© 1997 American Heart Association, Inc.
Articles |
Effect of 347-Serine Mutation in Apoprotein A-IV on Plasma LDL Cholesterol Response to Dietary Fat
From the Lipid Research Unit, University Hospital "Reina Sofía," University of Córdoba Medical School, Córdoba, Spain, and The Lipid Metabolism Laboratory, US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Mass (J.M.O.).
Correspondence to Dr Francisco Perez-Jimenez, Departamento de Patologia Médica, Facultad de Medicina de Córdoba, Avenida Menéndez Pidal s/n, Córdoba 14004, Spain.
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Abstract |
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Abstract Lipid response to dietary fat and cholesterol is, to a large extent, genetically controlled. Apoprotein (apo) A-IV has been related to fat absorption and to the activation of some of the enzymes involved in lipid metabolism. One mutation has been described in the apo A-IV gene that causes substitution of Ser for Thr at position 347. To study the influence of this mutation on the plasma LDL cholesterol (LDL-C) response in diets of various fat content and fatty acid saturation, 41 healthy male subjects were studied, 25 of whom were homozygous for the Thr allele (347Thr) and the rest who were either homozygous (n=2) or heterozygous carriers of the Ser allele (347Ser). They consumed three consecutive diets, each of 4 weeks' duration: one rich in saturated fat (SFA diet: 38% fat, 20% saturated), a National Cholesterol Education Program (NCEP) type 1 diet (28% fat, 10% saturated), and a third rich in monounsaturated fat (MUFA diet; 38% fat, 22% monounsaturated). Carriers of the 347Ser allele presented a greater decrease in total cholesterol (-0.7 vs -0.44 mmol/L, P<.034), LDL-C (-0.62 vs -0.31 mmol/L, P<.012), and apo B (-14 vs -8 mg/dL, P<.01) levels when they were switched from the SFA to the NCEP type 1 diet than homozygous carriers of the 347Thr allele. The change from the NCEP type 1 to the MUFA diet resulted in a greater increase in total cholesterol (0.18 vs -0.05 mmol/L, P<.028) and apo B (5 vs -1 mg/dL, P<.006) levels in the 347Ser than in the 347Thr individuals. In a previous study, we demonstrated that the G
A polymorphism at position -76
of the gene promoter of apo A-I affects the LDL-C response to dietary
fat. We therefore decided to study the effect of the interaction
between these mutations on this response. We found that both mutations
have an additive effect on total cholesterol, LDL-C, and
apo B dietary-induced changes. Our results suggest that total
cholesterol and LDL-C response to dietary fat is influenced
by the 347Ser mutation of apo A-IV.
Key Words: apolipoprotein A-IV • diet • genetic polymorphism • cholesterol
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Introduction |
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Changes in plasma lipids in response to dietary fat and cholesterol vary greatly among different members of a population. Several studies in humans have shown that this response is genetically controlled.1 Apo A-IV, a glycoprotein with a molecular weight of 46 000 Da, is synthesized in the intestine.2 Apo A-IV is found mainly as part of HDLs,3 and the role it plays in lipid metabolism is not yet fully understood, although it has been associated with fat absorption4 and cholesterol efflux.5 6 Moreover, in vitro studies have demonstrated that apo A-IV can activate the LCAT enzyme7 and regulate the action of LPL mediated by apo C-II.8 Recent studies have also shown that apo A-IV can regulate cholesterol ester transfer mediated by CETP between HDLs and LDLs.9
With the use of isoelectric focusing and immunoblotting
techniques, eight isoforms have been described in humans (apo A-IV-0
through A-IV-7).10 11 12 The most common is apo A-IV-1, with
an allele frequency ranging from .88 to .95.13
Application of DNA sequence analysis has revealed a variant of
apo A-IV-1 due to an AT gene substitution, which codes for Ser
