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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:289.)
© 2002 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Postprandial Plasma ApoB-48 Levels Are Influenced by a Polymorphism in the Promoter of the Microsomal Triglyceride Transfer Protein Gene

Björn Lundahl; Anders Hamsten; Fredrik Karpe

From the Atherosclerosis Research Unit (B.L., A.H., F.K.), King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital, Stockholm, Sweden, and the Oxford Lipid Metabolism Group (F.K.), Oxford Centre for Diabetes, Metabolism, and Endocrinology, Oxford, UK.

Correspondence to Dr Fredrik Karpe, Oxford Lipid Metabolism Group, Radcliffe Infirmary, Oxford OX2 6HE, UK. E-mail fredrik.karpe{at}oxlip.ox.ac.uk

	Abstract

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The microsomal triglyceride transfer protein (MTP) plays a key role in the secretion of apolipoprotein B (apoB)-containing lipoproteins. The rare variant of a functional polymorphism in the promoter region of the MTP gene has been associated with elevated transcriptional activity of the gene in vitro (MTP-493G/T). With use of a "recruit-by-genotype" approach, we investigated one of the potentially complex phenotypes of this polymorphism, the appearance in plasma of apoB-48 after a meal intake. A total of 12 homozygous carriers of the rare MTP-493T variant were identified from a population-based screening of 50-year-old healthy white men. All subjects were of the apoE3/3 genotype. Along with 48 baseline well-matched heterozygotes (n=24) plus homozygotes (n=24) for the common variant, they were given a standardized oral fat meal. Postprandial plasma concentrations of apoB-48 were determined by the combination of density gradient ultracentrifugation and analytical SDS-PAGE. The postprandial plasma concentrations of triglycerides did not differ between the groups, but homozygous carriers of the rare MTP-493T variant showed a >100% greater increase in apoB-48 in the smallest (Svedberg flotation rate constant 20 to 60) triglyceride-rich lipoprotein fraction (P=0.005). These data support the notion that elevated transcriptional activity of MTP leads to an increased generation of the smallest triglyceride-rich lipoprotein from the intestine.

Key Words: genetic variability • DNA bank • genetic screening • complex phenotype • alimentary lipemia

	Introduction

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Several studies have suggested that there is a heritable component determining the magnitude of postprandial lipemia.¹ In part, this can be attributed to functional polymorphisms in genes coding for proteins involved in regulatory steps in the pathways for postprandial lipid and lipoprotein metabolism. For this purpose, a number of candidate genes have been investigated in relation to postprandial lipemia; most of these genes are involved in the catabolic pathways, such as apoE, which is the ligand for receptor-mediated removal of remnant lipoproteins, and lipoprotein lipase (LPL), which hydrolyzes triglycerides from chylomicrons and VLDLs. The effect on postprandial lipemia exerted by the common 2/3/4 polymorphism in the apoE gene has been observed in several studies in which carriers of the 2 allele have shown consistently delayed clearance of triglyceride-rich lipoprotein (TRL) remnants.^2–4 In addition, it has been suggested that carriers of the 4 allele have increased plasma levels of endogenous TRL in the postprandial state.⁵

The LPL gene is the obvious candidate for studies of postprandial lipemia, inasmuch as it codes for the single-protein–hydrolyzing triglycerides from chylomicrons and large VLDLs. Talmud et al⁶ have studied the interaction between the functional variants involving the LPL-93T/G promoter polymorphism and the LPL D9N substitution. Carriers of the haplotype constituting the rare LPL-93G variant (presumably higher transcriptional activity) and the common LPL9N variant (presumably secretion-defective LPL protein) exhibit higher plasma triglyceride levels after meal intake than do carriers of other haplotypes.⁶ The LPL A291S residue variant affects the specific activity of the enzyme.⁷ Two studies show that carriers of this variant have significantly higher postprandial triglyceridemia.^8,9

Hepatic lipase (HL) has been implicated in the removal of remnant lipoproteins. The promoter of the HL gene contains several single nucleotide polymorphisms.¹⁰ The rare variant of the -480C/T (also called -514C/T) polymorphism has been associated with lower HL activity. This does not seem to affect total postprandial triglyceridemia but does affect the retention of a specific lipoprotein subspecies in the postprandial state, the LpCIII:B particles, which are likely to reflect remnant lipoproteins.¹¹

So far, polymorphisms in candidate genes involved in the secretion of apoB-containing lipoproteins have given less convincing evidence of influencing postprandial lipemia. The noncutting variant of the APOB XbaI polymorphism, which has been linked to neither a functional effect on the gene nor the gene product, has been associated with a small but statistically significant elevation of postprandial plasma retinyl palmitate and apoB-48 concentrations in healthy subjects.¹² Of note, this effect was independent of apoE carrier status and the fasting plasma triglyceride level.

