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Effects of variations in the APOA1/C3/A4/A5 gene cluster on different parameters of postprandial lipid metabolism in healthy young men

2009; Elsevier BV; Volume: 51; Issue: 1 Linguagem: Inglês

10.1194/jlr.m800527-jlr200

ISSN

1539-7262

Autores

Javier Delgado‐Lista, Francisco Pérez‐Jiménez, Juan Ruano, Pablo Pérez‐Martínez, Francisco Fuentes, Juan Criado-García, Laurence D. Parnell, Antonio García‐Ríos, José M. Ordovás, José López‐Miranda,

Tópico(s)

Peroxisome Proliferator-Activated Receptors

Resumo

The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092), and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 h after the meal. Total cholesterol and fractions [HDL-cholesterol, LDL-cholesterol, trifacylglycerols (TGs) in plasma, TG-rich lipoproteins (TRLs) (large TRLs and small TRLs), apolipoprotein A-I and apolipoprotein B] were determined. APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics but not its magnitude. We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism. The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092), and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 h after the meal. Total cholesterol and fractions [HDL-cholesterol, LDL-cholesterol, trifacylglycerols (TGs) in plasma, TG-rich lipoproteins (TRLs) (large TRLs and small TRLs), apolipoprotein A-I and apolipoprotein B] were determined. APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics but not its magnitude. We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism. Pronounced postprandial hypertriglyceridemia is proatherogenic (1Lopez-Miranda J. Perez-Martinez P. Marin C. Moreno J.A. Gomez P. Perez-Jimenez F. Postprandial lipoprotein metabolism, genes and risk of cardiovascular disease.Curr. Opin. Lipidol. 2006; 17: 132-138Crossref PubMed Scopus (60) Google Scholar). The extent of this phenomenon depends on several factors, both intrinsic and extrinsic. Diet is the main external determinant of postprandial lipemia magnitude. It has been stated that carbohydrate intake increases the plasma concentration of postprandial lipid particles [triacylglycerols (TGs) and VLDL] when replacing fat in the diet (2Mensink R.P. Zock P.L. Kester A.D. Katan M.B. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.Am. J. Clin. Nutr. 2003; 77: 1146-1155Crossref PubMed Scopus (2040) Google Scholar, 3Parks E.J. Skokan L.E. Timlin M.T. Dingfelder C.S. Dietary sugars stimulate fatty acid synthesis in adults.J. Nutr. 2008; 138: 1039-1046Crossref PubMed Scopus (203) Google Scholar). Dietary fat type also influences postprandial lipemia. Saturated fats induce a prolonged lipemia compared with other types of fat (4Lopez-Miranda J. Williams C. Lairon D. Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism.Br. J. Nutr. 2007; 98: 458-473Crossref PubMed Scopus (223) Google Scholar). Diets rich in monounsaturated fat provoke a faster postprandial TG-rich lipoprotein (TRL) clearance when compared with diets pronounced in saturated fat, thus, shortening the lipemia, which may be mediated by postprandial apolipoproteins (5Zheng C. Khoo C. Furtado J. Ikewaki K. Sacks F.M. Dietary monounsaturated fat activates metabolic pathways for triglyceride-rich lipoproteins that involve apolipoproteins E and C–III.Am. J. Clin. Nutr. 2008; 88: 272-281Crossref PubMed Scopus (38) Google Scholar) and TRL metabolism (6Silva K.D. Kelly C.N. Jones A.E. Smith R.D. Wootton S.A. Miller G.J. Williams C.M. Chylomicron particle size and number, factor VII activation and dietary monounsaturated fatty acids.Atherosclerosis. 