Biochemical, Molecular, and Genetic Mechanisms
The ABCG5 Polymorphism Contributes to Individual Responses to
Dietary Cholesterol and Carotenoids in Eggs1
Kristin L. Herron,* Mary M. McGrane,* David Waters,* Ingrid E. Lofgren,*
Richard M. Clark,* Jose M. Ordovas,yand Maria Luz Fernandez*2
*Department of Nutritional Sciences, University of Connecticut, Storrs, CT andyUSDA-HNRCA,
Tufts University, Boston, MA
response to dietary cholesterol. The objective of this study was to examine the contribution of the ABCG5 polymor-
phism on the plasma response to consumption of cholesterol and carotenoids from eggs. For this purpose, genotyping
was conducted for 40 men and 51 premenopausal women who were randomly assigned to consume an egg (EGG,
640 mg/d additional dietary cholesterol and 600 mg lutein1 zeaxanthin) or placebo (SUB, 0 mg/d cholesterol, 0 mg
lutein 1 zeaxanthin) diet for 30 d. The two arms of the dietary intervention were separated by a 3-wk washout period.
Plasma concentrations of total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol were determined. Because
eggs are an excellent source of lutein and zeaxanthin, the plasma levels of these carotenoids were also measured in
a subset of subjects to determine whether the response to carotenoid intake was similar to that seen for dietary
cholesterol and to evaluate the contribution of ABCG5 polymorphism to both responses. Individuals possessing the
C/C genotype experienced a greater increase in both LDL-C (P , 0.05) and a trend for lutein (P ¼ 0.08) during the
EGG period compared with those individuals with the C/G (heterozygote) or G/G genotypes (homozygotes). These
results, although obtained from a small number of subjects, suggest that the ABCG5 polymorphism may play a role in
the plasma response to dietary cholesterol and carotenoids.
The ATP binding cassette G5 (ABCG5) polymorphisms have been postulated to play a role in the
J. Nutr. 136: 1161–1165, 2006.
KEY WORDS: ? eggs ? lutein ? dietary cholesterol ? ABCG5 polymorphism ? LDL cholesterol
Epidemiological and intervention studies have shown that
dietary factors affect the concentration, composition, and me-
tabolism of lipoproteins (1). On the basis of this evidence, the
nutrition scientific community has been providing general
dietary guidelines as a method by which individuals may
decrease their risk for coronary heart disease (CHD)3through
normalizing plasma lipoprotein concentrations (2). One of the
recommendations has been to limit the intake of high choles-
terol foods, such as eggs, in an attempt to reduce atherogenic
concentrations of plasma total cholesterol (TC) and LDL
cholesterol (LDL-C). Early studies (3,4) provided evidence,
which remains consistent today, that increased consumption of
dietary cholesterol can elevate TC values to some extent in
certain individuals. However, extensive research does not sup-
incidence (5–7) This could be due to the fact that individuals
do not experience a homogeneous response to cholesterol
consumption (6). Therefore, it is difficult to predict the effect of
cholesterol intake on plasma lipoproteins and cardiovascular
risk at the individual level.
Interindividual variation in the response to cholesterol and
other dietary components can be attributed in part to factors
in genes that encode key proteins in lipoprotein metabolism
may also explain some of the variance. Several proteins were
identified that may function to regulate sterol absorption in the
intestine. Sterols that enter the mucosal cell are either directed
toward chylomicron synthesis or may be excreted back into
the intestinal lumen. This latter fate of dietary sterols may
be regulated by the activity of ATP-binding cassette (ABC)
transporters, found both in the intestine and the liver, which
utilize ATP as an energy source to drive the transport of lipids
and other metabolites across cell membranes (9). There is evi-
dence that ABCG5 may play an important role in limiting
dietary cholesterol absorption. The response of this possible
transport mechanism to dietary intake was examined in healthy
mice, which experienced an increase in ABCG5 expression
after intake of a high-cholesterol diet (10).
