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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:707-714.)
© 1997 American Heart Association, Inc.

Articles

LDL Subclass Patterns and Lipoprotein Response to a Low-Fat, High-Carbohydrate Diet in Women

Darlene M. Dreon; Harriett A. Fernstrom; Paul T. Williams; ; Ronald M. Krauss

From the Donner Laboratory, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley (D.M.D., H.A.F., P.T.W., R.M.K.), and the Children's Hospital, Oakland, Calif (D.M.D., H.A.F.).

Correspondence to Ronald M. Krauss, MD, Donner Laboratory, Room 465, Ernest Orlando Lawrence Berkeley National Laboratory, 1 Cyclotron Rd, Berkeley, CA 94720. E-mail rmkrauss{at}lbl.gov

	Abstract

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Abstract A predominance of small, dense LDL particles (subclass pattern B) characterizes a metabolic trait that is associated with higher levels of triglyceride-rich lipoproteins and lower levels of HDL compared with those of individuals with predominantly larger LDL (pattern A). This trait appears to be under the influence of one or more genes, with maximal expression in adult males and reduced expression in premenopausal females. In a previous study, men with LDL subclass pattern B had significantly greater reductions in LDL cholesterol (LDL-C) and apolipoprotein B than men with pattern A. We hypothesized that despite the low prevalence of pattern B in premenopausal women, genetic predisposition to this trait could affect dietary responsiveness. Specifically, we predicted that LDL-C reduction on a low-fat, high-carbohydrate diet would be greatest in daughters of two pattern B parents, intermediate in daughters with one pattern B parent, and least in daughters with no pattern B parents. When 72 premenopausal women were placed on a 20% fat diet for 8 weeks, the changes in LDL-C (mmol/L) compared with levels on basal diets were significantly related to the number of pattern B parents (two B parents: -0.92±0.61, one B parent: -0.23±0.10, no B parents: -0.05±0.06) and could not be explained by diet adherence or baseline characteristics including initial lipoprotein profile or body mass index. The number of pattern B parents was also related to reductions in plasma mass concentrations of IDL, total LDL, and large LDL and to increases in plasma triglycerides. There was a significant inverse correlation between changes in triglyceride and LDL-C induced by the low-fat, high-carbohydrate diet. Thus, genetic and metabolic factors underlying LDL subclass pattern B may result in enhanced LDL and triglyceride responsiveness to substitution of dietary carbohydrate for fat in premenopausal women.

Key Words: LDL pattern • women • lipoproteins • diet

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
A predominance of small, dense LDL particles (LDL subclass pattern B) characterizes a metabolic trait that appears to be under the influence of one or more major genes,^{1 2} with maximal expression in males over age 20 and with lower expression in younger males and premenopausal females.^{3 4} Family studies have identified linkage of LDL particle size to genetic loci on chromosomes 19, 11, 16, and 6.^{5 6}

Individuals with pattern B have higher levels of triglyceride-rich lipoproteins and apoB, reduced levels of HDL cholesterol and apoA-I,^{1 7} and a greater degree of insulin resistance⁸ than subjects with predominantly larger, more buoyant LDL (pattern A). Case-control studies have shown that pattern B is associated with increased risk of myocardial infarction⁹ and angiographically determined coronary artery disease.^{10 11}

We have demonstrated that men with pattern B on a high-fat diet have a twofold greater LDL-lowering response to low-fat, high-carbohydrate diets than men who do not exhibit this trait.¹² The relationship of LDL subclass pattern and lipoprotein response to low-fat diets in women has not been investigated.

We have devised a protocol to test the hypothesis that genetic factors underlying pattern B influence the lipoprotein response to a low-fat, high-carbohydrate diet in women. We hypothesized that LDL-C reduction should be greatest in daughters of two pattern B parents, intermediate in daughters with one pattern B parent, and least in daughters with no pattern B parents. This protocol is based on the assumption that even in women not expressing pattern B, those with one or two pattern B parents would be more likely to carry at least one allele predisposing to this trait.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Experimental Design
We investigated differences in lipoprotein response to reduced fat intake in association with LDL subclass pattern in 72 premenopausal women who were switched from their baseline diet (average 35% fat) to an outpatient low-fat (20% fat), high-carbohydrate diet for an average of 8 weeks. Because of reduced expression of pattern B in premenopausal women,³ presumed genetic predisposition for the trait was assessed by parental LDL subclass pattern: both parents pattern B (n=4), one parent pattern B (n=25), or neither parent pattern B (n=43). Since maximal expression of pattern B occurs after age 20 in men and after menopause in women, there is a high probability of detecting the phenotype in affected parents.

