Proceedings of the Nutrition Society (2009), 68, 162–172 doi:10.

1017/S0029665109001116
g The Authors 2009 First published online 27 February 2009

The Summer Meeting of the Nutrition Society was held at the University of Nottingham on 30 June–3 July 2008

Conference on ‘Multidisciplinary approaches to nutritional problems’

Nutrition Society Silver Medal Lecture

Nutrigenetics and personalised nutrition: how far have we
progressed and are we likely to get there?

Gerald Rimbach1 and Anne M. Minihane2*

1
Institute of Human Nutrition and Food Science, Christian Albrechts University, Hermann-Rodewald-Strasse 6,
24098 Kiel, Germany
2
Hugh Sinclair Human Nutrition Group, School of Chemistry, Food Biosciences and Pharmacy, University of Reading,
Proceedings of the Nutrition Society

Reading RG6 6AP, UK

Nutrigenetics and personalised nutrition are components of the concept that in the future geno-
typing will be used as a means of defining dietary recommendations to suit the individual. Over
the last two decades there has been an explosion of research in this area, with often conflicting
findings reported in the literature. Reviews of the literature in the area of apoE genotype and
cardiovascular health, apoA5 genotype and postprandial lipaemia and perilipin and adiposity
are used to demonstrate the complexities of genotype–phenotype associations and the aetiology
of apparent between-study inconsistencies in the significance and size of effects. Furthermore,
genetic research currently often takes a very reductionist approach, examining the interactions
between individual genotypes and individual disease biomarkers and how they are modified by
isolated dietary components or foods. Each individual possesses potentially hundreds of ‘at-
risk’ gene variants and consumes a highly-complex diet. In order for nutrigenetics to become a
useful public health tool, there is a great need to use mathematical and bioinformatic tools to
develop strategies to examine the combined impact of multiple gene variants on a range of
health outcomes and establish how these associations can be modified using combined dietary
strategies.

Nutrigenetics: Personalised nutrition: Inter-individual variability: ApoE and apoA5

genotypes: Perilipin genotype

Nutrigenetics refers to the interaction between genetic genotype determines food choice, appetite and satiety, and
make-up and dietary components to influence metabolism, therefore nutrient intake(1,2).
health status and risk of diet-related diseases. This inter- In addition to providing considerable mechanistic insight
action is complex, with the influence of genotype on pheno- into the aetiology of disease and the influence of nutrition
type known to be affected by numerous environmental on metabolic processes, the aim of ongoing nutrigenetics
components, including diet (Fig. 1). Similarly, the influ- research is to ultimately use genetic profiling for the earlier
ence of altered dietary composition on physiological pro- detection of disease risk and the personalisation of dietary
cesses and health status is in large part determined by recommendations provided to individuals or population sub-
an individual’s genetic make-up, which can impact on the groups (Fig. 2). It is hoped that such an approach, along
digestion, absorption, metabolism and partitioning, and with increasing consumer motivation to adapt lifestyle
cellular responsiveness to dietary components. Although a changes, will increase the physiological benefit afforded to
relatively new area of research, it is also recognised that the individual.

Abbreviations: GWA, genome-wide analysis; PLIN, perilipin; SNP, single-nucleotide polymorphisms.

*Corresponding author: Dr Anne Minihane, fax + 44 118 9310080, email [email protected]
 Nutrigenetics and personalised nutrition: progress 163

Health status order to progress this area of research into a public health
tool.

Approaches for identifying genotype–diet–phenotype

associations
Linkage studies and genome-wide association studies
A variety of tools and models are available in nutrigenetics
research, each with their particular strengths and limi-
tations. Segregation analysis and linkage studies in family
groups have led to the identification of the gene loci
associated with numerous Mendelian diseases such as
Genotype or epigenetic status Diet composition Huntington’s disease and cystic fibrosis(7–10) and have also
made some contribution to current understanding of the
Fig. 1. Overview of nutrigenetic interactions.
genetic basis of polygenic disorders such as CVD(11–13).
Over the last 5–10 years the use of genome-wide analysis
(GWA) in large cohorts of unrelated individuals, such as
Proceedings of the Nutrition Society

However, with increasing availability of published data the Wellcome Case-Control Consortium, has dramatically
comes the realisation of apparent inter-study incon- increased genomic discoveries. In these studies genetic
sistencies in the strength and direction of observed geno- variation in O80 % of the human genome is assessed using
type–diet–phenotype associations and the complexity of typically between 100 000 and 1 000 000 marker SNP and
nutrigenetic interactions, with a large number of environ- information on linkage disequilibrium from the HapMap
mental and physiological factors and other gene variants project(14). To date, using GWA approaches, O100 sus-
(epistatic interactions) influencing nutrigenetic associ- ceptibility gene loci for a range of chronic diseases have
ations(3–6). been confirmed, identified and replicated(15–21). Thus far,
Here, using a number of gene variant–nutrient inter- these studies have contributed little to the understanding
actions relevant to CHD as examples, in particular the of diet–genotype interactions, as most of them have not
apoE genotype, which to date represents the most-widely- captured any information on the habitual diet of the study
investigated single nucleotide polymorphisms (SNP), the participants. However, current and future application of
complexity of nutrigenetic interactions will be addressed GWA to cohorts such as the Framingham Heart Study
along with some insights into steps that need to be taken in (www.framinghamheartstudy.org), European Prospective

2008

Health maintenance
Generalised diet and Diagnosis
Clinical evidence of disease Often generalised therapy
other lifestyle
approaches Risk biomarkers

20..?

Early Personalised earlier

Predisposition detection more effective
prevention strategies or therapies

Genetic profile Based on classical and new

biomarkers

Fig. 2. Scheme of the potential of genetics, nutrigenetics and pharmacogenetics in health maintenance and treatment of
diseases. The potential advantages of genotype-based personalised nutrition are: start early; personalised therapy;
improved motivation.
 164 G. Rimbach and A. M. Minihane