Because it produces an important transporter of cholesterol
in the intestine and liver, polymorphisms of the ABCG5 gene
may have an effect on the absorption and subsequent appear-
ance of cholesterol in the circulation. A single nucleotide poly-
morphism (SNP; C! G) at nucleotide 1950 results in the
substitution of a glutamic acid for a glutamine at residue 640
(Q640E). Individuals classified as homozygous for the variant
1Supported in part by from a grant from the American Egg Board/Egg Nutrition
Center to M.L.F. and contracts 53-K06-5-10 and 58-3148-2-083 from U.S.
Department of Agriculture to J.M.O. K.L.H. is the 2002 recipient of the American
Egg Board Egg Nutrition Center Dissertation Fellowship in Nutrition.
2To whom correspondence should be addressed. E-mail: maria-luz.fernandez@
3Abbreviations used: ABC, ATP binding cassette; CHD, coronary heart
disease; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; MUFA, monounsatu-
rated fatty acids; PMSF, phenylmethylsulfonyl fluoride; SFA, saturated fatty acids;
SNP, single nucleotide polymorphism; TC, total cholesterol; TG, triglycerides.
0022-3166/06 $8.00 ? 2006 American Society for Nutrition.
Manuscript received 8 January 2006. Initial review completed 14 February 2006. Revision accepted 23 February 2006.
by guest on June 2, 2013
ABCG5 allele (G/G) were identified by a previous study to have
greater plasma total cholesterol response to dietary cholesterol
intake (11), which may be due to an increased efficiency of
dietary cholesterol absorption in the intestine.
The primary objective of the present study was to determine
whether genetic polymorphism could be identified within a pop-
ulation of healthy men and premenopausal women that would
explain their plasma response to an egg diet. Because it was sug-
gested that ABCG5 may play a role in the plasma lipid response
to dietary cholesterol intake, we focused on this locus in the
study population. Because eggs are also rich in both lutein and
tunity to examine the role that ABCG5 may play in carotenoid
absorption as well. Individual variation in the plasma response
to dietary cholesterol has been investigated for many years and
it was suggested that a similar hypo- and hyperresponse to die-
tary carotenoid consumption may exist. Data from our labo-
ratory showed that carotenoids and cholesterol have similar
plasma responses in subjects challenged with eggs, which con-
tain both dietary cholesterol and lutein and zeaxanthin (12,13).
Because of this association of carotenoids with lipoproteins
during absorption and in the circulation, we hypothesized that
an examination of the ABCG5 polymorphisms may provide
insight into the plasma response to both dietary cholesterol and
SUBJECTS AND METHODS
Liquid pasteurized whole eggs and cholesterol-free/fat-free eggs
(placebo) were purchased from Better Brands. Enzymatic TC and tri-
glyceride (TG) kits were obtained from Roche-Diagnostics; aprotinin,
from Sigma Chemical.
Experimental design. The experimental protocol was approved
by the University of Connecticut’s Institutional Review Board, and
written informed consent was obtained from each subject. A total of 40
men and 51 premenopausal women recruited from the University
criteria included the presence of hypercholesterolemia [cholesterol
.6.2 mmol/L (240 mg/dL)], hypertriglyceridemia [TG .3.7 mmol/L
(300 mg/dL)], hypertension, and diabetes. Furthermore, those receiv-
ing lipid-lowering drugs were also excluded.
The study utilized a randomized crossover design, with subjects
initially assigned to an egg (EGG) or placebo (SUB) group for 30 d,
followed by a 3-wk washout period, after which the second dietary
period began. Subjects assigned to the EGG group were expected to
consume the liquid equivalent of 3 whole eggs/d (adding ;640 mg/d
assigned to the SUB consumed an identical weight of cholesterol-free,
fat-free egg substitute (0 mg/d dietary cholesterol 1 0 mg of lutein 1
Subjects were expected to follow guidelines of the NCEP Step I diet
during the 2 treatment periods, and detailed instructions were pro-
vided for their self-selected diets. To ensure compliance, subjects com-
pleted 7-d dietary records during each treatment period. Nutrient
intake was determined using the NDS-R software version 4.0, devel-
oped by the Nutrition Coordinating Center, University of Minnesota,
Two fasting (12-h) blood samples were collected, on different days
within the same week into tubes containing 0.15 g/100 g EDTA.