instead of Thr at position 347 of the protein.14 The
frequency of the 347Ser allele in the population is .16 to
.216.14 15 16
Because the A-IV-2 isoform produces a different plasma LDL-C response
after consumption of diets with different fat and
cholesterol contents,17 18 our main objective
was to determine whether the 347Ser mutation of apo A-IV also controls
the degree of LDL-C response in diets with different fat contents and
degrees of fatty acid saturation. Moreover, another aim of this study
was to determine the effect of the interaction between this mutation
and other gene polymorphisms that control this response, such as
the GA mutation in the apo A-I gene promoter.19
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Methods |
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Subjects and Diets
The initial study population comprised 115 white male students from the University of Córdoba. All underwent a comprehensive medical history, physical examination, and clinical chemistry analysis before enrollment. Of these, 79 were homozygous for the 347Thr allele, 34 were heterozygous for this allele, and 2 were homozygous for the 347Ser allele. Subjects who were <30 years old, with LDL-C levels <5.7 mmol/L on their usual diets, and with no evidence of any chronic illness (such as hepatic, renal, thyroid, or cardiac dysfunction) or unusually high levels of physical activity were selected. The final study group consisted of 41 of these subjects who volunteered to participate in the study. Twenty-five were homozygous carriers of the 347Thr allele, and 16 had the 347Ser allele in its homozygous (2 subjects) or heterozygous (14 subjects) form. Moreover, 33 were homozygous carriers of the apo A-IV-360Gln allele (20 347Thr homozygotes and 13 carriers of the 347Ser allele, including the 2 homozygous subjects), and 8 were heterozygous for the 360His allele (5 347Thr homozygotes and 3 carriers of the 347Ser allele). In addition, 18 were heterozygous for the A allele at position -76 of the gene promoter of apo A-I, and the remaining 23 were homozygous for the G allele. Thirty-three subjects were homozygous for the apo E3 isoform (E-3/3; 21 347Thr/Thr, 10 347Thr/Ser, and 2 347Ser/Ser), 6 were E-3/2 (4 347Thr/Thr and 2 347Thr/Ser), 1 was E-3/4 (347Thr/Ser), and 1 was E-2/4 (347Thr/Ser). None of the subjects has a family history of coronary heart disease, and none had taken medication or vitamin supplements in the 6 months before the start of the study. Physical activity and diet were recorded in a personal log for 1 week and were used to calculate individual caloric requirements. Mean BMI was calculated as the weight in kilograms divided by height squared in meters squared at the start of the study and remained constant throughout the experimental period. Subjects were encouraged to maintain their regular physical activity and life style and asked to record in a diary any event that could affect the outcome of the study, such as stress, a change in smoking habits and alcohol consumption, or consumption of foods not included in the experimental design.
The study included an initial 28-day period during which all subjects consumed an SFA diet, with 15% of energy as protein, 47% as carbohydrate, and 38% as fat (20% SFA, 12% MUFA, and 6% PUFA). The second diet lasted 28 days, and all subjects consumed the NCEP type I diet containing 15% of energy as protein, 57% as carbohydrate, and 28% as fat (10% SFA, 12% MUFA, and 6% PUFA). The third diet also lasted 28 days, and all subjects consumed a MUFA-rich diet, with 15% of energy as protein, 47% as carbohydrate, and 38% as fat (10% SFA, 22% MUFA, and 6% PUFA). Dietary cholesterol was not a factor in this design, and the mean cholesterol intake was 115 mg/1000 kcal during the three diet periods. This study was approved by the human investigation review committee at the Reina Sofia University Hospital. Informed consent was obtained from all study subjects.