Investigation into Cancer and Nutrition (epic.iarc.fr), the meta-analyses(45–47). Data from fourteen published obser-
Nurses’ Health Study (www.channing.harvard.edu/nhs/) vational studies were summarised in the first of the meta-
and the Health Professionals Follow-up Study (www.hsph. analyses, with carriers of the e4 allele having an overall
harvard.edu/hpfs/), for which dietary data are available, OR for CHD of 1.26 (95 % CI 1.13, 1.41) and a non-
is likely to result in substantial advancement in current significant OR of 0.98 (95 % CI 0.85, 1.14) evident in e2
nutrigenetics knowledge. carriers(47). This finding is in agreement with a more recent
meta-analysis that includes data from 15 492 CHD cases
Candidate-gene studies and 32 965 controls. Overall OR of 1.42 (95 % CI 1.26,
1.61) and 0.98 (95% CI 0.66, 1.46) were observed in e4
Applying candidate-gene approaches to case–control and e2 carriers(46). In the most recent and comprehensive
and cohort studies have thus far provided the vast amount analysis, which included 121 studies (37 850 cases and
of available information on genetic–disease associ- 82 727 controls), a more modest effect of the e4 allele and
ations(11,22–28) and how they are influenced by diet and a protective effect of the e2 allele is reported, with OR of
other environmental factors(29–32). In contrast to the 1.06 (95 % CI 0.99, 1.13) and 0.80 (95 % CI 0.70, 0.90)
GWA studies, which are not hypothesis driven, traditional respectively(45). Examination of individual studies included
candidate-gene studies focus on gene loci for which bio- in these meta-analyses demonstrates the extent of hetero-
logical function is known and relevant to the phenotype of geneity in the observed associations. In the second of
interest. the meta-analyses it was reported that mean OR values
Proceedings of the Nutrition Society

derived from the individual studies ranged from 0.68 to

Inconsistencies in genotype–phenotype associations 4.35 when comparing risk in e4 carriers compared with the
wild-type E3/E3 genotype(46).
A comprehensive review of the literature based on both the
candidate-gene and GWA approaches demonstrates that
many reported associations have failed to be consistently
replicated in independent studies(33–35). The reasons for Physiological mediators of apoE genotype–phenotype
these inter-study inconsistencies are likely to be multi- associations
faceted. Some studies may be under-powered, which can Although a comprehensive review of the physiological
lead to a failure to detect the ‘subtle’ physiological impacts determinants of apoE genotype–disease associations is
of a particular gene variant, or provide an imprecise esti- lacking, there is evidence to suggest that gender, age and
mate of the size effect. Furthermore, emerging evidence body weight may have an impact. Data from the Fra-
indicates that an array of physiological, dietary or other mingham Offspring Study is suggestive of a divergent
lifestyle factors impact on the penetrance of a particular penetrance of the apoE2 genotype in females compared
gene variant and result in a change in the size of the geno- with males(48–50). In the prospective 15–20-year follow up
type effect. Gaining an understanding of these complexities from examination 1 (1971–8) to examination 5 (1991–4)
in order to be able to predict the likely impact of genetic OR of cardiovascular events of 1.79 (95 % CI 1.15, 2.77)
variation in particular population subgroups represents a 1.63 (95% CI 1.13, 2.34), 0.79 (95 % CI 0.42, 1.48) and
major challenge. 1.56 (95 % CI 0.99, 2.45) were reported for male E2, male
E4, female E2 and female E4 carriers respectively com-
pared with their wild-type E3/E3 reference group(49)
Inconsistencies in findings using the candidate-gene
(Table 1). In a cross-sectional analysis conducted at
approach: lessons from apoE genotype
examination 6 (1995–8) no impact of apoE genotype on
To date, the most-widely-investigated common SNP– carotid stenosis was evident in males. In contrast, a signifi-
disease association is the relationship between the apoE cant protective effect of the e2 allele was observed in
e (e2, e3, e4) genotype and CHD risk. ApoE was first females, with 51% lower incidence rates relative to the
described as a component of lipoproteins and mediator wild-type E3/E3 genotype (Table 1)(48).
of lipoprotein synthesis, circulatory metabolism and Available data are also highly suggestive of an attenu-
their receptor-mediated removal from the circulation(36). ating effect of apoE genotype according to age, with a lack
In recent years numerous additional roles have been of association in older cohorts(51–55). For example, in the
described, including its role as an anti-inflammatory and Helsinki Sudden Death Study, which conducted lesion
antioxidant agent(30,32,37–40). Globally, the apoE allelic staining of the coronary arteries of 700 individuals, sig-
distribution shows substantial variation. Approximately nificant age · genotype interactions were observed (P =
65% of Caucasian populations are homozygous e3/e3, 0.027), with a significant impact of genotype only in the
19% e3/e4, 10% e2/e3, 4% e2/e4, 2% e4/e4 and 0.5–1% <53 years age-group (P = 0.0085)(52). The reason for this
e2/e2(41). In Europe there is a geographic gradient, with reduction in size effect of genotype with age is likely to
2-fold higher prevalence of the e4 allele in northern Europe be because age is associated with an accumulation of
compared with southern Europe(42), which may contribute environmental influences(56) and an overall multi-faceted
to the North–South differences in CHD incidence(43,44). higher-risk phenotype, which may mask the relatively-
Over the last three decades numerous studies using modest physiological impact of the e4 allele. Furthermore,
both clinically- and angiographically-defined CHD end the lessening of the genotype size effect with age may
points have investigated the impact of apoE genotype on reflect the fact that individuals represented in this cohort
CHD risk. These studies have been summarised in three may be relatively insensitive to the effect of the apoE
 Nutrigenetics and personalised nutrition: progress 165

Table 1. The adjusted OR for cardiovascular events in the Framingham Offspring Study according to apoE genotype in males and
females (adapted from Elosua et al.(48) and Lahoz et al.(49))
Prospective study n Total events* OR1† 95 % CI P OR2‡ 95 % CI P

Males
E3 1097 139 – –
E2 216 40 1.65 1.10, 2.50 0.017 1.79 1.15, 2.77 0.010
E4 355 66 1.61 1.15, 2.27 0.006 1.63 1.13, 2.34 0.009
Females
E3 1097 74 – –
E2 216 13 0.75 0.40, 1.38 0.354 0.79 0.42, 1.48 0.456
E4 355 34 1.54 1.00, 2.38 0.052 1.56 0.99, 2.45 0.054

Cross-sectional n % with P25% OR1k 95% CI P OR2{ 95% CI P

study carotid stenosis§

Males
E3 874 23.8 – –
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E2 169 26.0 1.24 0.79, 1.94 NS 1.22 0.77, 1.95 NS

E4 272 27.6 1.25 0.90. 1.75 NS 1.26 0.89, 1.78 NS
Females
E3 908 16.0 – –
E2 204 10.3 0.54 0.33, 0.87 < 0.05 0.49 0.30, 0.81 < 0.05
E4 296 17.9 1.26 0.87, 1.83 NS 1.24 0.84, 1.83 NS

E3, E3/E3; E4, E3/E4 + E4/E4; E2, E2/E3 + E2/E2.