Plasma was separated by centrifugation at 1500 3 g for 20 min at 48C,
and placed into vials containing PMSF (0.05 g/100 g), sodium azide
(0.01 g/100 g), and aprotinin (0.01 g/100 g). Two additional blood
samples were collected and processed in the same manner at the end
of each diet period. The variables of weight, blood pressure, level of
activity, smoking, and alcohol intake were also measured at baseline
and after each dietary period to account for the possible influence of
these factors on plasma lipid levels.
Plasma lipids and apolipoproteins. Ourlaboratoryhas participated
in the CDC-National Heart, Lung and Blood Institute Lipid
program during the study period were 0.76–1.42 for TC, 1.71–2.72 for
HDL-C and 1.64–2.47 for TG. For this study, plasma TC was deter-
mined by enzymatic methods (16). HDL-C was measured in the super-
natant after precipitation of apolipoprotein B–containing lipoproteins
and LDL cholesterol (LDL-C) was calculated using the Friedewald
equation as previously reported (17). Plasma TG were determined by
draws were used to assess differences between treatment periods.
Plasma and product carotenoid analysis. Plasma samples from a
subset of subjects (20 men and 20 women) who were found to be
representative of the whole with regard to plasma lipid concentrations
and response to dietary cholesterol (20 hypo and 20 hyperresponders)
(12) were utilized for the carotenoid analysis. Plasma and product
(EGG and SUB) (200 mL) were prepared for HPLC analysis by initially
combining them with an internal standard of 50 mL ethyl-b-apo-8-
carotenoate and 200 mL methanol. The sample was then extracted 3
times using hexane. Centrifugation (1000 3 g; 2 min)was utilized to
facilitate phase separation. The resulting hexane layers were recon-
stituted with 0.1 mL of 2-propanol and placed into HPLC collection
vials. A Waters HPLC system was utilized and equipped with a Varian
column (100 3 4.6 mm microsorb-MN 100–3 C-18), which was
preceded by an Upchurch C-18 guard column (Upchurch Scientific).
The isocratic mobile phase consisted of 80% acetonitrile:15% diox-
ane:2.5% methanol:2.5% 2-propanol:0.01% triethylamine:0.01% am-
monium acetate. The internal standard and carotenoid content of the
plasma and product were detected at 450 nm. All solvents were HPLC
grade and were filtered and degassed before use.
Mononuclear cell isolation and DNA extraction. Mononuclear
cells were isolated according to the method of Boyum et al. (18). Blood
(15 mL) was diluted (1:1) with HSS and layered over Ficoll-Paque.
Samples were centrifuged at 400 3 g for 30 min, after which the mono-
nuclear cell interface was removed, washed twice with HBSS, re-
suspended in 0.2 mL TRIS buffer and kept at 2708C for later DNA
extraction. DNA was extracted using the FlexiGene DNA kit from
Qiagen and held at 48C for genotype determination.
Genotype determination of ABCG5. SNP genotyping was used.
Target genomic DNA regions were first amplified by PCR. The poly-
morphic site in codon 640 of the ABCG5 gene locus was examined.
The use of sequence-specific PCR primers (ABCG5, Fwd: 59CCT-
TGACAGGCACTCAAATG-3" and Rev: 59 TTTCTCAATGAAT-
TGAATTCCTT-39) allowed for the fragment of DNA containing the
polymorphism to be amplified. After PCR, mini-sequencing with fluores-
cent-labeled ddNTPs was conducted. The extension reaction was 5 mL
volume consisting of 2.5 mL of SNaPshot ready reaction mastermix
(Applied Biosystems), 0.5 mL water, 0.015 mL mixed PCR product, and
0.0005 mL of the following probe (5937c- TTTCTCAATGAATT-
35 cycles of 968C for 30 s, 508C for 30 s and 608C for 30 s. The reaction
products were incubated for 60 min at 378C with 5 U calf intestinal
phosphatase to remove unincorporated primers and dNTPs, followed by
incubation at 15 min at 758C to inactivate the enzyme. Genotyping was
carried with the final products on an ABI Prism 3100 genetic analyzer
(Applied Biosystems) using Genotyper version 3.7.
