Phytosterol plasma concentrations and coronary heart disease in the prospective Spanish EPIC cohort

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. 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 plasma phytosterols and coronary heart disease (CHD) risk J. T. P. E. J. of serum plant sterols and cholesterol in and of and coronary heart disease in and their Full Text PDF PubMed Scopus Google Scholar, R.A. H. Miettinen T.A. of serum and noncholesterol sterols with coronary disease in Cardiol. 2000; PubMed Scopus Google Scholar, T. Bergmann K. Serum plant sterols as a risk for coronary heart 2002; Full Text PDF PubMed Scopus Google Scholar, P. J. H. Plasma sitosterol are associated with increased of coronary in of a nested of the Prospective 2006; Full Text Full Text PDF PubMed Scopus Google Scholar) or a S. Bergmann K. K. D. R. S.M. Plasma levels of plant sterols and the risk of coronary the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. H. of plasma phytosterol concentrations with coronary heart from the a study of coronary disease in Full Text Full Text PDF PubMed Scopus Google Scholar) and K. D. M. J. S. Y. M. Bergmann K. elevated plant sterol levels are associated with Full Text Full Text PDF PubMed Scopus Google Scholar). is the CHD risk of phytosterols in the usual studies have a dietary phytosterol intake and plasma and levels J. L. S. A. H. of dietary plant sterols is related to serum cholesterol in and in the a J. Clin. PubMed Scopus Google Scholar, S. L. I. L. H. A. dietary intake of plant sterols and serum cholesterol in J. Clin. PubMed Scopus Google Scholar). in the Spanish cohort of European Prospective Investigation into Cancer and Nutrition a study in S. E. and The European Prospective Investigation into Cancer and Rev. PubMed Scopus Google have a higher of and than European and the A. P. A. A. M. et intake of and in of of European Prospective Investigation into Cancer and J. Clin. PubMed Scopus Google their to the dietary that plasma phytosterol concentrations are markers of a healthy diet and are associated with a decreased risk for of increased in the Spanish To address this we the dietary phytosterol intake, plasma levels of cardiometabolic risk factors, and the risk of a nested study participants of the Spanish study A. P. A. A. M. et intake of and in of of European Prospective Investigation into Cancer and J. Clin. PubMed Scopus Google Scholar). were as of a 10 study to dietary and of S. E. and The European Prospective Investigation into Cancer and Rev. PubMed Scopus Google Scholar). The population of the Spanish of were healthy and blood and and in in and and in and was to factors, and and a a of or and and with of index in and were by and a blood was to of blood were after To the were with the of the this analysis, the for was the was to a by review were as participants who had a or or a who had a of CHD that was were from (n = the of a the and was available in and was also cases of and and cases of were the CHD (n = were randomly selected for in this P. H. for molecular within cohort Epidemiol. 2005; PubMed Scopus Google controls, randomly selected in the cohort risk for CHD the of of case that had a CHD the their matched had were matched to case by and of the as a control more than Because we who a CHD the 10 year was to be a usual intake the year was by a diet of and of a diet in I. J. Epidemiol. Google Scholar, of and of a diet in J. Epidemiol. Google Scholar). and were a in a for the study in of phytosterols and their components was from the of Spanish foods developed by and A. and intake of plant sterols in the Spanish 2006; PubMed Scopus Google Scholar) of plasma and blood were to a and Plasma was by the in Cholesterol and were by were in HDL-cholesterol was after with and The of was as cholesterol HDL-cholesterol levels were in and by the of levels were and in The were in was to the apolipoprotein E genotype of apolipoprotein E by and with Lipid Res. 1990; Full Text PDF PubMed Google Scholar). Serum noncholesterol sterol levels were by a of the of and Bergmann T. Bergmann K. of intestinal absorption of cholesterol with plant sterols in J. Clin. PubMed Scopus Google Scholar). was to serum as and to sterols were a with in a lathosterol, and sitosterol. sterols are as ratios to cholesterol these are in and their concentrations are by in concentrations 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). and were and for lathosterol, and for and and for are as for are as Phytosterol and plasma levels of and noncholesterol sterols had a and are as and with more than from the of intake were to have dietary data and from control by tertiles of dietary phytosterol intake and plasma ratios and used and as to for for risk were to for intake of phytosterols and dietary Because phytosterol intake was related to and and and phytosterol were used with dietary or plasma or the as were used for of cases and These were and was < were ratios and confidence for CHD risk by plasma phytosterol ratios were by the by the were as for after by risk and and after by intake of and plant for the were from the of CHD were were to intake, and plasma sterol to or plasma the control were and The median phytosterol intake of the whole cohort (n = was and was higher in than in (P < for intake, were but in and in = that phytosterol intake in control was associated with the male and intake and with but was unrelated to plasma levels after by and intake. Plasma