*Events in the subsequent 15–20 years, where events are defined as the presence of CVD, which includes CHD (myocardial infarction, angina pectoris, coronary
insufficiency, coronary death), stroke, peripheral vascular disease and congenstive heart failure.
†Adjusted for age only.
‡Further adjusted for diabetes, smoking, systolic blood pressure, BMI, left ventricular hypertrophy and use of oestrogens in women.
§Measured in the internal carotid artery.
kAdjusted for age and familial correlation only.
{Further adjusted for diabetes, smoking, systolic blood pressure, hypertension treatment, BMI, menopausal status and use of oestrogen-replacement therapy for
women.

genotype, with particularly-sensitive individuals suffering association in E3/E4 and E4/E4 subgroups was not found
from premature mortality not represented. to be replicated in a subsequent more comprehensive
It is likely that the observation of a greater effect analysis (n 22 915)(65).
of apoE genotype in normal individuals v. overweight A review has been conducted of a number of interven-
individuals(57) is also attributable to the masking effect tion trials that have examined the impact of dietary total
of the obesity phenotype on apoE genotype–CHD associ- fat, saturated fat and cholesterol content on blood lipids
ations. according to apoE genotype(29). The results from these
trials are highly variable, with many failing to report a
significant genotype–diet interaction. Variable intervention
Behavioural mediators of apoE genotype–phenotype lengths, dietary manipulations and subject groups are likely
associations to explain, to a large extent, the lack of consistency. Fur-
The apoE genotype interacts with diet and other behav- thermore, the majority of these studies were not designed
ioural factors to influence risk of disease. Numerous to examine nutrigenetic interaction, with genotyping being
environmental factors have been shown to influence the conducted retrospectively as an afterthought. As a result
effects of apoE genotype on both coronary risk and risk many of the studies were underpowered to detect inter-
of age-related cognitive decline, including exercise(58,59) genotype difference in responses, with the distinct possi-
alcohol intake(60,61) smoking status(32,62) and dietary fat bility that a failure to detect significance is attributable to
composition(29), and the interactions have been recently small group sizes in the rare allele genotypes rather than a
reviewed(30,39). lack of a ‘real’ biological effect.
A limited number of epidemiological studies have Of the eleven (of thirty-six studies) that demonstrated
examined apoE genotype–dietary fat–phenotype associ- significance, six included more than fifty participants, with
ations. In a Costa Rican case–control study genotype– an additional study that included forty-five participants
saturated fat interactions were found, with the impact of a (fifteen each in E3/E3, E3/E4 and E4/E4 subgroups) pros-
high-saturated-fat diet on myocardial infarction risk and pectively recruited on the basis of apoE genotype(66).
LDL-cholesterol more evident in the presence of the e2 In this latter study reductions in LDL-cholesterol of 5%,
and e4 alleles(63). Similar greater responsiveness of LDL- 13% and 16 % for E3/E3, E3/E4 and E4/E4 individuals
cholesterol to saturated fat in individuals with the apoE4 respectively were reported following 8 weeks of interven-
genotype was evident in an initial analysis of a subsample tion with a modified National Cholesterol Education
(n 132) of the EPIC Norfolk cohort(64); however, this Programme diet.
 166 G. Rimbach and A. M. Minihane

Thus, available data are suggestive that individuals highly-active area of nutrigenetic research. Although the
with the E4 genotype (25 % of the UK population) may PLIN gene locus has not been associated with obesity
represent a large population subgroup that is particularly incidence in GWA studies, evidence from candidate-gene
sensitive to dietary total and saturated fat and should studies indicates that it may be an important factor deter-
be specifically targeted with advice to reduce overall mining obesity risk and responsiveness to weight-loss
consumption. However, there is great need to consolidate programmes. The heterogeneity of these associations re-
existing analysis using meta-analytical approaches ported in the literature provides another insightful example
(although variation in study design makes this task diffi- of the complexity of genotype–phenotype associations.
cult) and to conduct adequately-powered trials with pro-
spective recruitment by genotype and detailed analysis of Physiological mediators of perilipin genotype–phenotype
the blood lipid profile in order to conclusively address this associations
wide public health issue.
In addition, recent evidence is suggestive that indi- A recent review has indicated that gender may be an
viduals with the apoE4 genotype are more sensitive to important determinant of the penetrance of the PLIN
the lipid modulatory effects of the fish oil fatty acids EPA genotype(5). In a Spanish adult population OR for obesity
and DHA. Although there are numerous well-described of 0.58 and 0.56 were evident in female carriers of the
cardioprotective actions of these fatty acids(67,68), increases PLIN1 and PLIN4 rare alleles, with no effect of genotype
in LDL-cholesterol in the 5–10% range are commonly on BMI or waist:hip ratio in men(80). Although no impact
Proceedings of the Nutrition Society

evident following high-dose (>2 g/d) EPA + DHA of these particular SNP was evident in a US cohort, PLIN5
intakes(69,70). In an initial study conducted in individuals and PLIN6 SNP have emerged as significant predictors of
with an atherogenic lipoprotein phenotype retrospective percentage body fat and waist circumference in females
genotyping has indicated that the LDL-cholesterol-raising only, with 7–11% higher percentage body fat and waist
effects observed following supplementation with 3 g circumference in the homozygous rare allele v. wild-type
EPA + DHA/d were associated with an apoE4 geno- carriers(81). In a recently published analysis of the impact
type(71,72). Two further studies with prospective recruit- of PLIN genotype on postprandial TAG metabolism both
ment according to genotype have: (a) reconfirmed this PLIN1 and PLIN4 rare alleles were shown to be associated
association; (b) indicated that it is the DHA rather than with a more effective postprandial TAG clearance(82).
EPA that is the hypercholesterolaemic agent; (c) high- However, no gender · genotype effects were evident.
lighted no genotype · LDL-cholesterol interaction at in-
takes of < 2 g EPA + DHA/d. Modest 3–4% increases in Perilipin genotype and response to dietary and
LDL-cholesterol were found to be evident in both E3 and pharmacological interventions
E4 subgroups following supplementation for 8 weeks at
doses of 0.7 and 1.8 g EPA + DHA/d(73)(E Olano-Martin, Research in this area is currently limited to a small number
E Anil, MJ Caslake, CJ Packard, D Bedford, G Stewart, of studies, with available evidence suggesting that rare
D Peiris, CM Williams and AM Minihane, unpublished allele carriers of PLIN4 are resistant to weight loss fol-
results). lowing dietary restriction and are less prone to the weight
Overall, it appears that with intakes at the current UK gain typically associated with the administration of the
recommendation of 450 mg EPA + DHA/d there is little insulin-sensitising glitazones(83,84). Furthermore, an obser-
evidence of apoE genotype-mediated differences in the vational study has indicated that the genotype–diet associ-
LDL-cholesterol response. However, at intakes in the re- ations may be gender specific(85). In Asian women, but not
gion of those prescribed as hypotriacylglycerolaemic men, the PLIN4 genotype was shown to influence the
agents (2–4 g/d(74)) EPA-rich oil rather than DHA-rich oil association between saturated fat and insulin-resistance
may afford greater cardiovascular benefits in individuals measures (homeostatic model assessment of insulin resist-
with an E4 genotype, as a result of the LDL-cholesterol- ance), with a deleterious impact of high saturated fat only
raising effect of DHA. evident in minor allele homozygotes(85). Thus, early indi-
cations are that the PLIN4 genotype may be an important
determinant of the response of adiposity measures (and
its related phenotype) to behavioural changes. However,
Perilipin genotype and obesity risk much more evidence is needed in order to draw firm con-
Adipocyte-derived perilipin (PLIN) is a phosphoprotein clusions.
that coats intracellular lipid droplets. It has emerged as a
key regulator of adipose tissue TAG metabolism, hormone-
Nutrigenetics and postprandial lipaemia
sensitive-lipase-mediated lipolysis and body fat accumu-
lation(75–77). In experimental animals PLIN knock-out is The extent and duration of the postprandial TAG response
associated with increased basal lipolysis, leanness and is recognised to be an important determinant of CHD
resistance to diet-induced obesity(78) and in human subjects risk(86–89), with ever-increasing population incidence,
PLIN levels are elevated in obese individuals(79). given its strong association with excess body weight. The
With the rising global burden of obesity and over one impact of an exaggerated postprandial lipaemic response
billion individuals worldwide being either overweight or appears to be more evident in women relative to men. In
obese identification of genetic determinants of body-weight the Copenhagen City Heart Study adjusted hazard ratios
regulation and response to intervention is becoming a of myocardial infarction for women and men of 5.4 and
 Nutrigenetics and personalised nutrition: progress 167