The women followed the experimental diet for approximately 7 to 9 weeks, an interval sufficient to ensure stabilization of the dietary response.^{13 14} The variation in duration of the diet enabled baseline and follow-up blood samples to be obtained within approximately the same phase of each woman's menstrual cycle. The women were scheduled for blood sampling within 6 days after the first day of menstruation at baseline and follow-up. Detailed measurements of lipids, lipoproteins, and apolipoproteins were carried out at baseline and at completion of the experimental diet. In addition, participants were surveyed for dietary intake (by 4-day food records) at baseline and during the low-fat, high-carbohydrate dietary period. BMI (wt [kg]/ht [m]²) was calculated from weight and height measurements taken at baseline and after the experimental diet.

Subjects
Premenopausal women over age 20 in the San Francisco Bay Area were recruited through newspaper and radio announcements, flyers, and direct mail. Criteria for eligibility were as follows: willingness to participate in an 8-week dietary intervention program, no medication use likely to interfere with lipid metabolism, not above 30% of ideal body weight (Metropolitan Life Insurance Company Tables, 1985), free of chronic disease, nonsmoker, and both parents living and willing to donate blood samples. Women were excluded if they had had a hysterectomy or irregular menstrual cycles, were pregnant or breast feeding, or were using oral contraceptives. One hundred nine women volunteered for the study. Each participant and her parents signed a consent form approved by the Committee for the Protection of Human Subjects at Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley, and participated in a medical interview. Seven individuals were ineligible and 27 did not complete the study because of an inability to adhere to the requirements of the protocol. Seventy-five women, aged 25 through 44, completed the study. The data from 3 subjects were not included in the present analyses: one subject consumed alcohol during the trial, and two subjects' parents did not provide blood samples. Of the remaining 72 women, 3 had a personal history of breast cancer but were currently disease free. With the exception of 1 black woman, all of the subjects in the study were non-Hispanic whites.

For the parents' participation in this study there were no exclusion criteria for health status or medication. Daughters of parents taking lipid-lowering (n=8) or diabetes (n=5) medication were eliminated from later analyses without significant effects on the results. All of the mothers were postmenopausal.

Experimental Diet
Nutrient composition for the experimental diet was based on a 2-week-cycle menu and was calculated using the Minnesota Nutrition Data System software, version 2.1, developed by the Nutrition Coordinating Center, University of Minnesota, Minneapolis.^{15 16} The low-fat, high-carbohydrate study diet was designed to supply 20% of calories from fat, with 65% carbohydrate (half simple and half complex) and 15% protein. The cholesterol content was 125 to 150 mg/1000 kcal, dietary fiber was 5 to 6 g/1000 kcal, and the P:S ratio was 0.7. The subjects were allowed to consume up to three cups of coffee daily and other noncaloric beverages ad libitum. They abstained from alcohol throughout the study and were instructed to maintain their customary level of physical activity.

Registered dietitians supplied the participants with personalized menus, demonstrating the number and size of servings for the experimental low-fat, high-carbohydrate diet. The staff contacted the subjects weekly to encourage motivation and to ascertain compliance. Compliance with the experimental diet was assessed by a 4-day food record (Thursday to Sunday) of measured and weighed food intake¹⁷ and by a daily recording of added and missed foods from the menus. If the daily diet deviations averaged >5% of total calories, the subject was considered noncompliant and her data were not included in the analyses. Only one subject was eliminated for noncompliance. Nutrient calculation of the 4-day food record was performed using Nutrition Data System software.^{15 16} The subjects measured their own body weight daily at home and the staff adjusted energy intake on the menus weekly if necessary for body weight stability.