2003; 166: 73-84Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Diets rich in N3 PUFA (>2.7–4 g/d) can lower the postprandial TG response (7Williams C.M. Moore F. Morgan L. Wright J. Effects of n-3 fatty acids on postprandial triacylglycerol and hormone concentrations in normal subjects.Br. J. Nutr. 1992; 68: 655-666Crossref PubMed Scopus (77) Google Scholar). The effects of diet on postprandial metabolism were detailed elsewhere (4Lopez-Miranda J. Williams C. Lairon D. Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism.Br. J. Nutr. 2007; 98: 458-473Crossref PubMed Scopus (223) Google Scholar). In addition to external determinants, others that are specific to the individual may modulate the response to dietary interventions. A number of genes have been identified as responsible for triglyceride concentration in both the fasting and postprandial states. The most studied genetic region with regard to lipid metabolism is that encoding the apolipoprotein genes APOA1, APOC3, APOA4, and APOA5, also known as the APOA1/C3/A4/A5 gene cluster (8Lai C.Q. Parnell L.D. Ordovas J.M. The APOA1/C3/A4/A5 gene cluster, lipid metabolism and cardiovascular disease risk.Curr. Opin. Lipidol. 2005; 16: 153-166Crossref PubMed Scopus (108) Google Scholar). Apolipoprotein A1 (APOA1), the main protein included in HDL cholesterol particles, is an essential element of reverse cholesterol transport (9Reichl D. Miller N.E. Pathophysiology of reverse cholesterol transport. Insights from inherited disorders of lipoprotein metabolism.Arteriosclerosis. 1989; 9: 785-797Crossref PubMed Google Scholar), but it has been published that a genetic variation (−276 base pairs G/A) in the promoter region of this apolipoprotein is associated with altered postprandial lipid metabolism (10Marin C. Lopez-Miranda J. Gomez P. Paz E. Perez-Martinez P. Fuentes F. Jimenez-Pereperez J.A. Ordovas J.M. Perez-Jimenez F. Effects of the human apolipoprotein A-I promoter G-A mutation on postprandial lipoprotein metabolism.Am. J. Clin. Nutr. 2002; 76: 319-325Crossref PubMed Scopus (25) Google Scholar). Three other single nucleotide polymorphisms (SNPs) (APOA1 -2630G/A, APOA1 -2803G/A, and -3012A/G) in the promoter region were previously tested for their influence in fasting lipids and response to hypolipidemic medication (11Smith J.A. Arnett D.K. Kelly R.J. Ordovas J.M. Sun Y.V. Hopkins P.N. Hixson J.E. Straka R.J. Peacock J.M. Kardia S.L. The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment.Eur. J. Hum. Genet. 2008; 16: 603-613Crossref PubMed Scopus (27) Google Scholar). Although these variants were not associated with lipid concentrations, we decided to investigate their potential influence in postprandial lipids. Apolipoprotein C-III (APOC3) is a component of TRLs and HDL, whose major function in lipid metabolism is to inhibit LPL and, thereby, plasma APOC3 concentrations are positively associated with TG concentrations (12Ooi E.M. Barrett P.H. Chan D.C. Watts G.F. Apolipoprotein C–III: understanding an emerging cardiovascular risk factor.Clin. Sci. (Lond.). 