Data analysis. All statistical analysis was performed using SPSS
12.0 for windows. Differences with P , 0.05 were considered significant
for metabolic measurements; P , 0.1 was considered significant for the
interactions between genotype and diet. Unpaired t test was used to
compare initial characteristics between men and women. Repeated-
measures ANOVA was used to analyze changes in plasma lipids and
carotenoids during the EGG and the SUB periods. All allele frequencies
were analyzed using a x2-goodness-of-fit test to determine whether the
observed values differed from Hardy-Weinberg equilibrium. Differences
between allele groups with regard to baseline, EGG, and SUB plasma
measurements were examined using one-way ANOVA. Multivariate
ANOVA was performed to determine interactions between diet and
genotype while controlling for potential cofounders such as gender and
BMI. When necessary, post hoc testing was completed using the Least
Significant Difference procedure.
HERRON ET AL.
by guest on June 2, 2013
Participants maintained their body weight throughout the
study (data not shown). Women had higher baseline plasma
TC (P , 0.05) and HDL-C (P , 0.001) than men (Table 1).
In contrast, men had higher plasma TG concentration than
women (P , 0.05). Baseline plasma LDL-C concentrations
did not differ between gender groups (Table 1). As previously
reported, subjects complied with the requirements of the NCEP
step I diet during both dietary periods. The mean contribution
of energy derived from total (31.4 6 5.5%) and saturated (10.9
6 2.4%) fat during the EGG period was higher (P , 0.01) than
total (26.6 6 7.1%) and saturated (9.4 6 2.6%) fat consumed
during the SUB period for all participants. Furthermore, intakes
of monounsaturated fatty acids (MUFA; 13.05 6 2.77%) and
PUFA (6.6 6 1.97%) were also higher during the EGG period
compared with those values reported for the respective nutrients
(11.42 6 3.3 and 6.07 6 2.1%) during the SUB period. Dietary
analysis also confirmed that a significantly (P , 0.0001) greater
intake of dietary cholesterol was achieved by EGG consumption
compared with SUB. Similarly, the intake of lutein 1 zea-
xanthin was 1834 6 827 mg/d during the EGG and 1505 6 636
mg/d during the SUB period (P , 0.001).
In an examination of the genotype distributions (Table 2),
the observed genotype frequencies for ABCG5 were compatible
with Hardy-Weinberg expectations and the allele frequency for
the most common allele was 0.175. When the population as a
whole was separated on the basis of the ABCG5 genotype, TC
concentrations were significantly (P , 0.01) higher during the
EGG period than they were after SUB intake, independent of
allele or gender (Table 3). A significant (P , 0.05) interaction
also occurred between diet and genotype, which indicated that
carriers of the ABCG 5 C/C allele had higher TC concentra-
tions after egg consumption than those who were identified
with the ABCG5 G (C/G and G/G combined). A significant
interaction also occurred between diet and the ABCG5 allele
actionindicated that individual carriers of the ABCG5 G alleles
had lower LDL-C concentrations during the EGG period than
did their ABCG5 C/C counterparts. To better illustrate this
point, the individual data are plotted in Figure 1. Both gender
and baseline TC levels were factored into a step-wise regression
model and had negligible predictive value with regard to
dietary-induced changes in plasma TC cholesterol concentra-
tions. However, the addition of the ABCG genotype into the
model indicated that the change in TC that occurred as a result
of EGG consumption could be predicted (r2¼ 0.038, 4%) in
part by this polymorphism at the ABCG5 locus. Similarly, when
plasma concentrations of lutein and zeaxanthin were evaluated,
there was a significant diet effect with higher concentrations of
both carotenoids in plasma during the EGG period (P , 0.01)
(Table 4). There was an interaction (P ¼ 0.08) between diet
treatment and allele; the increase in plasma lutein concentra-
tion due to EGG in subjects with the C/C phenotype was 36%,
whereas it was 22.6% in subjects with the G allele (Table 4;
In this study, we showed that carriers of the ABCG5 G allele
(homozygous and heterozygous) have less of a response to
dietary cholesterol and carotenoids than their ABCG5 C/C
counterparts. Because our subjects participated in a study in
which they were challenged with excess dietary cholesterol and
carotenoids, by consuming 3 eggs/d during the EGG period, we
were able to demonstrate the interaction between the ABCG5
allele and the absorption of cholesterol and carotenoids, both of
which are absorbed simultaneously via intestinal micelles (19).