Lipid, Lipoprotein, and Apolipoprotein Analyses
Subjects reported to our clinic in the morning, having abstained for 12 to 14 hours from all food and vigorous activity. Plasma was prepared from venous blood collected in tubes containing Na₂EDTA, 1.4 mg/mL, at baseline (before dietary intervention) and at the conclusion of the experimental diet period. Blood and plasma were kept at 4°C for no more than 2 weeks until processed. The subjects' parents were sampled on their usual diets in the same manner. The parents who could not visit our clinic were instructed to use their local medical facility for blood sampling. We then mailed blood transport supplies to the designated clinic. Blood was spun in a refrigerated centrifuge and plasma was kept on wet ice during shipment. Plasma was received in our clinic within 24 hours of the blood draw.

Plasma total cholesterol and triglycerides were determined by enzymatic procedures on a Gilford Impact 400E analyzer. These measurements were consistently in control, as monitored by the CDC-NHLBI standardization program. HDL-C was measured after heparin-manganese precipitation of plasma,¹⁸ and LDL-C was calculated from the formula of Friedewald et al.¹⁹ ApoA-I and apoB concentrations in plasma were determined only for the 72 daughters by maximal radial immunodiffusion.^{20 21}

Measurement of the daughters' total mass of the major lipoprotein fractions as well as individual lipoprotein subfractions was performed by analytical ultracentrifugation.²² Lipoprotein mass concentrations were measured in milligrams per deciliter as a function of flotation rate, which is in turn related to the size and density of lipoprotein particles. Mass concentrations were determined for total LDL (S_f^o 0-12) and concentrations of four major LDL subclasses, LDL-I (S_f^o 7-12), LDL-II (S_f^o 5-7), LDL-III (S_f^o 3-5), and LDL-IV (S_f^o 0-3)²³ ; IDL (S_f^o 12-20); and VLDL (S_f^o 20-400). For LDL, this procedure also provides a measurement of peak flotation rate, which is an indication of the size and density of the major LDL subfraction present in plasma. Analytic ultracentrifugation is also used to measure concentrations of mass of total HDL as a function of flotation rate (F^o_1.20 0-9) and concentrations of two major HDL subclasses, HDL₂ (F^o_1.20 3.5-9) and HDL₃ (F^o_1.20 0-3.5).²²

Nondenaturing polyacrylamide gradient gel electrophoresis was performed for the daughters and their parents on whole plasma and on the density <1.063 g/mL plasma fraction using Pharmacia PPA 2/16 gradient gels as described previously.^{23 24} Stained gels were scanned with a Transidyne RFT scanning densitometer, and peak particle diameters of the major LDL subclasses were calculated from calibration curves using standards of known size.²³ On the basis of the resulting scans, LDL subclass patterns were identified as described previously.²⁵ Pattern B is characterized by a major peak of smaller, denser LDL particles (LDL-III or LDL-IV, diameter (258 Å), often with skewing to larger particle diameters. Pattern A is characterized by a predominance of larger, more buoyant LDL particles (LDL-I or LDL-II, diameter 264 Å), often with skewing to smaller particle diameters.²³ Some LDL profiles have an intermediate pattern with a single or double peak of LDL in the size range of 258 to 263 Å (LDL-II). For the analyses presented below, intermediate patterns were grouped with A patterns ("narrow" definition of pattern B^{1 3} ). Three readers, who were blinded as to the subjects' identity and diet treatment, assigned the LDL subclass patterns to the daughters' gradient gels at baseline and at the end of the low-fat, high-carbohydrate diet intervention and to the parents' gel scans on their usual diets. When all readers were not in initial agreement as to subclass pattern assignment, results were reviewed again by all readers to establish a consensus.