2008; 114: 611-624Crossref PubMed Scopus (209) Google Scholar). Several SNPs within APOC3 coding or promoter regions have been associated with altered triglycerides (4Lopez-Miranda J. Williams C. Lairon D. Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism.Br. J. Nutr. 2007; 98: 458-473Crossref PubMed Scopus (223) Google Scholar, 13Russo G.T. Meigs J.B. Cupples L.A. Demissie S. Otvos J.D. Wilson P.W. Lahoz C. Cucinotta D. Couture P. Mallory T. et al.Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study.Atherosclerosis. 2001; 158: 173-181Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 14Tas S. Abdella N.A. Blood pressure, coronary artery disease, and glycaemic control in type 2 diabetes mellitus: relation to apolipoprotein-CIII gene polymorphism.Lancet. 1994; 343: 1194-1195Abstract PubMed Scopus (24) Google Scholar, 15Woo S.K. Kang H.S. The apolipoprotein CIII T2854G variants are associated with postprandial triacylglycerol concentrations in normolipidemic Korean men.J. Hum. Genet. 2003; 48: 551-555Crossref PubMed Scopus (8) Google Scholar, 16Waterworth D.M. Hubacek J.A. Pitha J. Kovar J. Poledne R. Humphries S.E. Talmud P.J. Plasma levels of remnant particles are determined in part by variation in the APOC3 gene insulin response element and the APOCI-APOE cluster.J. Lipid Res. 2000; 41: 1103-1109Abstract Full Text Full Text PDF PubMed Google Scholar). The three SNPs analyzed here were also previously studied: APOC3 -2886T/G, reported as −2854T/G, has been associated with altered fasting triglycerides (17Minihane A.M. Finnegan Y.E. Talmud P. Leigh-Firbank E.C. Williams C.M. Influence of the APOC3–2854T>G polymorphism on plasma lipid levels: effect of age and gender.Biochim. Biophys. Acta. 2002; 1583: 311-314Crossref PubMed Scopus (12) Google Scholar). APOC3 -640, rs2542052, has been described as −641C/A and associated with longevity and HDL levels (18Novelli V. Viviani Anselmi C. Roncarati R. Guffanti G. Malovini A. Piluso G. Puca A.A. Lack of replication of genetic associations with human longevity.Biogerontology. 2008; 9: 85-92Crossref PubMed Scopus (64) Google Scholar, 19Atzmon G. Rincon M. Schechter C.B. Shuldiner A.R. Lipton R.B. Bergman A. Barzilai N. Lipoprotein genotype and conserved pathway for exceptional longevity in humans.PLoS Biol. 2006; 4: e113Crossref PubMed Scopus (172) Google Scholar), although other authors did not replicate the findings (18Novelli V. Viviani Anselmi C. Roncarati R. Guffanti G. Malovini A. Piluso G. Puca A.A. Lack of replication of genetic associations with human longevity.Biogerontology. 2008; 9: 85-92Crossref PubMed Scopus (64) Google Scholar). The minor allele of the APOC3 synonymous G34G variant (rs4520, also known as 1100C>T) has been widely studied, first reported to associate with elevated triglyceride levels (20Waterworth D.M. Talmud P.J. Bujac S.R. Fisher R.M. Miller G.J. Humphries S.E. Contribution of apolipoprotein C–III gene variants to determination of triglyceride levels and interaction with smoking in middle-aged men.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2663-2669Crossref PubMed Scopus (72) Google Scholar). Although these three SNPs were previously reported as putative functional SNPs, their influence in the postprandial situation has not been tested. Apolipoprotein A-IV (APOA4) influences dietary fat absorption and chylomicron synthesis (4Lopez-Miranda J. Williams C. Lairon D. Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism.Br. J. Nutr. 2007; 98: 458-473Crossref PubMed Scopus (223) Google Scholar), modulates the activation of LPL by apolipoprotein C-II (21Goldberg I.J. Scheraldi C.A. Yacoub L.K. Saxena U. Bisgaier C.L. Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV.J. Biol. Chem. 1990; 265: 4266-4272Abstract Full Text PDF PubMed Google Scholar), and activates lecithin-cholesterol acyltransferase (22Steinmetz A. Utermann G. Activation of lecithin: cholesterol acyltransferase by human apolipoprotein A-IV.J. Biol. Chem. 1985; 260: 2258-2264Abstract Full Text PDF PubMed Google Scholar). Previous information on altered postprandial lipemia depending on APOA4 SNPs has been published. The carriers of the minor allele of the Gln360His variant have an increased postprandial lipemia when exposed to a saturated fatty acid-rich diet, as they have increased peaks of small TRL-cholesterol (CHOL), small TRL-TG, and large TRL-TG particles (23Ostos M.A. Lopez-Miranda J. Marin C. Castro P. Gomez P. Paz E. Jimenez Pereperez J.A. Ordovas J.M. Perez-Jimenez F. The apolipoprotein A-IV-360His polymorphism determines the dietary fat clearance in normal subjects.Atherosclerosis. 2000; 153: 209-217Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar), but, interestingly, in a case control study (offspring of fathers who suffered a myocardial infarction before the age of 55 years vs. controls), the subgroup of controls who were carriers of the minor allele of this SNP presented lower body mass indices (BMIs), fasting cholesterol, and TG concentrations. Furthermore, and after consumption of an oral fat load, obese participants of this study (but not the rest of the population) who were carriers of the minor allele had significantly reduced postprandial lipemia (24Fisher 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. EARS Group.J. Lipid Res. 1999; 40: 287-294Abstract Full Text Full Text PDF PubMed Google Scholar). Carriers of the rare allele of Thr347Ser show a lower postprandial response in the TG levels of TRL remnants (25Ostos M.A. Lopez-Miranda J. Ordovas J.M. Marin C. Blanco A. Castro P. Lopez-Segura F. Jimenez-Pereperez J. Perez-Jimenez F. Dietary fat clearance is modulated by genetic variation in apolipoprotein A-IV gene locus.J. Lipid Res. 1998; 39: 2493-2500Abstract Full Text Full Text PDF PubMed Google Scholar). APOA4 N147S has been linked to fasting triglyceride levels but its importance to postprandial lipemia remains unknown (26Kamboh M.I. Crawford M.H. Aston C.E. Leonard W.R. Population distributions of APOE, APOH, and APOA4 polymorphisms and their relationships with quantitative plasma lipid levels among the Evenki herders of Siberia.Hum. Biol. 1996; 68: 231-243PubMed Google Scholar). APO4T29T is a synonymous SNP located in the coding region of APOA4 that has not been previously tested as a functional SNP. Both because of its location and its being a synonymous SNP, we selected it for the present study. Apolipoprotein V (APOA5) regulates TG metabolism by mechanisms that include hepatic VLDL and TRL catabolism (27Weinberg R.B. Cook V.R. Beckstead J.A. Martin D.D. Gallagher J.W. Shelness G.S. Ryan R.O. Structure and interfacial properties of human apolipoprotein A-V.J. Biol. Chem. 2003; 278: 34438-34444Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Some variations in this gene (T-1131C and Ser19Trp) have been linked to altered fasting and postprandial TG (28Moreno R. Perez-Jimenez F. Marin C. Moreno J.A. Gomez P. Bellido C. Perez-Martinez P. Jimenez-Gomez Y. Fuentes F.J. Lopez-Miranda J. A single nucleotide polymorphism of the apolipoprotein A-V gene -1131T>C modulates postprandial lipoprotein metabolism.Atherosclerosis. 