The composition of the experimental diets was calculated by using the US Department of Agriculture food tables and Spanish food composition tables for local foodstuffs. Fourteen menus, prepared with regular solid foods, were consumed in rotation during the experimental period. Virgin olive oil was used for cooking and preparation of salad dressing during the high-MUFA period and palm oil and butter during the SFA diet. Lunch and dinner were consumed in the hospital kitchen. Breakfast and an afternoon snack were prepared for each individual in his home according to recommended foodstuffs and form of preparation. Duplicate samples from each menu were collected, homogenized, and stored at -80°C. Protein, fat, and carbohydrate contents of the diet were analyzed by standard methods. For dietary follow-up, the fatty acids in the cholesteryl esters of LDL were determined at the end of each dietary period.
Lipid Analysis
Venous blood samples were collected into EDTA-containing tubes
from all patients after a 12-hour overnight fast at the end of each
dietary period. Plasma was obtained by low-speed
centrifugation at 4°C within 1 hour of
venipuncture. Cholesterol and TGs were assayed
by enzymatic procedures.20 21 HDL-C was measured after
precipitation of apo B–containing lipoproteins with phosphotungstic
acid.22 The LDL-C level was calculated from the total
cholesterol, TG, and HDL-C values by the Friedewald
formula.23 Apo A-I and apo B concentrations were found by
turbidimetry.24 To reduce interassay variation, plasma and
lipoprotein fractions were stored at -80°C and analyzed at
the end of the study in triplicate.
DNA Amplification and Genotyping of Apoproteins A-IV, A-I, and
E
The nomenclature for the apo A-IV isoforms is shown in Table 1
. DNA was extracted from 10 mL of
EDTA-containing blood. Apo A-IV sequences were amplified from DNA
samples by PCR. The forward primer used for restriction isotyping of
apo A-IV 347Thr, 347Ser, 360Gln, and 360His was
5'-GCCCTGGTGCAGCAGATGGAACAGCTCAGG-3', and the reverse primer (with a
mismatch underlined) was
5'-CATCTGCACCTGCTCCTGCTGCTGCTCCAG-3'.25 In
addition to the buffer and nucleotide components described
by the supplier of Taq polymerase (Promega), each
amplification reaction contained 0.5 µg DNA, 1 pmol/µL of
each primer in 10% DMSO, and 0.025 U/µL Taq polymerase in
a final volume of 20 µL. DNA was denatured at 95°C for 5 minutes,
followed by 30 cycles of amplification by primer annealing (65°C for
1 minute), extension (70°C for 2 minutes), and denaturation (95°C
for 1 minute).
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After amplification, two samples of 10 µL of each PCR product
were used digested with restriction enzymes.25 To one
sample, 5 U of HinfI (Promega) were added to distinguish
347Ser from 347Thr alleles (Figure).
To the other sample, 5 U of Pvu II (Promega) were added to
differentiate 360Gln and 360His (apo A-IV-2). In both cases, the
enzymes were added directly to each reaction mixture for digestion (>3
hours at 37°C). Digested DNA was separated by electrophoresis on an
8% nondenaturing polyacrylamide gel for 3 hours under constant
current (45 mA). Bands were visualized by silver staining. Samples
containing the 347Ser or 360His mutation were amplified a second time
to verify the genotype.
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For apo A-I, amplification of a 432-bp region of the apo A-I 5' region was done by PCR with 250 ng of genomic DNA and 0.2 µmoL of each oligonucleotide primer (P1, 5'-AGGGACAGAGCTGATCCTTGAACTCTTAAG-3'; P2, 5'-TTAGGGGACACCTACCCGTCAGGAAGAGCA-3') in 50 µL. DNA was denatured at 95°C for 5 minutes, followed by 30 cycles of denaturation at 95°C for 1 minute, annealing at 58°C for 1.5 minutes, and extension at 72°C for 2 minutes. Twenty microliters of PCR product was digested with 10 U of restriction enzyme Msp I (BRL) in a total volume of 35 µL. Digested DNA was separated by electrophoresis on an 8% nondenaturing polyacrylamide gel at 150 V for 2 hours. Bands were visualized by silver staining.