4·0 associated with an approximately 30–60 % higher post-

prandial TAG response relative to the wild-type apoA5*1
3·5 haplotype, defined by - 1131T and S19 alleles(28,97–101).
Five of these investigations have been conducted in young
3·0 males and ethnically-homogenous cohorts(97–101). Thus,
little information on gender, age and ethnicity · genotype
TAG (mmol/l)

2·5
interaction can be derived from these studies. However, the
2·0 most recently published study, which included 153 males
and 109 females, provides strong indications of an impact
1·5 of gender on the association between the - 1131C allele
and apoA5*2 haplotype and TAG metabolism (Fig. 4)(28).
1·0 A significant impact of genotype was only evident in males
29 g fat (corrected for baseline levels; P = 0.007). It is speculated
0·5 49 g fat that this finding may be in part attributable to the known
0
impact of oestrogen on many stages of TAG-rich lipopro-
0 60 120 180 240 300 360 420 480 tein metabolism, which may mask the deleterious impact
Time interval (min) of the apoA5 mutant.
In accordance with other gene variants that modulate
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Fig. 3. Example of the heterogeneity in response in plasma TAG

levels following standard fat-containing meals. The plot represents
lipoprotein metabolism, there is some evidence that dietary
the postprandial TAG response to a standard fat-containing break- fat composition influences the ‘size effect’; of the apoA5
fast (49 g fat, time 0 min) and lunch (29 g fat, time 330 min) for five T–1131C variant on TAG metabolism(95). An analysis of
individuals chosen randomly from the database of > 200 individuals. data from the Framingham cohort indicates that the associ-
Blood samples were taken at hourly intervals up to 8 h post break- ation is modulated by dietary PUFA composition(102). Fish
fast. (Data from AM Minihane, KG Jackson, JA Lovegrove and CM oil fatty acids are the most potent known dietary hypo-
Williams, unpublished results.) triacylglycerolaemic agents, with 20–40 % reduction typi-
cally observed following high-dose intakes (2–4 g EPA +
DHA/d)(72). Given that there is considerable mechanistic
overlap between fish oil action and apoA5 modulation of
2.4 were evident when comparing non-fasting TAG levels TAG metabolism, with fish oils reducing hepatic TAG
of <1 mmol/l with levels of >5 mmol/l(88). Pathological output and enhancing LPL activity, it is highly likely that
effects of postprandial TAG are thought to be a result of EPA + DHA intake would influence apoA5–TAG associ-
the ability of TAG-rich lipoprotein remnants to penetrate ations and in part negate the negative effects in those with
and sequester cholesterol into the arterial intima, along the apoA5*2 and apoA5*3 haplotypes. This interaction is
with an indirect effect of TAG-rich lipoprotein particles on worthy of investigation.
HDL and LDL metabolism, thrombosis and endothelial Investigations of the impact of specific genotypes,
function. haplotypes and genotype combinations on postprandial
Population TAG responses are known to be highly het- TAG metabolism are logistically difficult studies to con-
erogeneous (Fig. 3). In addition to rare gene variants and duct, as they require volunteers to provide regular blood
their associated familial hypertriacyglycerolaemias(90) samples typically up to 8 h post test meal. As a result
common polymorphisms in the genes for apo, lipases, cohorts are often small (< 100 individuals), making mean-
transport and other lipid-metabolising proteins modulate ingful analysis of genotype–phenotype associations diffi-
postprandial TAG metabolism (for review, see Perez- cult, in particular for rarer alleles. Furthermore, subgroup
Martinez et al.(91)). One of the most important loci to analysis according to gender, age etc. is often impossible.
emerge to date is that of apoA5. Combining existing smaller cohorts may allow more de-
tailed analysis to be conducted. However, this approach is
often difficult because of variations in study protocol, in
ApoA5 genotype and postprandial lipaemia
particular test meal composition. There is a strong justifi-
ApoA5 was first identified in 2001(92) and has been de- cation for the standardisation of postprandial protocols in
scribed as a protein involved in both hepatic TAG synth- order to allow cross-study comparisons and amalgamation
esis and secretion and the hydrolysis and clearance of of datasets.
TAG-rich lipoprotein from the circulation(93). Over the last
7 years numerous studies have reported associations be-
tween the apoA5 T–1131C and S19W rare alleles (which
define the apoA5*2 and apoA5*3 haplotypes respectively)
Future needs in nutrigenetic research
and CVD, and metabolic syndrome and diabetes risk(94–96),
and consequently the apo5 gene has emerged as one of the Nutrigenetics is undoubtedly a relatively new area of
most consistent loci associated with fasting and post- nutritional science, with research in its relatively infancy.
prandial TAG levels(28,95). Although the evidence base in nutrigenetics is grow-
Six studies relating apoA5 genotype and postprandial ing, with sufficient data available to provide a ‘proof of
TAG metabolism have been published thus far, with evi- principle’ of its potential utility in public health, this area
dence that the apoA5*2 and apoA5*3 haplotypes are currently suffers from a lack of consistent findings.
 168 G. Rimbach and A. M. Minihane