2005; 189: 163-168Abstract Full Text Full Text PDF Scopus (28) Google Scholar, 29Vrablik M. Horinek A. Ceska R. Adamkova V. Poledne R. Hubacek J.A. Ser19→Trp polymorphism within the apolipoprotein AV gene in hypertriglyceridaemic people.J. Med. Genet. 2003; 40: e105Crossref PubMed Scopus (27) Google Scholar). Haplotype analysis based on five polymorphisms (1131T>C, c.-3A>G, c.56C>G, IVS3+476G>A, and c.1259T>C) in the APOA5 gene define three common haplotypes (APOA5*1, APOA5*2, and APOA5*3) (30Olivier M. Wang X. Cole R. Gau B. Kim J. Rubin E.M. Pennacchio L.A. Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11.Genomics. 2004; 83: 912-923Crossref PubMed Scopus (94) Google Scholar). APOA5*2 and APOA5*3 carriers have a higher postprandial response, higher area under the curve of total plasma TG, large TRL-TG, small TRL-TG, small TRL-CHOL, and large TRL-CHOL than subjects with the APOA5*1 haplotype (31Moreno-Luna R. Perez-Jimenez F. Marin C. Perez-Martinez P. Gomez P. Jimenez-Gomez Y. Delgado-Lista J. Moreno J.A. Tanaka T. Ordovas J.M. et al.Two independent apolipoprotein A5 haplotypes modulate postprandial lipoprotein metabolism in a healthy Caucasian population.J. Clin. Endocrinol. Metab. 2007; 92: 2280-2285Crossref PubMed Scopus (46) Google Scholar). In the intergenic region between APOA4 and APOA5 resides A4A5_inter (rs1263177) SNP. Although its location suggests it might be a nonfunctional variant, an association of this SNP with altered TG levels has been reported. Talmud et al. (32Talmud P.J. Hawe E. Martin S. Olivier M. Miller G.J. Rubin E.M. Pennacchio L.A. Humphries S.E. Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides.Hum. Mol. Genet. 2002; 11: 3039-3046Crossref PubMed Scopus (340) Google Scholar), found a lower level of fasting TG in homozygotes for the minor allele compared with common allele homozygotes. Furthermore, the same SNP was further studied by the same group, but interestingly, this time the results were distinct; although the SNP did not affect the postprandial lipids after an oral fat tolerance test, homozygosity for the rare allele was associated with higher waist-to-hip ratio, systolic blood pressure, and area under the curve (AUC) and peak of insulin after an oral glucose tolerance test (33Martin S. Nicaud V. Humphries S.E. Talmud P.J. Contribution of APOA5 gene variants to plasma triglyceride determination and to the response to both fat and glucose tolerance challenges.Biochim. Biophys. Acta. 2003; 1637: 217-225Crossref PubMed Scopus (113) Google Scholar). These contradicting reports and the repetitive positive phenotype-genotype results made this SNP a good candidate for eventual study in lipid metabolism. The precise role of the regulatory elements present throughout the APOA1/C3/A4/A5 cluster is complex and incomplete, with numerous interactions with different transcription factors described in the immediate upstream regions of each gene (8Lai C.Q. Parnell L.D. Ordovas J.M. The APOA1/C3/A4/A5 gene cluster, lipid metabolism and cardiovascular disease risk.Curr. Opin. Lipidol. 