Intestinal absorption of triglycerides and intestinal handling of fatty acids might be influenced by a single nucleotide polymorphism leading to amino acid exchange in the intestinal fatty acid binding protein (the FABP-2 Ala54Thr polymorphism). Thr54 carrier status has been associated with higher postprandial plasma triglycerides,¹³ but these findings could not be reproduced in a much larger cohort.¹⁴

In summary, there is substantial evidence that functional changes in genes involved in catabolic pathways of postprandial lipoproteins have physiological and potentially pathophysiological consequences, whereas the corresponding evidence for genes implicated in the production of postprandial lipoproteins is sparse, with the potential exception being an as-yet-uncharacterized apoB polymorphism. Therefore, we set out to study the effects of a recently detected functional polymorphism in the promoter region of the gene encoding the microsomal triglyceride transfer protein (MTP). MTP plays a role in the formation of VLDL in the liver and of chylomicrons in the intestine by transferring core lipids to the apoB molecule. The rare variant of the MTP-493G/T transition has been shown to confer higher transcriptional activity in vitro¹⁵; therefore, we hypothesized that this might result in increased production of apoB-48-containing lipoproteins in the postprandial state. To test this hypothesis, we selected matched healthy carriers of either genetic variant from a well-characterized and homogeneous population and challenged them with an oral fat load to stimulate apoB-48 lipoprotein secretion.

	Methods

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Subjects, Recruitment, and Baseline Matching
Sixty healthy 50-year-old white men participated in the present study. They were recruited through an ongoing population survey of 50-year-old residents in the greater Stockholm area.^16–18 The original cohort consisted of 418 individuals at the time of recruitment into the study. The allele frequency of the MTP-493T variant was 0.24; for the apoE2/3/4, it was 0.08/0.77/0.15, respectively. The study consisted of 2 visits: the first visit was a screening visit, and the second consisted of the assessment of postprandial lipoprotein metabolism. Because of the relative infrequency of homozygous carriers of the rare MTP-493T variant (approximate frequency 5%), these men were mostly recruited by genotype for the second visit. Four of the 12 subjects were part of a previously reported study, whereas the remaining 8 subjects were recruited specifically for the present study. To create groups with very similar baseline characteristics, 2 homozygotes for the common MTP-493G variant and 2 heterozygotes were selected from the previously reported data set. Selection was made by ranking subjects according to fasting plasma triglycerides and body mass index (BMI); for each homozygote of the rare MTP variant, 2 subjects with the closest triglyceride and BMI values were selected. For 2 individuals, there were no perfect matches; therefore, 4 subjects with the more common variants were also recruited by genotype from the original population. In all, 24 homozygous carriers of the common variant and 24 heterozygotes were compared with 12 homozygotes of the rare variant. As part of the screening and matching procedure, apoE genotype was taken into account, and all participants were homozygous for the apoE3 allele. The time elapsed between the first screening visit and the second visit was between 3 and 12 months.

The present study was approved by the local Ethics Committee of the Karolinska Hospital, and all participants gave their informed consent before they were included in the study.