(a) all, P=0·002

5·0
4·5
4·0
3·5

TAG (mmol/l)
3·0
2·5
2·0
1·5
1·0
0·5
0
0 60 120 180 240 300 360 420 480
Time interval (min)

(b) females, P=0·280 (c) males, P=0·007

5·0 5·0
Proceedings of the Nutrition Society

4·5 4·5
4·0 4·0
3·5 3·5
TAG (mmol/l)
TAG (mmol/l)

3·0 3·0
2·5 2·5
2·0 2·0
1·5 1·5
1·0 1·0
0·5 0·5
0 0
0 60 120 180 240 300 360 420 480 0 60 120 180 240 300 360 420 480
Time interval (min) Time interval (min)
Fig. 4. Impact of apoA5 T–1131C genotype on the postprandial plasma TAG response. (a) All subjects: (&–&), TT (n 214);
(L– –L), TC (n 42); ( ), CC (n 3); P = 0.002. (b), Females: (&–&), TT (n 92); (L– –L), TC (n 16); P = 0.280. (c) Males
(&–&), TT (n 122); (L– –L), TC (n 26); P = 0.007. Values are means with their standard errors represented by vertical bars.
(Adapted from Olano-Martin et al.(28).)

In observational studies a lack of consistency may be a associations, and consideration of these apparent incon-
result of small group size, experimental error associated sistencies can be very insightful and provide information
with inaccurate assessment of the phenotype of interest or, about the relative importance of gene variants in particular
more commonly, a result of inaccuracies and bias as- population subgroups. A consensus relating to standardi-
sociated with the recording of dietary intake. It is highly sation in the capture of such information would greatly
likely that the reliability of dietary information may assist in study interpretation and amalgamation of datasets
depend on factors such as age, ethnicity, gender and health to allow larger meta-analyses.
status, which could introduce a considerable amount of Human intervention studies overcome, in part, inac-
error in the assessment of genotype–diet–phenotype– curacies in dietary assessment, as the investigator is sup-
associations. The quantification of biomarkers of dietary plying a known quantity of the food or food component
exposure in accessible biofluids holds great potential as a of interest. However, in the past many studies in this area
dietary assessment tool. To date few reliable dietary bio- have been of dubious quality, with short intervention
markers are available, with the exception of a number of periods, small numbers of participants and retrospective
micronutrients and specific fatty acids (e.g. EPA and DHA genotyping (as these trials were designed for purposes
and trans-fatty acids). Metabolomic profiles in biologi- other than to study nutrigenetic interactions) resulting in
cally-accessible tissues holds some potential. However, inadequate power to detect subtle nutrigenetic interactions.
it is difficult to assess at present its future role in the Prospective recruitment by genotype, with equal numbers
assessment of dietary exposure. in genotype subgroups of interest overcomes this problem.
As evidenced in the present review, perceived incon- Such approaches are however expensive and logistically
sistencies between studies often reflect the impact of phy- difficult to conduct and should be reserved to validate
siological (e.g. age, gender, ethnicity, health status) and nutrigenetic interactions reported in observation trials or
environmental factors on the direction and size of genetic in intervention studies with retrospective genotyping.
 Nutrigenetics and personalised nutrition: progress 169

Furthermore, much more attention needs to be given to the UK Food Standards Agency (N02028). The authors
identifying the functional gene variants and the metabolic report no conflict of interest. Both authors contributed to
basis for nutrigenetic interactions. Current candidate-gene the research included and the writing of the manuscript.
or GWA studies provide information on which SNP are
associated with, and are in linkage disequilibrium with, a
particular phenotype, but do not necessarily identify the
precise SNP. Such information, along with adding authen- References
ticity to the observed associations, is essential in order to 1. Mizuta E, Kokubo Y, Yamanaka I et al. (2008) Leptin gene
help identify diet and other behavioural strategies that may and leptin receptor gene polymorphisms are associated with
counteract the ‘at risk’ genotype. Stably-transfected cells sweet preference and obesity. Hypertens Res 31, 1069–1077.
lines and targeted-replacement animal models have proved 2. Wardle J, Carnell S, Haworth CM et al. (2008) Obesity as-
useful in this context. For example, traditionally the phy- sociated genetic variation in FTO is associated with dimin-
siological basis of the apoE genotype effect on CVD risk ished satiety. J Clin Endocrinol Metab 93, 3640–3643.
and risk of age-related cognitive decline has been thought 3. Combarros O, Cortina-Borja M, Smith AD et al. (2008)
to be its LDL-cholesterol-raising effect. However, using Epistasis in sporadic Alzheimer’s disease. Neurobiol Aging
(Epublication ahead of print version).
these models recent data are suggestive that the e4 allele is
4. Isaacs A, Aulchenko YS, Hofman A et al. (2007) Epistatic
also associated with a pro-inflammatory and pro-oxidative effect of cholesteryl ester transfer protein and hepatic lipase
state(38,39).
Proceedings of the Nutrition Society