Apo E polymorphism was determined by restriction enzyme analysis of the DNA amplified by PCR as previously described.26 In brief, amplification of a 266-bp region of exon 4 of apo E was done by PCR, with 250 ng of genomic DNA, 0.2 µmol of each oligonucleotide primer (P3, 5'-GAACAACTGACCCCGGTGGCGGAG-3'; P4, 5'-TCGCGGGCCCCGGCCTGGTACACTGCCA-3'), and 10% DMSO in 50 µL. DNA was denatured at 95°C for 5 minutes, followed by 30 cycles of denaturation at 96°C for 1 minute, annealing at 63°C for 1.5 minutes, and extension at 72°C for 2 minutes. Twenty microliters of PCR product were digested with 10 U of restriction enzyme Cfo I (Promega) in a total volume of 35 µL. Digested DNA was separated by electrophoresis on an 8% nondenaturing polyacrylamide gel at 150 V for 2 hours. Bands were visualized by silver staining.
Statistical Analysis
Data were analyzed by CSS software (Statsof Inc). Given
the small number of individuals homozygous for the 347Ser allele,
these were analyzed together with the heterozygous
individuals.
The statistical significance of differences in measurements at entry
and of those in the changes in plasma lipid levels after each diet
period between the apo A-IV-347Thr and apo A-IV-347Ser carriers was
determined by two-tailed, unpaired Student's t test. ANOVA
for repeated measures was used at the 5% significance level to test
for effects of the 347Ser mutation on total plasma
cholesterol, LDL-C, HDL-C, TG, apo A-I, and apo B
concentrations in each dietary phase. When statistical significance was
found, Tukey's post hoc comparison test was used to identify group
differences. All continuous variables except TGs were normally
distributed as assessed by the Kolmogorov-Smirnov test. TG values were
logarithmically transformed to achieve an approximately normal
distribution, and statistical tests were then applied to the
transformed values. The same process was used to determine the effect
of the interaction of this mutation with the GA mutation in the apo
A-I gene promoter on the increase in plasma lipids after the diets.
LDL-C and apo B responsiveness were used as dependent variables,
and stepwise multiple regression was applied to identify other
concomitant variables. The independent variables included apo
A-I (GA mutation in the promoter region) genotype, apo
A-IV-360GlnHis and 347ThrSer genotypes, apo E
genotype, BMI, and basal total cholesterol and TG
values. Apo A-I and apo A-IV 347ThrSer and 360GlnHis
genotypes were divided into 2 classes and apo E
genotype into 4 classes for analysis.
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Results |
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Results of the analysis of dietary composition are shown in Table 2
. These results are in
agreement with calculated values. There were no differences between
347Thr and 347Ser subjects with respect to age (20.4±1.4 versus
21.8±2.5 years) or BMI (24.6±2.6 versus 24.3±3
kg/m2). Dietary follow-up was excellent, as shown by
analysis of the plasma LDL–cholesteryl ester composition
(Table 3). Significant enrichment in
palmitic acid was observed during the SFA diet. There was also
significant enrichment in oleic acid during the MUFA diet compared with
the NCEP type 1 diet.
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Table 4 shows the basal plasma lipid
levels and lipid concentrations after the different diets. No
significant differences were observed during the basal diet for lipid
and apoprotein levels between both groups of subjects. However,
genotype was found to significantly affect changes in LDL-C
(P<.048) and apo B (P<.017) levels after the
different diets. Compared with the 347Thr individuals, total
cholesterol levels for 347Ser individuals were higher after
the SFA (4.4 versus 4.14 mmol/L, P<.031) and
MUFA (3.88 versus 3.65 mmol/L, P<.039) diets.