Genotyping
The genotyping for the MTP-493G/T promoter polymorphism was performed on a nested polymerase chain reaction (PCR) product. Primers for the first PCR reaction were as follows: 5'-CCC TCT TAA TCT CTT CCT AGA A and 5'-AAG AAT CAT ATT GAC CAG CAA TC. This PCR reaction was performed with a MgCl₂ concentration of 2.0 mmol/L. The PCR protocol used for amplification was as follows: 94°C for 3 minutes followed by 35 cycles of 94°C for 0.5 minutes, 55°C for 1 minute, and 72°C for 5 minutes and, finally, 72°C for 5 minutes. Primers for the second PCR reaction were as follows: 5'-AGT TTC ACA CAT AAG GAC AAT CAT CTA and 5'-GGA TTT AAA TTT AAA CTG TTA ATT CAT ATC AC. One microliter of the product of the first reaction was used for the second one. The MgCl₂ concentration was elevated to 5.0 mmol/L, and conditions were as follows: 94°C for 3 minutes followed by 35 cycles of 94°C for 0.5 minutes, 57°C for 1.0 minutes, and 72°C for 2.0 minutes and, finally, 72°C for 5 minutes. The product of the second PCR reaction was a fragment of 109 bp. This fragment was then incubated overnight with the restriction enzyme HphI, whereby the following genotype-specific fragments were obtained: homozygotes for the T variant, 1 fragment of 109 bp; G/T heterozygotes, 3 fragments of 109, 89, and 20 bp; and homozygotes for the G variant, 2 fragments of 89 and 20 bp. Because of the risk of contamination when a nested PCR reaction is performed, 1 DNA-free control sample was included for every eighth sample containing sample DNA.

Genotyping for the apoE polymorphism was performed as described by Hixson and Vernier,¹⁹ with minor modifications. Primers for PCR amplification were 5'AGG CCG CGC TCG GCG CCCT and 5'-TCC CCA CTG TGC GAC ACC CT.

Oral Fat Tolerance Test Meal
The oral fat tolerance test was of mixed-meal type, containing 1000 kcal; energy percentage from fat was 60%.²⁰

Blood Sampling and Analytical Procedures
Venous blood was drawn into precooled Na₂EDTA Vacutainer tubes. Plasma was recovered within 30 minutes after a low-speed centrifugation at 4°C. Phenylmethylsulfonyl fluoride and aprotinin (final concentrations 10 µmol/L and 28 µg/mL, respectively) were added to samples taken in connection with the oral fat tolerance test to inhibit degradation of apoB. Major fasting plasma lipoprotein lipids were determined after the combination of preparative ultracentrifugation and precipitation.²¹ Samples taken in connection with the oral fat tolerance test were subjected to density gradient ultracentrifugation to isolate subfractions of TRLs in which the concentrations of apoB-100 and apoB-48 were determined by analytical SDS-PAGE.²²

Statistical Analysis
Conventional methods were used for the calculation of mean±SD values. Coefficients of skewness and kurtosis were calculated to test deviations from a normal distribution. Logarithmic transformation was performed on the individual values of skewed variables, and a normal distribution of transformed values was confirmed before statistical computations and significance testing. The statistical method used was ANOVA, with the Scheffé post hoc test. Statview 5.0 for Windows 97 was used for statistical analysis.

	Results

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Fasting plasma lipid and major lipoprotein lipid concentrations and BMI are shown in Table 1. Average BMI and fasting plasma triglycerides were almost identical as a consequence of the matching procedure. There were no statistically significant differences in total plasma or major cholesterol concentrations according to MTP genotype. We have previously reported that the homozygous carriers of the MTP-493T variant have significantly lower LDL cholesterol levels,¹⁵ and this could be reproduced in the cohort from which the present subjects were matched and recruited (N=418; LDL cholesterol for MTP-493G/G [n=231], 3.53±0.85 mmol/L; LDL cholesterol for MTP-493G/T [n=161], 3.59+0.85 mmol/L; and LDL cholesterol for MTP-493TT [n=26], 3.09+0.73 mmol/L; P=0.02 by ANOVA). Therefore, the lack of difference between the genotypes for LDL cholesterol in the present study groups is likely to depend on the matching procedure, which focused on fasting plasma triglycerides, BMI, and apoE genotype to eliminate major confounders for the study of postprandial TRL metabolism.

View this table: [in this window] [in a new window]   Table 1. BMI and Fasting Plasma Lipid and Lipoprotein Concentrations in the MTP-493G/T Genotype Groups

Fasting plasma apoB-100 and apoB-48 concentrations in major subfractions of TRLs were also similar (Table 2). In most subjects, the amounts of apoB-100 and apoB-48 contained in the Svedberg flotation rate constant (S_f) >400 fractions in the fasting state were below the detection limit, whereas almost all subjects had detectable levels of apoB-48 in the S_f 60 to 400 and S_f 20 to 60 fractions. The ratio between apoB-48 and apoB-100 in fasting TRL fractions varied between 3% and 4%, reflecting the relationship between chylomicron remnants and VLDL particle number (calculating the particle number assumes that there is 1 apoB per particle). This ratio did not differ between genotype.