on serum high-density lipoprotein cholesterol levels. J Clin

Alongside basic research there is a great need to make Endocrinol Metab 92, 2680–2687.
the most of existing data using a variety of traditional 5. Ordovas JM (2007) Gender, a significant factor in the cross
statistical and mathematical methods along with newly- talk between genes, environment, and health. Gend Med 4,
developing bioinformatic techniques. Currently, a very Suppl. B, S111–S122.
reductionist approach is often taken, examining associ- 6. Wang K (2008) Genetic association tests in the presence of
ations between single loci, single dietary components and epistasis or gene-environment interaction. Genet Epidemiol
specific phenotypes. However, this approach must feed into 32, 606–614.
7. Botstein D & Risch N (2003) Discovering genotypes under-
a more holistic scenario, examining the interactive effect
lying human phenotypes: past successes for mendelian dis-
of genetic and environmental components on health. Each ease, future approaches for complex disease. Nat Genet 33,
individual possesses potentially hundreds (or more) of Suppl., 228–237.
gene variants that may influence metabolism and health 8. Gusella JF (1984) Genetic linkage of the Huntington’s dis-
status, the penetrance of which may be modified by many ease gene to a DNA marker. Can J Neurol Sci 11, 421–425.
physiological, dietary and other behavioural variables. 9. Riordan JR, Rommens JM, Kerem B et al. (1989) Identifi-
Although epidemiological studies and meta-analysis in cation of the cystic fibrosis gene: cloning and characteriz-
> 100 000 individuals can provide some interactive infor- ation of complementary DNA. Science 245, 1066–1073.
mation, this holistic overview can only be fully achieved 10. Strachan T & Read AP (2004) Mapping and Identifying
by mathematical modelling and bioinformatic technology. Genes Conferring Susceptibility to Complex Diseases. Lon-
don and New York: Garland Science.
Examples of this type of analysis are already appearing in
11. Arnett DK, Baird AE, Barkley RA et al. (2007) Relevance of
the literature(24,103,104). genetics and genomics for prevention and treatment of car-
In conclusion, genetic profiling is becoming increasingly diovascular disease: a scientific statement from the American
cost effective and high throughput(105) and holds great Heart Association Council on Epidemiology and Prevention,
potential as a means of estimating future disease risk and the Stroke Council, and the Functional Genomics and
personalisation of strategies to effectively reduce disease Translational Biology Interdisciplinary Working Group. Cir-
risk. However, it is currently not ready to be used as culation 115, 2878–2901.
a widespread public health strategy for chronic disease 12. Chiodini BD & Lewis CM (2003) Meta-analysis of 4 cor-
management. A much more comprehensive understanding onary heart disease genome-wide linkage studies confirms a
of the penetrance of genotypes in population subgroups, susceptibility locus on chromosome 3q. Arterioscler Thromb
Vasc Biol 23, 1863–1868.
the identity of the mechanistic basis of pathological var-
13. Helgadottir A, Manolescu A, Thorleifsson G et al. (2004)
iants and the impact of the combined effects of multiple The gene encoding 5-lipoxygenase activating protein confers
variants and their interaction with environment is needed. risk of myocardial infarction and stroke. Nat Genet 36, 233–
Alongside the progression of scientific evidence, attention 239.
should also be paid to some of the surrounding issues such 14. Pearson TA & Manolio TA (2008) How to interpret a gen-
as the ethics and consumer acceptability of genetic profil- ome-wide association study. JAMA 299, 1335–1344.
ing, issues that need to be resolved before this potentially 15. The Wellcome Trust Case Control Consortium (2007)
valuable public health tool can be used more widely. Genome-wide association study of 14,000 cases of seven
common diseases and 3,000 shared controls. Nature 447,
661–678.
16. Forabosco P, Bouzigon E, Ng MY et al. (2008) Meta-
Acknowledgements analysis of genome-wide linkage studies across autoimmune
diseases. Eur J Hum Genet (Epublication ahead of print
The published research of the authors that is included in version).
this review has been supported by the German Ministry of 17. Loos RJ & Bouchard C (2008) FTO: the first gene con-
Education and Science (0313856B), the UK Biotechnology tributing to common forms of human obesity. Obes Rev 3,
and Biological Sciences Research Council (D18350) and 246–250.
 170 G. Rimbach and A. M. Minihane

18. Ozaki K & Tanaka T (2005) Genome-wide association study 37. Dietrich M, Hu Y, Block G et al. (2005) Associations
to identify SNPs conferring risk of myocardial infarction between apolipoprotein E genotype and circulating F2-
and their functional analyses. Cell Mol Life Sci 62, 1804– isoprostane levels in humans. Lipids 40, 329–334.
1813. 38. Jofre-Monseny L, Loboda A, Wagner AE et al. (2007)
19. Samani NJ, Erdmann J, Hall AS et al. (2007) Genomewide Effects of apoE genotype on macrophage inflammation and
association analysis of coronary artery disease. N Engl J Med heme oxygenase-1 expression. Biochem Biophys Res Com-
357, 443–453. mun 357, 319–324.
20. Willer CJ, Sanna S, Jackson AU et al. (2008) Newly identi- 39. Jofre-Monseny L, Minihane AM & Rimbach G (2008)
fied loci that influence lipid concentrations and risk of cor- Impact of apoE genotype on oxidative stress, inflammation
onary artery disease. Nat Genet 40, 161–169. and disease risk. Mol Nutr Food Res 52, 131–145.
21. Zeggini E, Scott LJ, Saxena R et al. (2008) Meta-analysis 40. Vitek MP, Brown CM & Colton CA (2007) APOE genotype-
of genome-wide association data and large-scale replication specific differences in the innate immune response. Neuro-
identifies additional susceptibility loci for type 2 diabetes. biol Aging (Epublication ahead of print version).
Nat Genet 40, 638–645. 41. Eichner JE, Dunn ST, Perveen G et al. (2002) Apolipoprotein
22. Humphries SE, Cooper JA, Talmud PJ et al. (2007) Candi- E polymorphism and cardiovascular disease: a HuGE review.
date gene genotypes, along with conventional risk factor Am J Epidemiol 155, 487–495.
assessment, improve estimation of coronary heart disease risk 42. Singh P, Singh M & Mastana S (2006) APOE distribution in
in healthy UK men. Clin Chem 53, 8–16. world populations with new data from India and the UK. Ann
23. Keavney B, Palmer A, Parish S et al. (2004) Lipid-related Hum Biol 33, 297–308.
Proceedings of the Nutrition Society