However, LDL-C levels were significantly greater in 347Ser subjects
only after the SFA diet (2.79 versus 2.46 mmol/L,
P<.002). There were no differences in apo B levels. After
the three dietary periods, the two 347Ser homozygotes showed greater
concentrations of total cholesterol (SFA diet, 4.80 versus
4.34 mmol/L; NCEP type 1 diet, 4.16 versus 3.62
mmol/L; and MUFA diet, 4.40 versus 3.81 mmol/L),
LDL-C (SFA diet, 3.21 versus 2.74 mmol/L; NCEP type 1
diet, 2.75 versus 2.09 mmol/L; and MUFA diet, 2.95 versus
2.20 mmol/L), and apo B (SFA diet, 77 versus 60
mg/dL; NCEP type 1 diet, 68 versus 45 mg/dL; and MUFA
diet, 71 versus 50 mg/dL) than did 347Ser heterozygotes.
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Table 5 shows changes in lipid levels as
absolute values and percentages as the diet was changed from the SFA to
the NCEP type and the NCEP type 1 to the MUFA. Replacement of SFA by
carbohydrates produced a significantly greater decrease in total
cholesterol (-0.7 versus -0.44 mmol/L,
P<.034), LDL-C (-0.62 versus -0.31 mmol/L,
P<.012), and apo B levels (-14 versus -8 mg/dL,
P<.01) in carriers of the 347Ser allele than in 347Thr
individuals. Switching from the NCEP type 1 to the MUFA diet produced
greater increases in total cholesterol (0.18 versus
-0.05 mmol/L, P<.028) and apo B (5 versus -1
mg/dL, P<.006) levels in 347Ser individuals than in
347Thr individuals. After changing from the SFA to the NCEP type 1
diet, the 347Ser homozygotes showed decreases in total
cholesterol (-0.64 versus -0.72 mmol/L),
LDL-C (-0.46 versus -0.65), and apo B (-9 versus -15 mg/dL)
levels similar to those in the 347Ser heterozygote carriers, and the
same was observed when the switch was made from the NCEP type 1 to the
MUFA diet, with similar increases in total cholesterol
(0.24 versus 0.19 mmol/L), LDL-C (0.20 versus 0.11
mmol/L), and apo B (3 versus 5 mgr/dL) levels.
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Multiple regression analysis revealed that in our study
population, the 347Ser mutation was a predictor of LDL-C
(P<.038) and apo B (P<.048) response when diets
were changed from the SFA to the NCEP type 1. This mutation also
predicted the LDL-C (P<.02) and apo B (P<.0008)
responses when the diets were changed from the NCEP type 1 to the MUFA
diet. The GA mutation of the apo A-I promoter predicted the LDL-C
responses after the change from the SFA to the NCEP type 1 diet
(P<.013) and from the NCEP type 1 to the MUFA diet
(P<.009), with carriers of the A allele showing a
greater response. It also predicted the apo B response after the change
from the NCEP type 1 diet to the MUFA diet (P<.004). BMI
predicted the apo B response when the diets were changed from the SFA
to the NCEP type 1 diet, with overweight subjects showing a smaller
decrease in this parameter. Neither basal TG, total
cholesterol, apo E genotype, nor the 360His
mutation of apo A-IV could significantly predict the LDL-C or apo B
response after the different diets in any case.
Next, we examined the effects of the interaction between the 347Thr and
347Ser alleles of the apo A-IV and the GA mutation of the apo
A-I promoter on increases in total cholesterol, LDL-C, and
apo B after consumption of the different diets (Table 6). Significant GA
genotype–by-diet interactions were seen for changes in total
cholesterol (P<.0375), LDL-C
(P<.0351), and apo B (P<.0318) levels. Also,
significant 347Thr/Ser genotype–by-diet interactions were seen
for changes in total cholesterol (P<.0316),
LDL-C (P<.0316), and apo B (P<.004) levels. The
interactions between both genotypes and diet did not have any
significant effect on any of the lipid variables included in the
analysis. Substitution of saturated fats by carbohydrates
produced a significantly greater decrease in LDL-C levels in the
carriers of both mutations (347Ser/A) than in individuals in whom both
mutations were absent (347Thr/G) (-0.72 versus -0.15
mmol/L, P<.02). Carriers of one of the two mutations
(347Ser/G or 347Thr/A) showed intermediate decreases. Similar results
were observed for apo B levels in 347Ser/A individuals showing greater
decreases than 347Thr/G (-20 versus -7 mg/dL,
P<.01) or 347Thr/A (-20 versus -8 mg/dL,
P<.01) individuals. Likewise, changes from the NCEP type 1
to the MUFA diet resulted in greater increases in total
cholesterol (0.41 versus -0.18 mmol/L,
P<.004), LDL-C (0.31 versus -0.19 mmol/L,
P<.05), and apo B (9 versus -3 mg/dL,
P<.01) in 347Ser/A than in 347Thr/G individuals.