2005; 16: 153-166Crossref PubMed Scopus (108) Google Scholar). Both the study of the regulatory elements in the cluster region as well as the significance of the tight linkage disequilibrium (LD) between the SNPs in this region (highly influenced by the population under study) remain an active field of research (34Chien K.L. Chen M.F. Hsu H.C. Su T.C. Chang W.T. Lee C.M. Lee Y.T. Genetic association study of APOA1/C3/A4/A5 gene cluster and haplotypes on triglyceride and HDL cholesterol in a community-based population.Clin. Chim. Acta. 2008; 388: 78-83Crossref PubMed Scopus (29) Google Scholar, 35Hamon S.C. Kardia S.L. Boerwinkle E. Liu K. Klos K.L. Clark A.G. Sing C.F. Evidence for consistent intragenic and intergenic interactions between SNP effects in the APOA1/C3/A4/A5 gene cluster.Hum. Hered. 2006; 61: 87-96Crossref PubMed Scopus (37) Google Scholar, 36Qi L. Liu S. Rifai N. Hunter D. Hu F.B. Associations of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride and HDL cholesterol levels in women with type 2 diabetes.Atherosclerosis. 2007; 192: 204-210Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 37Suviolahti E. Lilja H.E. Pajukanta P. Unraveling the complex genetics of familial combined hyperlipidemia.Ann. Med. 2006; 38: 337-351Crossref PubMed Scopus (29) Google Scholar). The specific purpose of this study was to further characterize SNPs in the APOA1/C3/A4/A5 cluster, describing their relationship with postprandial lipemia. With this aim, we genotyped three SNPs at APOA1 (all in the promoter region: APOA1 -2630, APOA1 -2803, APOA1 -3012), three at APOC3 (APOC3 -2886, APOC3 -640, APOC3 G34G), two in the APOA4 region (APOA4 N147S, APOA4 T29T), and one SNP in the intergenic region of APOA4/APOA5 (A4A5_inter), in order to investigate possible associations to measures of blood lipids during the time of postprandial lipid metabolism. Eighty-eight healthy men aged 18 to 33 years were enrolled in two studies conducted by the Lipids and Atherosclerosis Research Unit at Reina Sofia University Hospital. The first study included 50 participants and the second study included 38 patients. All tests were performed using the same methodology as described below. We included only young normolipemic APOE E3/E3 males in order to avoid possible effects of different APOE isoforms or gender. Other results of these studies have been published elsewhere (10Marin C. Lopez-Miranda J. Gomez P. Paz E. Perez-Martinez P. Fuentes F. Jimenez-Pereperez J.A. Ordovas J.M. Perez-Jimenez F. Effects of the human apolipoprotein A-I promoter G-A mutation on postprandial lipoprotein metabolism.Am. J. Clin. Nutr. 2002; 76: 319-325Crossref PubMed Scopus (25) Google Scholar, 23Ostos M.A. Lopez-Miranda J. Marin C. Castro P. Gomez P. Paz E. Jimenez Pereperez J.A. Ordovas J.M. Perez-Jimenez F. The apolipoprotein A-IV-360His polymorphism determines the dietary fat clearance in normal subjects.Atherosclerosis. 2000; 153: 209-217Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 25Ostos M.A. Lopez-Miranda J. Ordovas J.M. Marin C. Blanco A. Castro P. Lopez-Segura F. Jimenez-Pereperez J. Perez-Jimenez F. Dietary fat clearance is modulated by genetic variation in apolipoprotein A-IV gene locus.J. Lipid Res. 1998; 39: 2493-2500Abstract Full Text Full Text PDF PubMed Google Scholar, 28Moreno R. Perez-Jimenez F. Marin C. Moreno J.A. Gomez P. Bellido C. Perez-Martinez P. Jimenez-Gomez Y. Fuentes F.J. Lopez-Miranda J. A single nucleotide polymorphism of the apolipoprotein A-V gene -1131T>C modulates postprandial lipoprotein metabolism.Atherosclerosis. 