. Boeing H. Association of plasma phytosterol concentrations with incident coronary heart disease. Data from the CORA study, a case-control study of coronary artery disease in women.Atherosclerosis. 2009; 203: 284-290Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar) and even inverse association (15Fassbender K. Lutjohann D. Dik M.G. Bremmer M. Konig J. Walter S. Liu Y. Letièmbre M. von Bergmann K. Jonker C. Moderately elevated plant sterol levels are associated with reduced cardiovascular risk—The LASA study.Atherosclerosis. 2008; 196: 283-288Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). A relevant yet unexplored issue is the effect on CHD risk of naturally occurring phytosterols in the usual diet. Two large cross-sectional studies have shown a weak inverse association between dietary phytosterol intake and plasma total and LDL-cholesterol levels (16Andersson S.W. Skinner J. Ellegard L. Welch A.A. Bingham S. Mulligan A. Andersson H. Khaw K.T. Intake of dietary plant sterols is inversely related to serum cholesterol concentration in men and women in the EPIC Norfolk population: a cross-sectional study.Eur. J. Clin. Nutr. 2004; 58: 1378-1385Crossref PubMed Scopus (145) Google Scholar, 17Klingberg S. Ellegård L. Johansson I. Hallmans G. Weinehall L. Andersson H. Winkvist A. Inverse relation between dietary intake of naturally occurring plant sterols and serum cholesterol in northern Sweden.Am. J. Clin. Nutr. 2008; 87: 993-1001Crossref PubMed Scopus (95) Google Scholar). Participants in the Spanish cohort of European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective study in Europe (18Bingham S. Riboli E. Diet and cancer. The European Prospective Investigation into Cancer and Nutrition.Nat. Rev. Cancer. 2004; 4: 206-215Crossref PubMed Scopus (305) Google Scholar), have a higher consumption of phytosterol-rich vegetables and fruits than most European countries and the US (19Agudo A. Amiano P. Barcos A. Barricarte A. Beguiristain J.M. Chirlaque M.D. Dorronsoro M. Gonzalez C.A. Laceras C. Martinez C. et al.Dietary intake of vegetables and fruits among adults in five regions of Spain. EPIC Group of Spain. European Prospective Investigation into Cancer and Nutrition.Eur. J. Clin. Nutr. 1999; 53: 174-180Crossref PubMed Scopus (53) Google Scholar), confirming their adherence to the Mediterranean dietary pattern. We hypothesized that plasma phytosterol concentrations are markers of a healthy diet and are associated with a decreased risk for CHD, instead of an increased risk, in the Spanish EPIC cohort. To address this issue, we examined the association among dietary phytosterol intake, plasma levels of phytosterols, cardiometabolic risk factors, and the risk of future CHD. We performed a nested case-control study among participants of the Spanish EPIC study (19Agudo A. Amiano P. Barcos A. Barricarte A. Beguiristain J.M. Chirlaque M.D. Dorronsoro M. Gonzalez C.A. Laceras C. Martinez C. et al.Dietary intake of vegetables and fruits among adults in five regions of Spain. EPIC Group of Spain. European Prospective Investigation into Cancer and Nutrition.Eur. J. Clin. Nutr. 1999; 53: 174-180Crossref PubMed Scopus (53) Google Scholar). Subjects were recruited as part of a 10 country collaborative study designed to investigate dietary and other determinants of cancer (18Bingham S. Riboli E. Diet and cancer. The European Prospective Investigation into Cancer and Nutrition.Nat. Rev. Cancer. 2004; 4: 206-215Crossref PubMed Scopus (305) Google Scholar). The population of the Spanish branch of EPIC included 41,440 individuals. Participants were healthy men and women volunteers, principally blood donors, aged between 30 and 69 years at enrolment between October 1992 and July 1996 in five regions, three in Northern Spain (Asturias, Navarra, and Gipuzkoa) and two in Southern Spain (Murcia and Granada). In face-to-face interviews, each participant was administered questionnaires to collect information on lifestyle factors, including food consumption and smoking, and a complete medical history, including a prior diagnosis of