Statistical Procedures
Permutation tests were used to test whether diet-induced changes in LDL-C and other variables were related to the number of LDL subclass pattern B parents. Specifically, the standard least-squares regression slope was computed, with the daughters' values as the dependent variable and the number of pattern B parents (2, 1, or 0) as the independent variable. To assess whether the slope was significantly different from zero (the null hypothesis), we compared the slope for the original data with the slopes from 10 000 random permutations of the dependent variable, which estimates the distribution of the statistic under the null hypothesis. The two-tailed probability of a type I error () was then calculated from the proportion of the slopes from the permuted data, which were more extreme than the observed slope. The nonparametric permutation test was used because many of the baseline measurements and dietary changes were not normally distributed and use of this test also reduced any disproportionate effect of the four women with two pattern B parents. Comparison of the results with the traditional significance levels indicated no discrepancies between the parametric regression analysis and the nonparametric permutation test. Multiple regression analyses were used to adjust lipoprotein response for selected baseline characteristics in subjects and their parents. Significance of changes in variables from the baseline diet to the low-fat, high-carbohydrate diet within each group was analyzed by paired t tests. Comparison of baseline characteristics of pattern A versus pattern B parents was analyzed by unpaired t tests. Throughout the text, group averages are reported as mean±SEM.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Table 1 shows the characteristics of the women's parents by LDL subclass pattern. The pattern B mothers and fathers had significantly higher triglycerides and lower HDL-C than the pattern A mothers and fathers, which is consistent with earlier findings.¹ The pattern B parents were also younger and had a higher BMI than the pattern A parents.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Parents by LDL Subclass Pattern (Mean±SD)

On the basis of parental LDL subclass patterns, three groups of offspring were identified: those with two pattern B parents (n=4), one pattern B parent (n=25), and no pattern B parents (n=43). Table 2 presents the daughters' dietary and lipoprotein variables at baseline by the number of LDL subclass pattern B parents. A higher number of pattern B parents was associated with decreasing age and increasing adiposity in the daughters. The daughters' LDL peak flotation rate decreased and their plasma concentrations of triglycerides, VLDL mass, and IDL mass increased in association with their number of pattern B parents. No other variables, including nutrient intakes, were related to LDL subclass pattern (Table 2). At baseline, there were three daughters with LDL subclass pattern B (two had one pattern B parent and the other had two pattern B parents).

View this table: [in this window] [in a new window]   Table 2. Baseline Distribution of Age, Adiposity, Dietary Variables, and Plasma Lipids, Lipoproteins, and Lipoprotein Mass Concentrations in 72 Women by the Number of Their LDL Subclass Pattern B Parents (Mean±SEM)

Table 3 presents the daughters' dietary and lipoprotein variables on the experimental low-fat, high-carbohydrate diet by number of LDL subclass pattern B parents. Since this diet was designed to maintain constant body weight, a higher number of pattern B parents was also associated with increasing adiposity, similar to the baseline diet. The daughters' HDL-C, LDL-I mass, and LDL peak flotation rate and diameter decreased and their plasma concentrations of triglycerides and VLDL mass increased in association with number of pattern B parents. Other variables, including intake of nutrients on the low-fat, high-carbohydrate diet, were unrelated to their parental LDL subclass pattern (Table 3). On the low-fat, high-carbohydrate diet, there were nine daughters with LDL subclass pattern B (three of these had no pattern B parents, four had one pattern B parent, and two had two pattern B parents).

View this table: [in this window] [in a new window]   Table 3. Distribution of Adiposity, Dietary Variables, Plasma Lipids, Lipoproteins, and Lipoprotein Mass Concentrations in 72 Women on the Low-Fat Diet by the Number of Their LDL Subclass Pattern B Parents (Mean±SEM)

Table 4 presents changes in lipoprotein parameters (low-fat minus baseline diet) by the number of LDL subclass pattern B parents. The significance of the dose-response relationship between the number of pattern B parents and the daughters' changes in lipoproteins is shown in the far right column. Footnotes designate the significance of the changes within two groups: daughters with no pattern B parents and daughters with one pattern B parent (since there were only four daughters with two pattern B parents, they were eliminated for the within-group analyses). There was no significant difference between the groups for change in nutrient intakes (data not shown) with the exception of total energy intake, which showed a significant (P=.04) dose-response relationship with the number of pattern B parents (none, 152.1±76.8 kcal; one, 386.1±99.7 kcal; and two, 457.4±99.8 kcal).