2005; 189: 163-168Abstract Full Text Full Text PDF Scopus (28) Google Scholar, 31Moreno-Luna R. Perez-Jimenez F. Marin C. Perez-Martinez P. Gomez P. Jimenez-Gomez Y. Delgado-Lista J. Moreno J.A. Tanaka T. Ordovas J.M. et al.Two independent apolipoprotein A5 haplotypes modulate postprandial lipoprotein metabolism in a healthy Caucasian population.J. Clin. Endocrinol. Metab. 2007; 92: 2280-2285Crossref PubMed Scopus (46) Google Scholar, 38Perez-Martinez P. Lopez-Miranda J. Ordovas J.M. Bellido C. Marin C. Gomez P. Paniagua J.A. Moreno J.A. Fuentes F. Perez-Jimenez F. Postprandial lipemia is modified by the presence of the polymorphism present in the exon 1 variant at the SR-BI gene locus.J. Mol. Endocrinol. 2004; 32: 237-245Crossref PubMed Scopus (35) Google Scholar, 39Moreno J.A. Perez-Jimenez F. Marin C. Perez-Martinez P. Moreno R. Gomez P. Jimenez-Gomez Y. Paniagua J.A. Lairon D. Lopez-Miranda J. The apolipoprotein E gene promoter (-219G/T) polymorphism determines insulin sensitivity in response to dietary fat in healthy young adults.J. Nutr. 2005; 135: 2535-2540Crossref PubMed Scopus (20) Google Scholar, 40Moreno J.A. Lopez-Miranda J. Marin C. Gomez P. Perez-Martinez P. Fuentes F. Fernandez de la Puebla R.A. Paniagua J.A. Ordovas J.M. Perez-Jimenez F. The influence of the apolipoprotein E gene promoter (-219G/ T) polymorphism on postprandial lipoprotein metabolism in young normolipemic males.J. Lipid Res. 2003; 44: 2059-2064Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 41Mata P. 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Influence of the -514C/T polymorphism in the promoter of the hepatic lipase gene on postprandial lipoprotein metabolism.Atherosclerosis. 2004; 174: 73-79Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 44Bellido C. Lopez-Miranda J. Blanco-Colio L.M. Perez-Martinez P. Muriana F.J. Martin-Ventura J.L. Marin C. Gomez P. Fuentes F. Egido J. et al.Butter and walnuts, but not olive oil, elicit postprandial activation of nuclear transcription factor kappaB in peripheral blood mononuclear cells from healthy men.Am. J. Clin. Nutr. 2004; 80: 1487-1491Crossref PubMed Scopus (132) Google Scholar, 45Delgado-Lista J. Perez-Jimenez F. Tanaka T. Perez-Martinez P. Jimenez-Gomez Y. Marin C. Ruano J. Parnell L. Ordovas J.M. Lopez-Miranda J. An apolipoprotein A-II polymorphism (-265T/C, rs5082) regulates postprandial response to a saturated fat overload in healthy men.J. Nutr. 2007; 137: 2024-2028Crossref PubMed Scopus (34) Google Scholar). No participants had diabetes or liver, renal, or thyroid disease, nor were they taking any medication. Anthropometric measures (weight, height, and BMI) and blood pressure were assessed and all subjects were encouraged to maintain regular lifestyle and levels of physical activity. All volunteers had plasma cholesterol and TG concentrations below 200 mg/dl. Baseline characteristics of the participants are summarized in Table 1TABLE 1Baseline characteristics of the participantsVariableAPOA1 -2630APOA1 -2803APOA1 -3012APOC3 -2886APOC3 -640APOC3 G34GAPOA4 N147SAPOA4 T29TAPOA4A5_interAge(years)GG 22.1 ± 2.1GG 22.2 ± 2.1AA 22.6 ± 4.3AA 22.7 ± 3.9CC 21.7 ± 1.5CC 21.9 ± 2.1GG 22.5 ± 3.3AA 22.5 ± 3.4TT 22.3 ± 3.7GA 22.5 ± 3.8GA 