hypertension, hyperlipidemia, or diabetes, and medication use. Anthropometric measurements [height and weight, with calculation of body mass index (BMI) in kg/m2, and waist circumference] were obtained by using standardized procedures, and a blood sample was taken. Close to 60% of blood samples were collected after an overnight fast. To ascertain the vital status, annual record linkages were carried out with the national databases of the Instituto Nacional de Estadística, Spain. For this analysis, the follow-up for vital status was complete until December 31, 2004; the mean follow-up period was ≈10 years. All subjects provided written informed consent to a protocol approved by local ethical review boards. Cases were defined as participants who had a definite fatal or nonfatal myocardial infarction or angina requiring a revascularization procedure. Participants who at recruitment had a prior diagnosis of CHD that was validated thereafter were excluded from further analyses (n = 193). For the identification of potential cases, a record linkage between the EPIC database and local hospital discharge registers was performed. A Population Myocardial Infarction Register available in three participating regions (Navarra, Guipuzkoa, and Murcia) was also used. At censoring, 468 definite cases of incident fatal and nonfatal myocardial infarction and 141 cases of angina were identified. Of the 609 confirmed CHD cases, approximately one-half (n = 315) were randomly selected for inclusion in this analysis. Using an incidence density method (20Rundle A.G. Vineis P. Ahsan H. Design options for molecular epidemiology research within cohort studies.Cancer Epidemiol. Biomarkers Prev. 2005; 14: 1899-1907Crossref PubMed Scopus (86) Google Scholar), two controls, randomly selected among subjects in the cohort still at risk for CHD at the time of diagnosis of each case (namely, subjects that had not suffered a CHD event at the time their matched case-pair had an event) were matched to each case by center, sex, age (within 5 years), and time of enrolment (within 3 months). If needed, the same subjects could serve as a control more than once. Because we analyzed incident (new) cases, any individual who suffered a CHD event during the 10 year follow-up period was no longer eligible to be a control. Information on usual food intake over the year before enrolment was collected by a validated computerized diet history questionnaire (21EPIC Group of Spain Relative validity and reproducibility of a diet history questionnaire in Spain. I. Foods.Int. J. Epidemiol. 1997; 26: S91-S99PubMed Google Scholar, 22EPIC Group of Spain Relative validity and reproducibility of a diet history questionnaire in Spain. II. Nutrients.Int. J. Epidemiol. 1997; 26: S100-S109PubMed Google Scholar). Energy and nutrient intakes were estimated using a conversion table in a computerized database especially compiled for the EPIC study in Spain. Intake of total phytosterols and their main components was estimated from the database of Spanish foods developed by Jiménez-Escrig, Santos-Hidalgo, and Saura-Calixto (23Jiménez-Escrig A. Santos-Hidalgo A.B. Saura-Calixto F. Common sources and estimated intake of plant sterols in the Spanish diet.J. Agric. Food Chem. 2006; 54: 3462-3471Crossref PubMed Scopus (114) Google Scholar) Coded samples of plasma and blood cells (buffy coat) were shipped to a central laboratory and stored at −80°C until assay. Plasma glucose was measured by the glucose-oxidase method in fasting samples. Cholesterol and triglycerides were determined by enzymatic procedures; triglycerides were measured only in fasting samples. HDL-cholesterol was quantified after precipitation with phosphotungstic acid and magnesium chloride. The concentration of LDL-cholesterol was calculated as total cholesterol minus HDL-cholesterol minus triglycerides/5 when triglyceride levels were ≤3.36 mmol/l in fasting samples, and by the homogeneous method of Daiichi Pure Chemicals (N-geneous® LDL; Genzyme Diagnostics, Cambridge, MA) when triglyceride levels were >3.36 mmol/l and in nonfasting specimens. The determinations were made in an ADVIA 1800 chemical analyzer (Siemens Healthcare Diagnostics, Madrid, Spain). Genomic DNA was obtained to determine the apolipoprotein E (apoE) genotype (24Hixson J.E. Vernier D.T. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.J. Lipid Res. 1990; 31: 545-548Abstract Full Text PDF PubMed Google Scholar). Serum noncholesterol sterol levels were determined by gas chromatography using a modification of the method of Heinemann, Axtmann, and von Bergmann (25Heinemann T. Axtmann G. von Bergmann K. Comparison of intestinal absorption of cholesterol with different plant sterols in man.Eur. J. Clin. Invest. 1993; 23: 827-831Crossref PubMed Scopus (350) Google Scholar). Epicoprostanol (2 μg) was added to serum (0.1 ml) as internal standard. After alkaline hydrolysis, extraction, and derivatization to trimethylsilyl ethers, sterols were quantified on a 30-m nonpolar capillary column (TRB-Esterol, Teknokroma, Barcelona) equipped with flame ionization detection in a Perkin-Elmer GC AutosystemTM (Norwalk, CT) apparatus. Each run quantified lathosterol, campesterol, and sitosterol. Noncholesterol sterols are expressed as ratios to cholesterol (μg/mg cholesterol) because, like cholesterol, these molecules are transported exclusively in lipoprotein particles and their concentrations are altered by changes in carrier lipoprotein concentrations (2von Bergmann K. Sudhop T. Lütjohann D. Cholesterol and plant sterol absorption: recent insights.Am. J. Cardiol. 2005; 96: 10D-14DAbstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Inter- and intra-assay coefficient variations were 5.0% and 3.2% for lathosterol, 1.9% and 1.6% for campesterol, and 2.0% and 1.8% for sitosterol, respectively. Qualitative variables are expressed as numbers (percentage). Data for continuous variables are presented as mean ± SD. Phytosterol intakes and plasma levels of triglycerides and noncholesterol sterols had a skewed distribution and are presented as medians and interquartile ranges. Participants with more than 3 SDs from the mean of daily total energy intake were considered to have implausible dietary data and excluded from further analysis. We categorized control subjects by tertiles of both dietary phytosterol intake and plasma phytosterol-to-cholesterol ratios and used ANOVA, χ2, and Kruskall-Wallis statistics, as appropriate, to calculate tests for trend for cardiovascular risk factors. Pearson correlation coefficients were constructed to test for relationships between intake of phytosterols and other dietary variables. Because phytosterol intake was strongly related to total energy consumption and showed age and gender differences, age-, gender-, and energy-adjusted phytosterol values were used when examining associations with other dietary variables or plasma lipid values. Unpaired t-tests, χ2 tests, or the Mann-Whitney test, as appropriate, were used for comparisons of variables between cases and controls. These statistical tests were two-tailed, and significance was set at P < 0.05. Analyses were performed using SPSS, version 15.0 (Chicago, IL). Odds ratios (ORs) and 95% confidence intervals for CHD risk by plasma phytosterol ratios were calculated by conditional logistic regression using the PHREG procedure (SAS statistical software, v. 9; SAS Institute, Cary, NC), stratified by the case-control set. Risk estimates were computed as "crude" (adjustment for matching variables only), after adjustment by cardiovascular risk factors and apoE genotype, and after additional adjustment by intake of energy and nutrients, including plant sterols. We did not adjust for statin use because the few subjects under statin treatment at recruitment were excluded from calculations. From the total number of 315 CHD cases, 16 were excluded, seven because they were under statin treatment, one due to implausible energy intake, and eight because plasma sterol determination failed due to insufficient or spoilt plasma samples; corresponding exclusions among the 630 control subjects were 8, 3, and 35. The median total phytosterol intake