The dietary variations in cholesterol, SFA, MUFA, and
PUFA that occurred between EGG and SUB can be attributed
primarily to the eggs consumed. One whole egg provides 313.5
kJ, 1.5 g of saturated fatty acid (SFA), 1.9 g of MUFA, and
0.682 g of PUFA(20). Epidemiologic data clearly indicate that a
strong positive relation exists between the percentage of energy
obtained from SFA and CHD incidence (21). It was determined
Baseline characteristics of study subjects by gender1
Men (n = 40)Women (n = 51)
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
LDL cholesterol, mg/dL
HDL cholesterol, mg/dL
32.6 6 10.3
25.6 6 4.4
115.0 6 9.5
78.1 6 9.3
160.6 6 29.5
93.8 6 25.1
44.8 6 7.6
109.1 6 65.7
29.5 6 8.2
23.9 6 5.0
121.0 6 12.1
72.5 6 8.1
174.8 6 29.3*
97.4 6 3.9
60.1 6 12.0*
86.5 6 42.1*
1Values are means 6 SD; *different from men, P , 0.01.
2To convert to mmol/L, multiply by 38.67.
3To convert to mmol/L, multiply by 88.54.
The distribution of genotypes in men and women
Plasma TC, LDL-C, and HDL-C concentrations of men
and women classified by ABCG5 genotype during the
EGG and SUB periods1
182.6 6 32.7a
168.9 6 27.6b
105.0 6 29.5a
93.8 6 24.4b
57.0 6 14.6
54.2 6 11.5
169.9 6 27.4b
165.8 6 27.8b
92.5 6 25.6b
90.9 6 27.1b
57.7 6 15.6
56.1 6 13.3
2-way ANOVA, P-values
Diet 3 Allele
1Values are means 6 SD. Means in a column with superscripts
without a common letter differ, P , 0.05.
2To convert to mmol/L multiply by 38.67.
3For the purpose of this analysis, the homozygous and heterozy-
gous variants of the ABCG5 G allele were combined.
4NS, nonsignificant; P $ 0.05.
ABCG5 POLYMORPHISM AND EGG INTAKE
by guest on June 2, 2013
that a fluctuation in LDL-C of 0.120 mmol/L (4.6 mg/dL) can
be expected for every 1% change in SFA intake with relation to
the percentage of total energy consumed (22). It was also
determined previously that diets that replace SFA with MUFA
and PUFA decrease plasma LDL-C concentrations (23). We
suggest that the changes in plasma cholesterol were due to the
dietary cholesterol challenge because both types of fatty acids
(SFA and MUFA) increased during the EGG period and
counterbalanced their effects on plasma lipids.
In contrast to the results presented here, Weggemans et al.
(11) found that the plasma TC response to dietary cholesterol
tended (P , 0.25) to be higher in carriers of the G allele. That
study analyzed the results of 3 different interventions with
various experimental designs. These designs were similar to the
one used in the present study in that participants consumed
both a high- and low-cholesterol diet. Participants either re-
ceived egg as a supplement to their regular diet or received all of
the food that they were to consume during the high-cholesterol
period. For the low-cholesterol period, subjects were given
dietary guidelines to follow. The study examined 99 people who
participated in one (44%) or more (56%) of 8 trials for a total of
202 samples. The authors suggested that the precision of the
data was improved by multiple measurements obtained for ;55
of the study participants and should be considered more ac-
curate than a single trial. However, the multiple measurements
were not combined to produce one mean response for each
duplicate subject, and each trial utilized a different study design
with varying amounts of cholesterol intake over different time
periods. Furthermore, because the reproducibility of individual
differences in response was documented previously in several
controlled and field trials (24), we are confident that our results
would not be different if the study were repeated with the same
subjects. The discrepancy that exists with the available data
influence over the regulation of cholesterol absorption after
excess dietary cholesterol consumption. Using a mouse model
obtained from a genetic cross between 2 strains, Sehayek et al.