genes and myocardial infarction in 4685 cases and 3460 43. Allender S, Scarborough P, Rayner M et al. (2008) European
controls: discrepancies between genotype, blood lipid con- cardiovascular disease statistics 2008. http://www.heartstats.
centrations, and coronary disease risk. Int J Epidemiol 33, org/datapage.asp?id=7683
1002–1013. 44. Lao O, Dupanloup I, Barbujani G et al. (2008) The Medi-
24. Knoblauch H, Bauerfeind A, Toliat MR et al. (2004) terranean paradox for susceptibility factors in coronary heart
Haplotypes and SNPs in 13 lipid-relevant genes explain most disease extends to genetics. Ann Hum Genet 72, 48–56.
of the genetic variance in high-density lipoprotein and low- 45. Bennet AM, Di Angelantonio E, Ye Z et al. (2007) As-
density lipoprotein cholesterol. Hum Mol Genet 13, 993– sociation of apolipoprotein E genotypes with lipid levels and
1004. coronary risk. JAMA 298, 1300–1311.
25. Lusis AJ, Fogelman AM & Fonarow GC (2004) Genetic 46. Song Y, Stampfer MJ & Liu S (2004) Meta-analysis: apoli-
basis of atherosclerosis: part II: clinical implications. Circu- poprotein E genotypes and risk for coronary heart disease.
lation 110, 2066–2071. Ann Intern Med 141, 137–147.
26. Lusis AJ, Fogelman AM & Fonarow GC (2004) Genetic 47. Wilson PW, Schaefer EJ, Larson MG et al. (1996) Apolipo-
basis of atherosclerosis: part I: new genes and pathways. protein E alleles and risk of coronary disease. A meta-
Circulation 110, 1868–1873. analysis. Arterioscler Thromb Vasc Biol 16, 1250–1255.
27. McCarthy JJ, Parker A, Salem R et al. (2004) Large scale 48. Elosua R, Ordovas JM, Cupples LA et al. (2004) Association
association analysis for identification of genes underlying of APOE genotype with carotid atherosclerosis in men and
premature coronary heart disease: cumulative perspective women: the Framingham Heart Study. J Lipid Res 45, 1868–
from analysis of 111 candidate genes. J Med Genet 41, 334– 1875.
341. 49. Lahoz C, Schaefer EJ, Cupples LA et al. (2001) Apolipo-
28. Olano-Martin E, Abraham EC, Gill-Garrison R et al. protein E genotype and cardiovascular disease in the
(2008) Influence of apoA-V gene variants on postprandial Framingham Heart Study. Atherosclerosis 154, 529–537.
triglyceride metabolism: impact of gender. J Lipid Res 49, 50. Wilson PW, Myers RH, Larson MG et al. (2001) Apolipo-
945–953. protein E alleles, dyslipidemia, and coronary heart disease.
29. Masson LF, McNeill G & Avenell A (2003) Genetic vari- The Framingham Offspring Study. JAMA 272, 1666–1671.
ation and the lipid response to dietary intervention: a sys- 51. Banares VG, Peterson G, Aguilar D et al. (2005) Association
tematic review. Am J Clin Nutr 77, 1098–1111. between the APOE*4 allele and atherosclerosis is age
30. Minihane AM, Jofre-Monseny L, Olano-Martin E et al. dependent among Argentine males. Hum Biol 77, 247–256.
(2007) Apolipoprotein E genotype, cardiovascular risk and 52. Ilveskoski E, Perola M, Lehtimaki T et al. (1999) Age-
responsiveness to dietary fat manipulation. Proc Nutr Soc 66, dependent association of apolipoprotein E genotype with
183–197. coronary and aortic atherosclerosis in middle-aged men: an
31. Ordovas JM & Tai ES (2008) Why study gene-environment autopsy study. Circulation 100, 608–613.
interactions? Curr Opin Lipidol 19, 158–167. 53. Jarvik GP, Austin MA, Fabsitz RR et al. (1994) Genetic
32. Stephens JW, Bain SC & Humphries SE (2008) Gene- influences on age-related change in total cholesterol, low
environment interaction and oxidative stress in cardiovas- density lipoprotein-cholesterol, and triglyceride levels: longi-
cular disease. Atherosclerosis 200, 229–238. tudinal apolipoprotein E genotype effects. Genet Epidemiol
33. Hirschhorn JN, Lohmueller K, Byrne E et al. (2002) A 11, 375–384.
comprehensive review of genetic association studies. Genet 54. Kolovou GD & Anagnostopoulou KK (2007) Apolipoprotein
Med 4, 45–61. E polymorphism, age and coronary heart disease. Ageing Res
34. Ioannidis JP, Ntzani EE, Trikalinos TA et al. (2001) Repli- Rev 6, 94–108.
cation validity of genetic association studies. Nat Genet 29, 55. Kuusisto J, Mykkanen L, Kervinen K et al. (1995) Apolipo-
306–309. protein E4 phenotype is not an important risk factor for cor-
35. NCI-NHGRI Working Group on Replication in Association onary heart disease or stroke in elderly subjects. Arterioscler
Studies, Chanock SJ, Manolio T et al. (2007) Replicating Thromb Vasc Biol 15, 1280–1286.
genotype-phenotype associations. Nature 447, 655–660. 56. Zdravkovic S, Wienke A, Pedersen NL et al. (2002) Herit-
36. Shore VG & Shore B (1973) Heterogeneity of human plasma ability of death from coronary heart disease: a 36-year
very low density lipoproteins. Separation of species differing follow-up of 20 966 Swedish twins. J Intern Med 252, 247–
in protein components. Biochemistry 12, 502–507. 254.
 Nutrigenetics and personalised nutrition: progress 171

57. Pardo Silva MC, Janssens AC, Hofman A et al. (2008) 75. Brasaemle DL, Rubin B, Harten IA et al. (2000) Perilipin A
Apolipoprotein E gene is related to mortality only in normal increases triacylglycerol storage by decreasing the rate of
weight individuals: the Rotterdam Study. Eur J Epidemiol triacylglycerol hydrolysis. J Biol Chem 275, 38486–38493.
23, 135–142. 76. Tai ES & Ordovas JM (2007) The role of perilipin in human
58. Corella D, Guillen M, Saiz C et al. (2001) Environmental obesity and insulin resistance. Curr Opin Lipidol 18, 152–
factors modulate the effect of the APOE genetic poly- 156.
morphism on plasma lipid concentrations: ecogenetic studies 77. Wang S, Soni KG, Semache M et al. (2008) Lipolysis and
in a Mediterranean Spanish population. Metabolism 50, 936– the integrated physiology of lipid energy metabolism. Mol
944. Genet Metab 95, 117–126.
59. Etnier JL, Caselli RJ, Reiman EM et al. (2007) Cognitive 78. Tansey JT, Sztalryd C, Gruia-Gray J et al. (2001) Perilipin
performance in older women relative to ApoE-epsilon4 geno- ablation results in a lean mouse with aberrant adipocyte
type and aerobic fitness. Med Sci Sports Exerc 39, 199–207. lipolysis, enhanced leptin production, and resistance to diet-
60. Corella D, Tucker K, Lahoz C et al. (2001) Alcohol drinking induced obesity. Proc Natl Acad Sci USA 98, 6494–6499.
determines the effect of the APOE locus on LDL-cholesterol 79. Kern PA, Di Gregorio G, Lu T et al. (2004) Perilipin
concentrations in men: the Framingham Offspring Study. expression in human adipose tissue is elevated with obesity.
Am J Clin Nutr 73, 736–745. J Clin Endocrinol Metab 89, 1352–1358.
61. Djousse L, Pankow JS, Arnett DK et al. (2004) Apolipopro- 80. Qi L, Corella D, Sorli JV et al. (2004) Genetic variation at
tein E polymorphism modifies the alcohol-HDL association the perilipin (PLIN) locus is associated with obesity-related
observed in the National Heart, Lung, and Blood Institute phenotypes in White women. Clin Genet 66, 299–310.
Proceedings of the Nutrition Society