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Discussion |
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Most hyperlipemias are polygenic due to the interaction of several genes and environmental factors, of which diet is one of the most important. Apo E27 28 and B29 are among the genetic loci that have been implicated in variable lipid responses to dietary changes. In a previous study, we demonstrated that the G
A
mutation of the apo A-I gene promoter was responsible for changes in
plasma LDL-C levels after changes in dietary fat
content.19 Moreover, the presence of isoform 2 of the apo
A-IV has been shown to regulate these changes.17 18
Despite the fact that the 347Ser mutation is one of the most prevalent
of those described in apo A-IV,30 no studies have yet
focused on the influence that this mutation may have on lipid response
to diets with different fat compositions. In cross-sectional studies,
carriers of the 347Ser allele have been reported to present
lower levels of apo B in both sexes and of LDL-C in
males.16 Nevertheless, this finding was not confirmed in
another study.15 We did not find differences in basal
lipid levels between carriers of the mutation and individuals
homozygous for the 347Thr allele. However, the 347Ser individuals
did show higher total cholesterol levels after the two
fat-rich diets and in LDL-C after the SFA diet. Because differences in
these parameters were not recorded after the NCEP type
1 diet, this finding suggests that the 347Ser individuals are more
likely to increase their plasma cholesterol levels in
response to an increase in dietary fat than are 347Thr individuals. In
fact, decreases in total cholesterol, LDL-C, and apo B
levels after the change from the SFA to the NCEP type 1 diet and the
increase in total cholesterol and apo B after the change
from the NCEP type 1 to the MUFA diet were significantly greater in
347Ser individuals. However, this group of individuals did not
present the changes in LDL-C levels predicted by the Mensink and
Katan equation.31 According to this equation, the LDL-C
level should decrease by 0.33 mmol/L after the change from
the SFA to the NCEP type 1 diet and by 0.06 mmol/L after
the change from the NCEP type 1 to the MUFA diet. In accordance with
this, in our study of individuals homozygous for the 347Thr allele,
there was a decrease of 0.31 mmol/L with the NCEP type 1
diet and of 0.08 mmol/L with the MUFA diet. However, in the
347Ser individuals, LDL-C levels decreased by 0.62 mmol/L
on the NCEP type 1 compared with the SFA diet and increased by
0.13 mmol/L on the MUFA diet. The same patterns of changes
in total cholesterol, LDL-C, and apo B plasma levels were
observed in homozygotes for the 347Ser allele as in heterozygous
individuals, with the homozygotes showing higher levels of these
parameters after the different diets. However, because only
2 of the study participants were homozygous for this allele, it was
not possible to analyze these data statistically. The
differences between 347Thr homozygotes and 347Ser carriers cannot be
attributed to differences in diet because the diet was the same in both
groups. Age could also have influenced the degree of plasma lipid
response to dietary fat,32 but there were no significant
differences between the groups in this respect. Both the GA mutation
of the apo A-I promoter and the 347Thr/Ser of apo A-IV were independent
predictors of LDL-C response to changes in dietary fat.