of the whole cohort (n = 883) was 315 mg/day and was higher in men (337 mg/day, range 82–851) than in women (237 mg/day, range 26–501) (P < 0.001). After adjustment for energy intake, between-gender differences were blunted but still significant (321 mg/day in men and 293 mg/day in women, P = 0.001). Table 1 shows that phytosterol intake in control subjects was associated directly with both the male sex and total energy intake and inversely with age, but was unrelated to plasma lipid levels after adjusting by sex, age, and energy intake. Plasma campesterol- and sitosterol-to-cholesterol ratios increased across tertiles of phytosterol intake, but only the sitosterol increase was significant (P = 0.029). Sex-, age-, and energy-adjusted phytosterol intake was directly correlated (P < 0.001) with intake of vegetables (r = 0.316), fruits (r = 0.475), legumes (r = 0.293), cereals (r = 0.238), fiber (r = 0.605), vegetable protein (r = 0.397), and polyunsaturated fatty acids (r = 0.269) and inversely correlated (P < 0.001) with intake of animal protein (r = –0.185), saturated fatty acids (r = –0.282), and cholesterol (r = –0.245). Intake of measurable phytosterol subclasses showed similar associations (data not shown).TABLE 1Distribution of plasma lipids and noncholesterol sterol ratios by tertiles of total plant sterol intake in control subjectsCharacteristicsTertile 1Tertile 2Tertile 3PaP for linear trend calculated by ANOVA, χ2, or Kruskall-Wallis statistics, as appropriate.Plant sterol intake, mg/day≤260.1260.2–360.0≥360.1n194195195Sex, male (%)109 (56)166 (85)180 (92)<0.001Age, years55.4 ± 7.653.7 ± 6.853.3 ± 7.10.008Total energy intake, kJ/day8,348 ± 2,52210,191 ± 2,55312,576 ± 2,918<0.001Plasma lipids, mmol/lTotal cholesterolUnadjusted5.68 ± 0.865.66 ± 0.915.67 ± 0.910.982AdjustedbAdjusted by sex, age, and energy intake.5.685.665.670.798LDL-cholesterolUnadjusted3.62 ± 0.803.65 ± 0.843.73 ± 0.830.391AdjustedbAdjusted by sex, age, and energy intake.3.623.653.730.260HDL-cholesterolUnadjusted1.46 ± 0.361.37 ± 0.341.32 ± 0.33<0.001AdjustedbAdjusted by sex, age, and energy intake.1.461.371.320.077Cholesterol/HDL ratioUnadjusted4.11 ± 1.134.38 ± 1.244.57 ± 1.430.002AdjustedbAdjusted by sex, age, and energy intake.4.114.384.570.058TriglyceridescMeasured in 356 fasting samples.1.09 (0.82–1.49)1.23 (0.84–1.62)1.14 (0.87–1.66)0.365Plasma noncholesterol sterol-to-cholesterol ratios, μmol/mmolLathosterol1.59 (1.10–2.09 )1.63 (1.33–2.18)1.68 (1.31–2.17)0.378Campesterol1.43 (1.16–2.03)1.57 (1.23–1.86)1.73 (1.25–2.11)0.125Sitosterol1.27 (0.96–1.75)1.34 (1.09–1.85)1.53 (1.18–1.87)0.029Values are mean ± SD or number (percentage). Triglycerides and noncholesterol sterol ratios are medians (interquartile ranges).a P for linear trend calculated by ANOVA, χ2, or Kruskall-Wallis statistics, as appropriate.b Adjusted by sex, age, and energy intake.c Measured in 356 fasting samples. Open table in a new tab Values are mean ± SD or number (percentage). Triglycerides and noncholesterol sterol ratios are medians (interquartile ranges). Table 2 shows the distribution of cardiovascular risk factors, plasma noncholesterol sterol ratios, and dietary phytosterol intake across tertiles of plasma sitosterol-to-cholesterol ratios in the control group. Plasma sitosterol tertiles were associated directly with HDL-cholesterol levels, plasma campesterol-to-cholesterol ratios, and phytosterol intake and inversely with BMI, waist circumference, plasma glucose and triglyceride levels, cholesterol/HDL ratios, and lathosterol-to-cholesterol ratios. The total cholesterol level increased nonsignificantly with increasing plasma sitosterol. Tertiles of plasma campesterol-to-cholesterol ratios showed similar associations (data not shown).TABLE 2Distribution of cardiovascular risk factors and noncholesterol sterols by tertiles of plasma sitosterol-to-cholesterol ratios in control subjectsCharacteristicsTertile 1Tertile 2Tertile 3PaP value for linear trend calculated by ANOVA, χ2, or Kruskall-Wallis statistics, as appropriate.Sitosterol-to-cholesterol ratio, μg/mg≤1.161.17–1.62≥1.63n195195194Age, years60.8 ± 7.160.6 ± 7.859.7 ± 7.70.321Male sex, n (%)148 (75.9)158 (81.0)149 (76.8)0.428BMI, kg/m230.2 ± 4.328.4 ± 3.027.5 ± 3.2<0.001Waist circumference, cm102.3 ± 10.297.7 ± 9.295.1 ± 9.9<0.001Hypertension, n (%)46 (23.7)54 (27.7)43 (22.2)0.425Fasting glucose, mmol/lbMeasured in 356 fasting samples.5.09 ± 1.934.57 ± 0.974.51 ± 0.880.002Plasma lipids, mmol/lTotal cholesterol5.67 ± 0.915.59 ± 0.845.74 ± 0.920.255LDL-cholesterol3.66 ± 0.823.61 ± 0.743.72 ± 0.910.417HDL-cholesterol1.30 ± 0.311.36 ± 0.321.48 ± 0.39<0.001TriglyceridesbMeasured in 356 fasting samples.1.31 (0.93–2.09)1.12 (0.84–1.52)1.01 (0.78–1.36)<0.001Cholesterol/HDL ratio4.57 ± 1.234.31 ± 1.164.18 ± 1.410.009apoE genotype, n (%)cDetermined in 524 participants and classified as apoE2 (E2/2+E2/3), apoE3 (E3/3), or apoE4 (E3/4+E4/4), with exclusion of seven subjects with the E2/4 genotype.0.534apoE215 (8.8)13 (7.7)15 (8.4)apoE3130 (76.0)121 (72.0)139 (78.1)apoE426 (15.2)34 (20.2)24 (13.5)Plasma noncholesterol sterol-to-cholesterol ratios, μmol/mmolLathosterol1.90 (1.35–2.36)1.54 (1.21–1.96)1.36 (0.99–1.78)<0.001Campesterol1.07 (0.92–1.26)1.53 (1.34–1.74)2.17 (1.83–2.62)<0.001Total plant sterol intake, mg/day286 (224–375)315 (248–393)317 (238–397)0.041Sitosterol179 (141–227)202 (156–245)197 (149–253)0.028Campesterol29 (22–36)34 (24–42)31 (25–40)0.006a P value for linear trend calculated by ANOVA, χ2, or Kruskall-Wallis statistics, as appropriate.b Measured in 356 fasting samples.c Determined in 524 participants and classified as apoE2 (E2/2+E2/3), apoE3 (E3/3), or apoE4 (E3/4+E4/4), with exclusion of seven subjects with the E2/4 genotype. Open table in a new tab The baseline characteristics of assessable CHD cases (n = 299) and controls (n = 584) are shown in Table 3. Matching secured that sex and age were comparable between cases and controls. Predictably, participants with incident CHD during follow-up had higher waist circumference and BMI and were more likely to smoke and have obesity, diabetes, hypertension, and hyperlipidemia than controls. Also, total cholesterol, LDL-cholesterol, and triglyceride levels were higher, and HDL-cholesterol was lower in cases than controls. apoE genotype frequency distribution and plasma noncholesterol sterol ratios were similar between the two groups. Intakes of total phytosterols and sitosterol, the main dietary noncholesterol sterol, were nonsignificantly lower in cases compared with controls. There were no case-control differences in energy or nutrient intake (data not shown).TABLE 3Baseline characteristics of CHD cases and matched control subjectsVariablesCases (n = 299)Controls (n = 584)PaUnpaired t-test, χ2, or Mann-Whitney test, as appropriate.Age, years54.1 ± 7.254.3 ± 7.30.768Men, n (%)236 (78.9)455 (77.9)0.728Smoking, n (%)Never90 (30.1)247 (42.3)Past65 (21.7)140 (24.0)Current144 (48.2)197 (33.7)<0.001BMI, kg/m229.6 ± 3.728.7 ± 3.70.001Waist circumference, cm100.5 ± 9.898.3 ± 10.20.003Obese, n (%)122 (40.8)176 (30.1)0.002Hypertension, n (%)106 (35.5)143 (24.5)0.001Type 2 diabetes, n (%)41 (13.7)39 (6.7)0.001Hyperlipidemia, n (%)120 (40.3)142 (24.3)<0.001Fasting glucose, mmol/lbMeasured in 540 fasting samples (184 cases and 356 controls).5.18 ± 1.604.72 ± 1.370.001Total cholesterol, mmol/l6.11 ± 0.955.70 ± 0.89<0.001LDL-cholesterol, mmol/l4.07 ± 0.903.66 ± 0.82<0.001HDL-cholesterol, mmol/l1.27 ± 0.381.38 ± 0.35<0.001Triglycerides, mmol/lbMeasured in 540 fasting samples (184 cases and 356 controls).1.39 (1.06–2.02)1.14 (0.84–1.59)<0.001Cholesterol/HDL ratio5.16 ± 1.484.36 ± 1.28<0.001apoE genotype, n (%)cDetermined in 808 participants and classified as apoE2 (E2/2+E2/3), apoE3 (E3/3), or apoE4 (E3/4+E4/4), with exclusion of 10 subjects with the E2/4 genotype.apoE217 (6.4)43 (8.3)0.513apoE3201 (75.3)390 (75.4)apoE449 (18.4)84 (16.2)Total dietary plant sterols, mg/day287 (227–372)309 (234–386)0.144Campesterol, mg/day30 (23–39)31 (23–40)0.517Sitosterol, mg/day178 (144–231)192 (148–241)0.100Plasma noncholesterol sterol-to-cholesterol ratios, μmol/mmolLathosterol1.54 (1.24–2.06)1.57 (1.15–2.06
Referência(s)