View this table: [in this window] [in a new window]   Table 4. Changes in (Low-Fat Minus Baseline Diet) Adiposity, Dietary Variables, Plasma Lipids, Lipoproteins, and Lipoprotein Mass Concentrations in 72 Women by the Number of Their LDL Subclass Pattern B Parents (Mean±SEM)

The results in Table 4 show that the diet-induced decrease in LDL-C was significantly related (P=.005) to the number of pattern B parents (two B parents, -0.92±0.61 mmol/L; one B parent, -0.2±0.10 mmol/L; and no B parents, -0.05±0.06 mmol/L). This relationship remained significant (P=.025) when adjusted for the daughters' baseline adiposity, age, triglycerides, VLDL mass, IDL mass, LDL peak flotation rate, and change in total energy intake. The relationship also remained significant (P=.012) when adjusted for the parents' BMI, triglycerides, LDL-C, and HDL-C. The differences between the daughters with no pattern B parents and those with one pattern B parent were not statistically significant.

A higher probability of inheriting a pattern B gene also was significantly related to greater increases in plasma triglyceride and VLDL mass and greater reductions in IDL mass and total LDL mass. There were significantly greater decreases in the daughters' plasma LDL-I and LDL-II mass concentrations as the number of pattern B parents increased. The parents' LDL subclass patterns were not related to changes in their daughters' LDL-III or LDL-IV mass concentrations after the low-fat, high-carbohydrate diet. There was a significant inverse correlation (r=-.61, P<.0001) between changes in triglyceride and LDL-C on the low-fat, high-carbohydrate diet and changes in VLDL mass and LDL-C (r=-.54, P<.0001). There was also a significant positive correlation (r=.62, P<.0001) between changes in IDL mass and LDL-C.

When the daughters (n=13) of parents taking lipid-lowering or diabetes medication were eliminated from the analyses, the regression slope between the number of pattern B parents remained significantly related to diet-induced decreases in plasma LDL-C (P=.017), IDL mass (P=.030), total LDL mass (P=.022), and LDL-II mass (P=.043), and to increases in triglycerides (P=.014).

One woman with two pattern B parents had an increase of plasma triglyceride level of 14.8 mmol/L (1312 mg/dL) on the low-fat, high-carbohydrate diet. The regression slope between the change in LDL-C and the number of pattern B parents remained significant (P=.05) when she was excluded from the analysis. Mean changes for the remaining three daughters of two pattern B parents were: triglycerides, 0.53 mmol/L (46.7 mg/dL); LDL-C, -0.35 mmol/L (-13.7 mg/dL); VLDL mass, 36.8 mg/dL; IDL mass, 1.2 mg/dL; total LDL mass, -32.4 mg/dL; LDL-I mass, -38.8 mg/dL; LDL-II mass, -12.5 mg/dL; LDL-III mass, 17.3 mg/dL; and LDL-IV mass, 1.6 mg/dL.

All 3 pattern B daughters on the baseline diet remained pattern B on the low-fat, high-carbohydrate diet, while 6 of the 69 pattern A daughters on the baseline diet changed to pattern B. Of these, 3 had no pattern B parents, 2 had one pattern B parent, and 1 had two pattern B parents.

The current study was not designed to test the effects of replacing dietary fat with carbohydrates on lipoprotein levels. Specifically, all of the women went from their baseline diet to a low-fat, high-carbohydrate diet (ie, there was no control group or control diet period for comparison) so that other variables concomitant to the reduction in fat could have contributed to the lipoprotein changes. Nevertheless, the paired t tests indicate significant lipoprotein changes during the intervention that are consistent with expected effects of the low-fat, high-carbohydrate diet. Notably, the combined group of 29 daughters with one or two pattern B parents, but not the group of daughters with no B parents, showed significant reductions (P<.05) in LDL-C and total LDL mass on changing to a low-fat, high-carbohydrate diet (Table 4).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Several studies have described the effects of a reduced-fat diet on plasma lipids in premenopausal women.^{26 27 28 29 30 31 32 33 34} As with men, women seem to respond to a reduced-fat diet with reductions in LDL-C and HDL-C and increases in triglycerides, the magnitude of responsiveness being related to baseline lipoprotein levels,^{27 30 34} body weight,^{26 28} and the degree of dietary fat modification.^{26 34}