View this table: [in this window] [in a new window]   Table 2. Fasting Plasma ApoB-100 and ApoB-48 Concentrations in Subfractions of TG-Rich Lipoproteins

Plasma triglycerides peaked at 3 hours after meal intake in all groups (Figure 1). Overall, postprandial triglyceride levels did not differ between the genotype groups, either when they were calculated as the area under the curve or when they were assessed as the incremental area under the curve (P=0.34 and P=0.29, respectively, by ANOVA; Table 3).

View larger version (14K): [in this window] [in a new window]   Figure 1. Line plots of plasma triglycerides (TGs) according to genotype after fat intake. Open circles indicate MTP-493T/T (n=12); filled circles, MTP-493G/G (n=24); and filled squares, MTP-493G/T (n=24). There is no statistically significant difference between the groups. Data are shown as mean, with SEM error bars.

View this table: [in this window] [in a new window]   Table 3. Plasma TG AUC and Baseline to Peak Increment of ApoB-48 in Sf >400, Sf 60–400, and Sf 20–60 TRL Fractions

Plasma concentrations of apoB-48 in TRLs increased after fat intake (Figure 2). The largest increase was seen in the S_f 60 to 400 fraction. However, there was no genotype-specific effect (Table 3). This was also true for the S_f >400 fraction. In contrast, homozygous carriers of the MTP-493T allele showed a markedly greater elevation of apoB-48 in the S_f 20 to 60 fraction in response to fat intake. The increase was >2-fold greater than that of the other genotype groups, but the apoB-48 level returned to baseline after 6 hours (Table 3).

View larger version (22K): [in this window] [in a new window]   Figure 2. Line plots of incremental plasma concentrations of apoB-48 in Sf >400, Sf 60 to 400, and Sf 20 to 60 TG-rich lipoprotein fractions after fat intake. Open circles indicate MTP-493T/T (n=12); filled circles, MTP-493G/G (n=24); and filled squares, MTP-493G/T (n=24). The increase of apoB-48 in the Sf 20 to 60 fraction is approximately twice as high in the MTP-493TT carriers compared with the MTP-493GG and MTP-493GT carriers (P<0.005 by ANOVA and Scheffé post hoc test after logarithmic normalization of data).

View larger version (21K): [in this window] [in a new window]   Figure 3. Line plots of incremental plasma concentrations of apoB-100 in Sf 60 to 400 and Sf 20 to 60 TG-rich lipoprotein fractions after fat intake. Open circles indicate MTP-493T/T (n=12); filled circles, MTP-493G/G (n=24); and filled squares, MTP-493G/T (n=24). There is no statistically difference between the groups (by ANOVA and Scheffé post hoc test after logarithmic normalization of data).

The apoB-100 concentrations in TRLs did not differ according to MTP genotype (Figure 3).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study investigated the physiological consequences of a common polymorphism in the MTP gene in relation to the generation of chylomicrons and chylomicron remnants in the plasma after the intake of a fatty meal. Homozygous carriers of the rare MTP-493T variant, which is associated with higher transcriptional activity of the gene in vitro,¹⁵ showed markedly elevated accumulation of small apoB-48-containing lipoproteins in the postprandial state. In contrast, the postprandial plasma triglyceride concentrations did not differ according to MTP genotype.

Why would increased transcriptional activity of the MTP gene be associated with increased postprandial plasma levels of small apoB-48-containing particles? There is considerable evidence that the intestine secretes apoB-48 particles of a wide range of sizes. When large amounts of lipid substrate become available, as is the case after oral intake of fat, some of these particles are recruited to be particularly filled with triglycerides, and they are then secreted as "chylomicrons." Simultaneously, there is continued secretion of smaller-sized apoB-48 particles, and our results indicate that the rate at which these particles are filled with triglycerides is likely to be determined by the MTP activity. This finding is in accordance with the 2-step model for chylomicron assembly in which the availability of primordial apoB particles would be enhanced by higher MTP activity.²³ In addition, small and relatively lipid-poor chylomicrons are likely to compete less well for LPL because of the presence of larger chylomicrons and large VLDLs in the postprandial state.^24,25 This is likely to further enhance the accumulation of small apoB-48-containing particles. We do not believe that the postprandial accumulation of the small apoB-48-containing particles is the consequence of a higher secretion rate of larger particles for 2 reasons. First, there was no sign of higher apoB-48 concentrations in the chylomicron (S_f >400) and the large TRL (S_f 60 to 400) fraction in "the high MTP activity group." Second, we have previously shown that there is almost no substrate-product relationship between the S_f 60 to 400 and the S_f 20 to 60 fractions in the postprandial state; ie, there is hardly any input of apoB-48 into the S_f 20 to 60 fraction from the more triglyceride-rich fractions.²⁶