and ratios increased across tertiles of phytosterol intake, but the sitosterol was (P = and phytosterol intake was (P < with intake of = = = = = = and = and (P < with intake of = = and cholesterol = of phytosterol similar of plasma and noncholesterol sterol ratios by tertiles of plant sterol intake in control for by or as sterol intake, male intake, by and by and by and by and in noncholesterol ratios, are or and noncholesterol sterol ratios are for by or as by and in in a are or and noncholesterol sterol ratios are the of risk factors, plasma noncholesterol sterol ratios, and dietary phytosterol intake across tertiles of plasma ratios in the control Plasma sitosterol tertiles were associated with HDL-cholesterol levels, plasma ratios, and phytosterol intake and with plasma and levels, cholesterol/HDL ratios, and The cholesterol level increased nonsignificantly with plasma sitosterol. of plasma ratios similar of risk and noncholesterol sterols by tertiles of plasma ratios in control for by or as glucose, in in in participants and as or with of with the noncholesterol ratios, plant sterol intake, for by or as in in participants and as or with of with the in a The baseline of CHD cases (n = 299) and controls (n = 584) are in that and were cases and participants with CHD had higher and and were more to and have and than and levels were and HDL-cholesterol was lower in cases than genotype and plasma noncholesterol sterol ratios were similar the of phytosterols and the dietary noncholesterol were nonsignificantly lower in cases compared with were in or intake of CHD cases and matched control (n = (n = or as glucose, in cases and in cases and in participants and as or with of 10 with the dietary plant noncholesterol ratios, are or and noncholesterol sterol ratios are or as in cases and in participants and as or with of 10 with the in a are or and noncholesterol sterol ratios are the and for CHD by tertiles of plasma and ratios Because this cases and controls used were used by the The multivariable-adjusted risk for CHD was lower in the highest plasma tertile compared with the lowest The plasma campesterol ratios were associated with the risk of (95% confidence for CHD across tertiles of plasma phytosterol to cholesterol by and by intake of and and plant for for by and by intake of and and plant in a The of this study in the Spanish cohort suggest that elevated levels of plasma phytosterols are associated with increased risk of the tertile of plasma the dietary was related to CHD risk and after for various phytosterol intake with natural foods, a measure of healthy dietary choices, and HDL-cholesterol increased, and adiposity measures, cholesterol/HDL ratios, and levels of glucose, triglycerides, and lathosterol, a cholesterol decreased across plasma sitosterol suggest that plasma phytosterols are a of a healthy diet and a lower cardiometabolic risk and are associated with a risk for The whether raised plasma phytosterols are a CHD risk in nonsitosterolemic individuals has been by the of epidemiological studies J. T. P. E. J. of serum plant sterols and cholesterol in and of and coronary heart disease in and their Full Text PDF PubMed Scopus Google Scholar, R.A. H. Miettinen T.A. of serum and noncholesterol sterols with coronary disease in Cardiol. 2000; PubMed Scopus Google Scholar, T. Bergmann K. Serum plant sterols as a risk for coronary heart 2002; Full Text PDF PubMed Scopus Google Scholar, P. J. H. Plasma sitosterol are associated with increased of coronary in of a nested of the Prospective 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Bergmann K. K. D. R. S.M. Plasma levels of plant sterols and the risk of coronary the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. H. of plasma phytosterol concentrations with coronary heart from the a study of coronary disease in Full Text Full Text PDF PubMed Scopus Google Scholar, K. D. M. J. S. Y. M. 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Full Text Full Text PDF PubMed Scopus Google Scholar) suggest that elevated plasma phytosterols and decreased synthesis markers are associated with disease or is that the of plasma phytosterols and risk is with those of recent studies S. Bergmann K. K. D. R. S.M. Plasma levels of plant sterols and the risk of coronary the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. H. of plasma phytosterol concentrations with coronary heart from the a study of coronary disease in Full Text Full Text PDF PubMed Scopus Google Scholar, K. D. M. J. S. Y. M. Bergmann K. elevated plant sterol levels are associated with Full Text Full Text PDF PubMed Scopus Google Scholar) in a of and a role of elevated plasma phytosterol concentrations risk of The median phytosterol intake in the EPIC-Spain cohort was similar to that from Spanish population A. and intake of plant sterols in the Spanish 2006; PubMed Scopus Google Scholar) and from the study J. L. S. A. 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PubMed Scopus Google the phytosterol content in the usual diet of EPIC-Spain participants with of healthy foods and as and seeds, and and with intake of diet as and cholesterol. plasma sitosterol levels were associated with phytosterol intake. the of with foods, available in the the cohort was in this that plasma phytosterol levels are related in to phytosterol intake with the usual which in healthy plasma phytosterol levels (see review in Ref. 