The present study was designed to test the hypothesis that one or more genetic factors underlying LDL subclass pattern B influence the magnitude of the LDL-C response to a low-fat, high-carbohydrate diet in premenopausal women. The experimental approach was based on two assumptions: (1) in premenopausal women, the number of pattern B parents increases the likelihood of carrying at least one allele predisposing to this trait and (2) the average responsiveness of LDL-C to the dietary intervention increases with the probability of inheriting the allele. The present results demonstrated that the number of pattern B parents significantly predicted the daughter's reduction in LDL-C after a low-fat, high-carbohydrate diet. These results are consistent with our earlier cross-over study in 105 men, which showed that decreasing dietary fat from 46% to 24% produced a twofold greater reduction in LDL-C in pattern B men than in pattern A men.¹² Whereas the probability of carrying an allele could be inferred directly from the men's LDL subclass pattern (the penetrance being relatively high), the probability of carrying an allele could be inferred only indirectly from the daughters' parents (the penetrance being very low before menopause).³ Yet there may have been incomplete penetrance of pattern B among the daughters' parents, since the four pattern B offspring of AxA parents would ordinarily not have been expected.³ Other nongenetic or environmental factors,^{2 12 35 36 37 38} specifically those affecting plasma triglyceride metabolism,³⁹ could also have given rise to pattern B in the daughters of AxA parents.

We were unable to attribute the dose-response relationship between the daughters' LDL-C–lowering response and the number of pattern B parents to other measured variables. For example, on the baseline diet, the daughters' initial LDL-C was unrelated to the number of pattern B parents. Thus, the daughters' initial LDL-C level was unlikely to account for the relationship between the LDL-C response and the parents' LDL subclass patterns. Although the daughters' change in energy intake was related to the number of pattern B parents, energy intake did not account for the relationship between LDL-C response and the number of pattern B parents. The increased calories needed by the subjects during the intervention diet to maintain body weight is probably due to the findings that individuals undereat and/or underreport food intake when asked to complete food records.^{40 41} It has also been found that overweight individuals underreport energy intake to a greater amount than normal-weight individuals.^{40 42} Although the number of pattern B parents was significantly related to the daughters' adiposity (concordant) and age (discordant), the daughters' LDL-C response to the low-fat, high-carbohydrate diet nonetheless remained significantly related to the number of pattern B parents when adjusted for these variables. Thus, we surmise that the LDL-C responsiveness to the diet in the daughters must be inherited, in part, through factors that are associated with the expression of the pattern B trait in the parents. Previous segregation and linkage studies suggest that the inheritance is genetic and is specifically determined by one or more major dominant genes having reduced penetrance before menopause.^{2 3 6}

The reductions in the daughters' plasma mass concentrations of IDL, total LDL, LDL-I, and LDL-II all exhibited significant dose-response relationships with the probability of inheriting pattern B from their parents. The relationship of the reduction in LDL-II mass with the number of pattern B parents is similar to that previously reported in pattern B men, in whom a substantial proportion of the reduction in LDL-C was due to the LDL-II subfraction.⁴³ Whereas LDL-III mass is increased in pattern A men on a reduced-fat diet, pattern B men show a significant reduction in LDL-III mass.⁴³ Similarly, the daughters of two pattern A parents showed significant increases in mass of LDL-III on a reduced-fat diet, while the daughters of two pattern B parents showed reductions in mass of LDL-III (although this result did not reach statistical significance). The lack of significance for this result and for those involving other lipoprotein variables could be the result of the limited statistical power provided by the four daughters with two pattern B parents.

Plasma triglyceride levels in the daughters increased on the low-fat, high-carbohydrate diet, with the magnitude dependent on the number of pattern B parents. This result is again consistent with our previous observation that men with pattern B have significantly greater increases in triglycerides on changing from a high-fat to a low-fat diet than men who do not express this trait.⁴³ LDL subclass pattern, in addition to its association with LDL-C response, may also be associated with the wide variation in triglyceride response to diet that has been observed among women.²⁶ Increases in triglyceride and VLDL were correlated with a decrease in LDL-C on the low-fat, high-carbohydrate diet. The mechanism of this effect is unknown but could involve a decrease in conversion of VLDL to LDL on the high-carbohydrate diet.⁴⁴