22.4 ± 3.6AG 22.5 ± 1.9AC 22 ± 2.1CA 22.4 ± 3.4CT 22.6 ± 3.7GA 21.9 ± 2.6AG 21.6 ± 2.5TC 22.3 ± 2.5AA 20.8 ± 2.1AA 21 ± 1.6GG 21.4 ± 2.9CC 22.2 ± 3.5AA 22.6 ± 3.5TT 21 ± 2AA 22.3 ± 3.1GG 21.3 ± 3.1CC 21.7 ± 2.7p 0.47p 0.5p 0.35p 0.58p 0.52p 0.48p 0.38p 0.25p 0.74BMI(kg/m2)GG 25.7 ± 2.8GG 25.6 ± 2.9AA 25 ± 2.7AA 25.3 ± 2.6CC 25.5 ± 2.8CC 25.6 ± 2.9GG 25.4 ± 2.7AA 25.4 ± 2.8TT 25.6 ± 2.6GA 24.4 ± 2.7GA 24.7 ± 2.8AG 25.1 ± 2.6AC 25 ± 2.9CA 24.8 ± 2.8CT 24.3 ± 2.7GA 24.3 ± 2.9AG 24.1 ± 2.9TC 24.9 ± 3.1AA 23.2 ± 2.5AA 23.1 ± 2.2GG 24.5 ± 3.4CC 24.3 ± 3AA 24.1 ± 2.9TT 24.2 ± 0.8AA 23.5 ± 2.8GG 24 ± 6.8CC 24.1 ± 2p 0.12p 0.11p 0.77p 0.64p 0.37p 0.09p 0.2p 0.06p 0.22CHOL(mg/dl)GG 151.7 ± 18.8GG 152 ± 18.9AA 139.6 ± 38.6AA 140.1 ± 35.6CC 138 ± 35.9CC 150.4 ± 18.6GG 143.6 ± 34.6AA 146.3 ± 26.5TT 141 ± 43GA 139.7 ± 37.5GA 142.6 ± 36.1AG 147.8 ± 30AC 148.1 ± 26.9CA 148.1 ± 27CT 139.8 ± 37.5GA 150.4 ± 21.5AG 151.4 ± 21.1TC 149.5 ± 20.6AA 141.5 ± 23.3AA 139.6 ± 18.1GG 147.5 ± 13.9CC 150.3 ± 18.9AA 151.8 ± 18.4TT 159.5 ± 20.6AA 146 ± 30.6GG 146 ± 30.6CC 142.1 ± 15.9p 0.17p 0.32p 0.53p 0.44p 0.26p 0.19p 0.34p 0.38p 0.43TG(mg/dl)GG 75.4 ± 35.4GG 73.3 ± 31.8AA 80.6 ± 35.8AA 81.5 ± 31.8CC 81.3 ± 32.4CC 74.5 ± 35.8GG 81.1 ± 36.2AA 79.9 ± 38TT 92.8 ± 41.2GA 85.8 ± 34GA 88 ± 36.3AG 81.8 ± 35.7AC 78.4 ± 32.8CA 78.7 ± 32.4CT 86.9 ± 33GA 82.1 ± 34AG 82.3 ± 33.7TC 71.1 ± 22.8AA 67.4 ± 21.4AA 60.4 ± 18.7GG 72.4 ± 24.1CC 86.2 ± 53.1AA 84.9 ± 50.3TT 58.9 ± 9.1AA 81.5 ± 35.3GG 81.5 ± 45.3CC 81.1 ± 40.5p 0.29p 0.05p 0.54p 0.8p 0.85p 0.14p 0.9p 0.78p 0.03HDL(mg/dl)GG 47 ± 10.5GG 47.1 ± 9.1AA 44.8 ± 12.2AA 45.9 ± 9.8CC 46.2 ± 9.3CC 46.8 ± 10.8GG 46.6 ± 10.8AA 46.6 ± 10.6TT 45.3 ± 10.6GA 45.8 ± 10.3GA 45.6 ± 11AG 47.2 ± 10.1AC 45.8 ± 9.2CA 45.8 ± 9.4CT 45.8 ± 10GA 45.1 ± 9.5AG 45.1 ± 9.8TC 46 ± 9.4AA 46.2 ± 7.5AA 47.5 ± 10.5GG 47.2 ± 8.3CC 50.5 ± 16.5AA 49.3 ± 16TT 48.8 ± 5.4AA 46.1 ± 10.3GG 44.1 ± 20.3CC 49 ± 11.8p 0.86p 0.78p 0.62p 0.43p 0.61p 0.84p 0.52p 0.55p 0.5LDL(mg/dl)GG 89.5 ± 15.4GG 90.3 ± 16.2AA 93.2 ± 24.4AA 89.1 ± 23.9CC 88.1 ± 22.5CC 88.6 ± 15.7GG 91.3 ± 22.7AA 87.6 ± 19.3TT 95.5 ± 26.3GA 90.2 ± 26.5GA 91.1 ± 24.6AG 89.6 ± 23.6AC 90.8 ± 20.4CA 90.6 ± 21.3CT 89.7 ± 26.5GA 88.9 ± 20.2AG 89.8 ± 20.5TC 89.3 ± 18.4AA 81.8 ± 23.3AA 80.1 ± 16.8GG 85.9 ± 11.9CC 82.1 ± 20.3AA 85.2 ± 21.4TT 98.9 ± 15.1AA 90.4 ± 21.8GG 90.4 ± 21.8CC 76.9 ± 14.1p 0.76p 0.44p 0.5p 0.54p 0.73p 0.72p 0.63p 0.64p 0.02APOA1(mg/dl)GG 108.3 ± 19.3GG 109.1 ± 20.1AA 106 ± 22.4AA 109.4 ± 19.6CC 110.3 ± 19CC 108.8 ± 20.7GG 109.6 ± 20.3AA 110 ± 20.3TT 106.5 ± 18.2GA 103.9 ± 20.6GA 103.6 ± 19.3AG 107 ± 19.4AC 105.6 ± 19.3CA 105.3 ± 19.6CT 104.4 ± 18.7GA 99 ± 17.5AG 100.3 ± 17.2TC 105.7 ± 19.6AA 114 ± 7.9AA 111.4 ± 20.1GG 105.6 ± 18.8CC 102.4 ± 22AA 101.6 ± 20.9TT 103.3 ± 19.1AA 105.8 ± 19.9GG 103.8 ± 19.9CC 108.4 ± 22.8p 0.45p 0.37p 0.96p 0.56p 0.39p 0.56p 0.02p 0.04p 0.89APOB(mg/dl)GG 70.6 ± 13.3GG 70.4 ± 13.5AA 68.8 ± 19.3AA 67.5 ± 17.3CC 67.1 ± 16.4CC 69.4 ± 13.4GG 69.2 ± 16.1AA 67.8 ± 15.2TT 70.7 ± 19.2GA 65.2 ± 19.2GA 67.6 ± 18.4AG 69.1 ± 18.3AC 68.4 ± 15.5CA 68.3 ± 16.2CT 65.3 ± 19.2GA 65.8 ± 18.3AG 65.9 ± 18.3TC 67.5 ± 13.4AA 59.8 ± 13.3AA 57.3 ± 11.3GG 64.2 ± 9CC 62.8 ± 20.4AA 63.2 ± 19.3TT 73.7 ± 13.6AA 68 ± 16.9GG 64 ± 24.9CC 60.8 ± 17.7p 0.21p 0.16p 0.5p 0.65p 0.67p 0.43p 0.4p 0.63p 0.15The p value in each cell corresponds

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