(25) identified loci on chromosomes 14 and 12 (independent of
the ABCG5 locus) that may contain additional genes involved
in the regulation of intestinal plant sterol and cholesterol
Dietary cholesterol and carotenoids are metabolized in a
similar manner. Carotenoids, in their ester form, are hydrolyzed
in the lumen of the small intestine by various lipases and ester-
ases for incorporation into the lipid core of the micelle. Micelles
then transport these nutrients into the enterocyte where they
are packaged into a chylomicron particle and released into the
circulation. Plasma chylomicrons are remodeled by the action
of lipoprotein lipases that hydrolyze TG to result in the for-
mation of a smaller remnant, which can be taken up by the
liver. Once in the hepatocyte, cholesterol and carotenoids are
packaged into lipoproteins. Most of the lutein and zeaxanthin is
directed to HDL; a smaller percentage of the total concentra-
tion is incorporated into the VLDL particle. In contrast, a- and
b-carotene are carried primarily in the VLDL particle. When
excess dietary cholesterol is consumed, a certain percentage of
the population may experience increased intestinal absorption,
which allows for more cholesterol to reach the circulating pool
via lipoproteins. It is possible that these individuals may
also increase absorption of carotenoids in response to elevated
Evidence suggests that increased consumption of foods rich
in lutein and zeaxanthin can be directly associated with ele-
vated serum (12,13) and adipose tissue concentrations of these
carotenoids. Because of their antioxidant properties and their
association with lipoproteins in the plasma, lutein and zeaxan-
thin may also function to protect against CHD. Circulating
lutein and zeaxanthin may function to reduce arterial plaque
formation by decreasing the expression of adhesion molecules,
which are needed for monocyte association with the artery
(26). In addition, studies showed that consumption of foods
high in lutein results in an increased concentration of this
carotenoid within the LDL particle (27,28). Lutein contained
in LDL demonstrated antioxidant function in vivo as a scav-
enger of peroxynitrite, the reaction product of nitirc oxide and
SUB periods for individuals classified with the C/C (n ¼ 68) or G/G or C/G
phenotypes (n ¼ 23).
Changes in plasma LDL-C between the EGG and the
Plasma lutein and zeaxanthin concentrations of men
and women classified by ABCG5 genotype1
0.16 6 0.07
0.14 6 0.13
0.89 6 0.42a
0.57 6 0.23c
0.84 6 0.43a
0.65 6 0.38b
0.17 6 0.13
0.14 6 0.10
2-way ANOVA, P-values
Diet 3 Allele
P , 0.01
P = 0.08
P , 0.05
1Values are means 6 SD. Means in a column with superscripts
without a common letter differ, P , 0.10.
2For the purpose of this analysis, the homozygous and heterozy-
gous variants of the ABCG5 G allele were combined.
3NS, nonsignificant; P $ 0.05.
SUB periods for individuals classified with the C/C (n ¼ 27) or G/G or C/G
phenotypes (n ¼ 13).
Changes in plasma lutein between the EGG and the
HERRON ET AL.
by guest on June 2, 2013
superoxide (29). Peroxynitrite, when in the presence of LDL, Download full-text
can destroy lipid-protein complexes, creating a particle that is
Furthermore, 2 epidemiological studies, which examined carotid
intima thickness as a measure of CHD, showed that high levels
of plasma lutein produced a significant reduction in disease risk
In conclusion, although the number of individuals examined
in this study was small (91 for dietary cholesterol and 40 for the
carotenoids), we were able to identify a possible effect of an
ABCG5 polymorphism on the absorption of dietary cholesterol
and carotenoids. This information provides some insight into
the mechanisms that control the plasma response to dietary
components. However, it is difficult to determine what effect a
single nucleotide polymorphism has on lipoprotein metabolism
in isolation from other factors. Overall, it is likely influenced by
variation at multiple loci, which could be further affected by
various environmental factors. Therefore, we are reminded that
these findings are pieces of a bigger puzzle and that further
research is required to understand their effect on metabolism
and disease risk.
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ABCG5 POLYMORPHISM AND EGG INTAKE
by guest on June 2, 2013