The metabolic basis for the relationships between lipoprotein changes on the low-fat, high-carbohydrate diet and LDL subclass pattern B is not known. It was previously shown that pattern B is characterized by interrelated metabolic differences from pattern A including increased triglycerides, reduced HDL-C,¹ and insulin resistance.^{8 38} In addition, it was recently demonstrated in men that pattern B is associated with increased postprandial lipemia,⁴⁵ suggesting that some diet-induced changes in the LDL profile in pattern B may be connected with impaired clearance of triglyceride-rich lipoproteins. For example, on a high-fat diet, prolonged postprandial increases in levels of chylomicron remnants in pattern B may lead to their enrichment in cholesteryl esters via transfer from HDL⁴⁶ and hence to increased cholesterol return to the liver, with suppression of hepatic LDL receptor expression. Thus, pattern B subjects may be more susceptible to increases in LDL-C with diets higher in total and saturated fat. It is also possible that reduced lipoprotein lipase activity in subjects with pattern B^{47 48 49} may limit conversion of VLDL to LDL and that this effect may be amplified by further reduction in lipoprotein lipase on a low-fat diet.⁵⁰

Several of the baseline variables in the daughters were related to the LDL subclass pattern of their parents. A higher probability of inheriting a gene underlying pattern B was associated with the daughters being younger and somewhat heavier for their height and having a lower LDL particle peak flotation rate and higher plasma concentrations of triglycerides, VLDL mass, and IDL mass. The younger age of the daughters of pattern B parents could be attributed to the study requirement that both parents be living. Since the pattern B trait is associated with an increase in heart disease risk, earlier deaths in pattern B parents may have resulted in the selection of younger parents (Table 1), who in turn have younger daughters. Adiposity, lower LDL particle peak flotation rate, and elevated triglycerides, VLDL mass, and IDL mass are all characteristics associated with pattern B.¹ The lack of a significant association between the daughters' baseline LDL-C and the number of pattern B parents is consistent with earlier reports showing no differences in LDL-C levels between individuals with pattern A versus pattern B.¹

Few studies have reported on the relationship of genetic predisposition and lipoprotein response to variation in dietary fat and cholesterol in women. Those that evaluated the effect of apoE^{51 52 53 54} and apoA-IV phenotypes,⁵⁵ which are reported to influence diet response in men, found no association with diet-induced lowering of plasma LDL-C in women. On the other hand, polymorphisms in the apoB gene have been associated with differences (P<.06) in reductions in total cholesterol, LDL-C, and apoB in healthy women who followed low-fat, low-cholesterol diets for a 6-week intervention period.⁵⁶

T he present findings suggest that the biological effects of the major genes underlying susceptibility to the pattern B trait may be manifest by response to a low-fat, high-carbohydrate diet even without expression of pattern B. Moreover, these effects may contribute significantly to interindividual variation in lipoprotein response to reduced fat intake in the general population.

	Selected Abbreviations and Acronyms

 

apo = apolipoprotein BMI = body mass index Fo = flotation rate of HDL HDL-C = HDL cholesterol LDL-C = LDL cholesterol P:S = ratio of polyunsaturated to saturated fat Sfo = flotation rate of VLDL, IDL, and LDL

	Acknowledgments

 
This work was supported in part by the National Dairy Promotion and Research Board and administered in cooperation with the National Dairy Council, NIH R03 grant HL-52617, and NIH program project grant HL-18574 from the National Heart, Lung, and Blood Institute and was conducted at the Ernest Orlando Lawrence Berkeley National Laboratory through the US Department of Energy under contract No. DE-AC03-76SF00098. The authors gratefully thank Adelle Cavanaugh, RN, Kathy Berra, RN, BSN, Cindy Lamendola, RN, BSN, Linda Garcia, RN, and Dorothy Jackson, RN, BA, for clinical measurements; Sally Maier, MS, RD, and Karla Oliveira, MS, RD, for dietary assessment; Linda Abe for data management; Pat Blanche and the laboratory staff for blood analyses; and the research subjects for their invaluable contribution.

Received December 18, 1995; accepted July 17, 1996.

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