The precise mechanism by which the 347Ser mutation regulates a different response to dietary fat is as yet unknown. The apo A-IV gene is located on chromosome 11 in close association with those for apo C-III and A-I.33 It is possible that there is another mutation attached to the acquired 347Ser allele that affects cholesterol metabolism. In fact, Kamboh et al30 have shown linkage disequilibrium between polymorphisms at positions 347 and 360 of apo A-IV. In our study, multiple regression analysis showed that the presence of the 360His mutation did not predict LDL-C response after the NCEP type 1 or MUFA diet. Nevertheless, in view of the existence of this linkage disequilibrium, more studies in other populations are required to confirm our data and rule out the possibility that our results reflect the existence of linkage disequilibrium between other mutations.
Apo A-IV contains 396 amino acids including a signal peptide that is 20
residues long.34 This protein has a high number of repeats
of 22 amino acids forming 
-helixes that are related to lipid
binding.33 34 The substitution of Ser for Thr at position
347 of apo A-IV produces changes in the secondary structure of the
protein and a slight increase in hydrophilic profile at this
position,35 which could result in a decrease in its
affinity for lipoproteins. Apo A-IV has been associated with fat
absorption,4 and its synthesis and secretion are
stimulated by absorption of TGs from the diet.2 36 The apo
A-IV secreted into chylomicrons is rapidly replaced by apo C-II from
HDL.37 By this exchange with apo C-II, an essential
cofactor of LPL,38 apo A-IV can regulate the activation of
LPL and therefore chylomicron hydrolysis.8 The lower
affinity of apo A-IV 347Ser for the lipoprotein particles could
facilitate exchange with apo C-II, thereby increasing the activation of
LPL which would in turn accelerate clearance of chylomicron remnants.
This action would increase the amount of cholesterol that
reaches the liver in a postprandial state and would increase
downregulation of the LDL receptors, which would bring about further
increases in plasma LDL-C. Therefore, via this mechanism, consumption
of fat-rich diets would produce a greater increase in LDL-C in carriers
of the mutation.
Recently, the GA mutation of the apo A-I gene promoter has been
shown to affect the LDL-C response to dietary fat.19
Multiple regression analysis revealed that the presence of this
mutation predicted the LDL-C response when the dietary fat content was
changed and that of apo B when diets were changed from the NCEP type 1
to the MUFA diet, in accordance with our previous study.19
After consuming the NCEP type 1 diet, carriers of the A allele of
the apo A-I gene promoter and the apo A-IV 347Ser mutation showed a
greater decrease in total cholesterol, LDL-C, and apo B
levels than homozygous carriers of the G and 347Thr alleles. In
addition, when the MUFA content of the diet was increased, the
association of A and 347Ser alleles produced a greater increase in
total cholesterol and apo B levels. The separate
interactions of the GA polymorphism in the apo A-I gene promoter
and of the 347Thr/Ser genotype in apo A-IV with diet had a
significant effect on total cholesterol, LDL-C, and apo B
levels. However, neither the interaction between both genotypes
nor the interaction between either genotype and diet had any
effect on lipid changes. This observation suggests that both mutations
have an additive but not a synergic effect on changes in plasma lipids
in response to modifications in dietary fat content.
Independent of the mechanism(s) involved, our results suggest that the presence of the 347Ser allele of apo A-IV is responsible, at least partially, for the differences in individual lipid response to dietary fat. In turn, carriers of both this mutation and the A allele at position -76 of the apo A-I gene promoter are more susceptible to developing hypercholesterolemia on a fat-rich diet.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant from the DGICYT of the Ministerio de Educacion y Ciencia (PB 92-0914), Consejería de Agricultura, Junta de Andalucía, and Fondo de Investigación Sanitarias (FIS 93/0746, 94/1547), Ministerio de Sanidad y Consumo, Spain, and Fundación Cultural "Hospital Reina Sofía-Cajasur."
Received May 22, 1996; accepted October 21, 1996.
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