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). The genotype has been in this circulating phytosterols are markers for cholesterol absorption, and a role in but have been (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. 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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, S. Varady K.A. S. Jones P.J. and cholesterol a relationship cholesterol absorption and synthesis PubMed Scopus Google a were from the the plasma sitosterol and campesterol ratios to cholesterol were in the physiological as in studies J. T. P. E. J. of serum plant sterols and cholesterol in and of and coronary heart disease in and their Full Text PDF PubMed Scopus Google Scholar, R.A. H. Miettinen T.A. of serum and noncholesterol sterols with coronary disease in Cardiol. 2000; PubMed Scopus Google Scholar, T. Bergmann K. Serum plant sterols as a risk for coronary heart 2002; Full Text PDF PubMed Scopus Google Scholar, P. J. H. Plasma sitosterol are associated with increased of coronary in of a nested of the Prospective 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Bergmann K. K. D. R. S.M. Plasma levels of plant sterols and the risk of coronary the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. H. of plasma phytosterol concentrations with coronary heart from the a study of coronary disease in Full Text Full Text PDF PubMed Scopus Google Scholar, K. D. M. J. S. Y. M. Bergmann K. elevated plant sterol levels are associated with Full Text Full Text PDF PubMed Scopus Google Scholar, M. in cholesterol markers study participants with Lipid Res. Full Text Full Text PDF PubMed Scopus Google the of This study has The the that have the and controls were matched for and of but for risk we for to be associated with cholesterol and CHD risk in the we the of a measure of dietary and risk baseline was in diet and that might have CHD risk the year were be that the are for the cohort but the of plasma noncholesterol levels with those in studies from the J. T. P. E. J. of serum plant sterols and cholesterol in and of and coronary heart disease in and their Full Text PDF PubMed Scopus Google Scholar, Yu L. S.M. Hobbs H.H. plasma levels of plant sterols and in and PubMed Scopus Google Scholar, M. in cholesterol markers study participants with Lipid Res. Full Text Full Text PDF PubMed Scopus Google R.A. H. Miettinen T.A. of serum and noncholesterol sterols with coronary disease in Cardiol. 2000; PubMed Scopus Google T. Bergmann K. Serum plant sterols as a risk for coronary heart 2002; Full Text PDF PubMed Scopus Google Scholar, P. J. H. Plasma sitosterol are associated with increased of coronary in of a nested of the Prospective 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. H. of plasma phytosterol concentrations with coronary heart from the a study of coronary disease in Full Text Full Text PDF PubMed Scopus Google the S. Bergmann K. K. D. R. S.M. Plasma levels of plant sterols and the risk of coronary the Lipid Res. Full Text Full Text PDF PubMed Scopus Google and The K. D. M. J. S. Y. M. Bergmann K. elevated plant sterol levels are associated with Full Text Full Text PDF PubMed Scopus Google Scholar) that be to circulating phytosterols are unrelated to the risk of CHD in the cohort of the Spanish are also of efficient intestinal cholesterol absorption, which cholesterol levels but is and related to of the Plasma concentrations of the sitosterol and to be markers of a lower cardiometabolic These suggest that elevated plasma but might individuals with a risk for into the epidemiological studies with this J. T. P. E. J. of serum plant sterols and cholesterol in and of and coronary heart disease in and their Full Text PDF PubMed Scopus Google Scholar, R.A. H. Miettinen T.A. of serum and noncholesterol sterols with coronary disease in Cardiol. 2000; PubMed Scopus Google Scholar, T. Bergmann K. Serum plant sterols as a risk for coronary heart 2002; Full Text PDF PubMed Scopus Google Scholar, P. J. H. Plasma sitosterol are associated with increased of coronary in of a nested of the Prospective 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Bergmann K. K. D. R. S.M. Plasma levels of plant sterols and the risk of coronary the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. H. of plasma phytosterol concentrations with coronary heart from the a study of coronary disease in Full Text Full Text PDF PubMed Scopus Google Scholar, K. D. M. J. S. Y. M. Bergmann K. elevated plant sterol levels are associated with Full Text Full Text PDF PubMed Scopus Google Scholar, Yu L. S.M. Hobbs H.H. plasma levels of plant sterols and in and PubMed Scopus Google Scholar, T.A. M. M. H. sterols in serum and in of Cardiol. 2005; PubMed Scopus Google Scholar, Lütjohann D. S. N. Sudhop T. Bergmann K. K. J. et of diet with plant Cardiol. PubMed Scopus Google Scholar, The of cholesterol and plasma plant sterols with the of coronary Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, M. in cholesterol markers study participants with Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, K.E. Bergmann K. D. R. Grundy S.M. Hobbs H.H. of plasma noncholesterol sterols and relationship to in ABCG5 and Lipid Res. 2002; Full Text Full Text PDF PubMed Google we the important question of whether circulating phytosterols are or The the participants of the Spanish cohort for their to the apolipoprotein E index coronary heart disease European Prospective Investigation into Cancer and Nutrition odds ratio