This finding is unique in the context of genetic regulation of postprandial lipoprotein metabolism, inasmuch as there are no examples of common functional polymorphisms regulating postprandial plasma apoB-48 concentrations. Lopez-Miranda et al¹² have studied the effect of the common apoB XbaI polymorphism in the postprandial state in a rather large cohort of well-matched subjects and found that carriers of the cutting variant had significantly lower plasma apoB-48 concentrations than did carriers of the noncutting variant. However, the functional significance of this polymorphism is unknown. The apoB signal peptide SP24/27 variant has been implicated to play a role in determining the magnitude of postprandial lipoproteinemia,²⁷ but the effect is likely to be due to a genotype-specific effect on fasting plasma triglycerides.²⁸ In addition, in a large cohort of 274 healthy subjects given an oral fat meal, there was no effect at all by the apoB SP24/27 variant on the postprandial elevation of plasma triglycerides.²⁹

The present study involved a "recruit-by-genotype" approach. Because postprandial lipemia and lipoproteinemia are very much dependent on the fasting plasma triglyceride concentration, it is of utmost importance to eliminate that factor in the study of more subtle aspects of regulation of postprandial lipemia. The obvious benefit of the approach is that it enables matching for baseline factors that may interfere with an intermediary phenotype determined after a provocation test, such as the interference between fasting plasma triglycerides and the postprandial rise of TRLs in plasma. However, a limitation of this approach is that the matching-recruiting procedure may restrict the expression of the phenotype by "overmatching."

The question arises of whether the greater postprandial increase of S_f 20 to 60 apoB-48-containing lipoproteins exhibited by homozygous carriers of the MTP-493T allele is proatherogenic. We have previously reported on an association between the accumulation of apoB-48 in postprandial plasma and the progression of coronary atherosclerosis in young survivors of myocardial infarction³⁰; this association fits well with the notion that excessive postprandial lipemia might be a risk factor for coronary heart disease.^31,32 However, the pattern of postprandial plasma apoB-48 concentrations observed in those studies is somewhat different from the pattern encountered in the present study. In the present study, the rare MTP-493T variant exhibited increased postprandial plasma apoB-48 concentrations at 3 hours, whereas the concentration had returned completely to baseline at 6 hours; ie, there was no sign of a delayed removal of those lipoprotein particles. Therefore, it might not be justifiable to compare this pattern with the delayed catabolism of S_f 20 to 60 apoB-48 particles that has been associated with coronary progression of coronary lesions in patients with premature coronary atherosclerosis.³⁰ However, the total vessel wall exposure of small chylomicron remnants is certainly greater in the MTP-493T/T carriers, and this could potentially have an atherogenic effect. Furthermore, the postprandial lipoprotein phenotype of this polymorphism on a hyperlipidemic background remains to be established.

	Acknowledgments

 
The project was supported by the Swedish Medical Research Council (grant No. 82659) and the Swedish Heart-Lung Foundation.

Received September 28, 2001; accepted November 13, 2001.

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				H. Ledmyr, A. D. McMahon, E. Ehrenborg, L. B. Nielsen, M. Neville, H. Lithell, P. W. MacFarlane, C. J. Packard, F. Karpe, and on behalf of the WOSCOPS executive; The Microsomal Triglyceride Transfer Protein Gene-493T Variant Lowers Cholesterol But Increases the Risk of Coronary Heart Disease Circulation, May 18, 2004; 109(19): 2279 - 2284. [Abstract] [Full Text] [PDF]

				C. Phillips, K. Mullan, D. Owens, and G.H. Tomkin Microsomal triglyceride transfer protein polymorphisms and lipoprotein levels in type 2 diabetes QJM, April 1, 2004; 97(4): 211 - 218. [Abstract] [Full Text] [PDF]

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