Family Heart Study. Am J Clin Nutr 80, 1639–1644. 81. Qi L, Shen H, Larson I et al. (2004) Gender-specific as-
62. Humphries S, Talmud P, Hawe E et al. (2001) Apolipo- sociation of a perilipin gene haplotype with obesity risk in a
protein E4 and coronary heart disease in middle-aged men white population. Obes Res 12, 1758–1765.
who smoke: a prospective study. Lancet 358, 115–119. 82. Perez-Martinez P, Yiannakouris N, Lopez-Miranda J et al.
63. Yang Y, Ruiz-Narvaez E, Kraft P et al. (2007) Effect of (2008) Postprandial triacylglycerol metabolism is modified
apolipoprotein E genotype and saturated fat intake on plasma by the presence of genetic variation at the perilipin (PLIN)
lipids and myocardial infarction in the Central Valley of locus in 2 white populations. Am J Clin Nutr 87, 744–752.
Costa Rica. Hum Biol 79, 637–647. 83. Corella D, Qi L, Sorli JV et al. (2005) Obese subjects car-
64. Loktionov A, Scollen S, McKeown N et al. (2000) Gene- rying the 11482G > A polymorphism at the perilipin locus are
nutrient interactions: dietary behaviour associated with high resistant to weight loss after dietary energy restriction. J Clin
coronary heart disease risk particularly affects serum LDL Endocrinol Metab 90, 5121–5126.
cholesterol in apolipoprotein E epsilon4-carrying free-living 84. Kang ES, Cha BS, Kim HJ et al. (2006) The 11482G > A
individuals. Br J Nutr 84, 885–890. polymorphism in the perilipin gene is associated with weight
65. Wu K, Bowman R, Welch AA et al. (2007) Apolipoprotein E gain with rosiglitazone treatment in type 2 diabetes. Diabetes
polymorphisms, dietary fat and fibre, and serum lipids: the Care 29, 1320–1324.
EPIC Norfolk study. Eur Heart J 28, 2930–2036. 85. Corella D, Qi L, Tai ES et al. (2006) Perilipin gene variation
66. Sarkkinen E, Korhonen M, Erkkila A et al. (1998) Effect of determines higher susceptibility to insulin resistance in
apolipoprotein E polymorphism on serum lipid response to Asian women when consuming a high-saturated fat, low-
the separate modification of dietary fat and dietary choles- carbohydrate diet. Diabetes Care 29, 1313–1319.
terol. Am J Clin Nutr 68, 1215–1222. 86. Bansal S, Buring JE, Rifai N et al. (2007) Fasting compared
67. GISSI-Prevenzione Investigators (1999) Dietary supple- with nonfasting triglycerides and risk of cardiovascular
mentation with n-3 polyunsaturated fatty acids and vitamin E events in women. JAMA 298, 309–316.
after myocardial infarction: results of the GISSI-Prevenzione 87. Eberly LE, Stamler J & Neaton JD (2003) Relation of tri-
trial. Gruppo Italiano per lo Studio della Sopravvivenza glyceride levels, fasting and nonfasting, to fatal and nonfatal
nell’Infarto miocardico. Lancet 354, 447–455. coronary heart disease. Arch Intern Med 163, 1077–1083.
68. Kris-Etherton PM, Harris WS & Appel LJ (2002) Fish con- 88. Nordestgaard BG, Benn M, Schnohr P et al. (2007) Non-
sumption, fish oil, omega-3 fatty acids, and cardiovascular fasting triglycerides and risk of myocardial infarction,
disease. Circulation 106, 2747–2757. ischemic heart disease, and death in men and women. JAMA
69. Balk EM, Lichtenstein AH, Chung M et al. (2006) Effects of 298, 299–308.
omega-3 fatty acids on serum markers of cardiovascular 89. Stensvold I, Tverdal A, Urdal P et al. (1993) Non-fasting
disease risk: a systematic review. Atherosclerosis 189, 19–30. serum triglyceride concentration and mortality from coronary
70. Harris WS (1997) n-3 fatty acids and serum lipoproteins: heart disease and any cause in middle aged Norwegian
human studies. Am J Clin Nutr 65, Suppl., 1645S–1654S. women. Br Med J 307, 1318–1322.
71. Leigh-Firbank EC, Minihane AM, Leake DS et al. (2002) 90. Benlian P, De Gennes JL, Foubert L et al. (1996) Premature
Eicosapentaenoic acid and docosahexaenoic acid from fish atherosclerosis in patients with familial chylomicronemia
oils: differential associations with lipid responses. Br J Nutr caused by mutations in the lipoprotein lipase gene. N Engl
87, 435–445. J Med 335, 848–854.
72. Minihane AM, Khan S, Leigh-Firbank EC et al. (2000) ApoE 91. Perez-Martinez P, Lopez-Miranda J, Perez-Jimenez F et al.
polymorphism and fish oil supplementation in subjects with (2008) Influence of genetic factors in the modulation of
an atherogenic lipoprotein phenotype. Arterioscler Thromb postprandial lipemia. Atheroscler Suppl 9, 49–55.
Vasc Biol 20, 1990–1997. 92. Pennacchio LA, Olivier M, Hubacek JA et al. (2001) An
73. Caslake MJ, Miles EA, Kofler BM et al. (2008) Effect of sex apolipoprotein influencing triglycerides in humans and mice
and genotype on cardiovascular biomarker response to fish revealed by comparative sequencing. Science 294, 169–173.
oils: the FINGEN Study. Am J Clin Nutr 88, 618–629. 93. Wong K & Ryan RO (2007) Characterization of apolipo-
74. Kris-Etherton PM, Harris WS & Appel LJ (2002) AHA protein A-V structure and mode of plasma triacylglycerol
Scientific Statement. Fish consumption, fish oil, omega-3 regulation. Curr Opin Lipidol 18, 319–324.
fatty acids, and cardiovascular disease. Circulation 106, 94. Elosua R, Ordovas JM, Cupples LA et al. (2006) Variants at
2747–2757. the APOA5 locus, association with carotid atherosclerosis,
 172 G. Rimbach and A. M. Minihane

and modification by obesity: the Framingham Study. J Lipid 100. Moreno R, Perez-Jimenez F, Marin C et al. (2006) A single
Res 47, 990–996. nucleotide polymorphism of the apolipoprotein A-V gene –
95. Tai ES & Ordovas JM (2008) Clinical significance of apoli- 1131T > C modulates postprandial lipoprotein metabolism.
poprotein A5. Curr Opin Lipidol 19, 349–354. Atherosclerosis 189, 163–168.
96. Talmud PJ, Martin S, Taskinen MR et al. (2004) APOA5 101. Moreno-Luna R, Perez-Jimenez F, Marin C et al. (2007)
gene variants, lipoprotein particle distribution, and progres- Two independent apolipoprotein A5 haplotypes modulate
sion of coronary heart disease: results from the LOCAT postprandial lipoprotein metabolism in a healthy Caucasian
study. J Lipid Res 45, 750–756. population. J Clin Endocrinol Metab 92, 2280–2285.
97. Jang Y, Kim JY, Kim OY et al. (2004) The - 1131T33!C 102. Lai CQ, Corella D, Demissie S et al. (2006) Dietary intake
polymorphism in the apolipoprotein A5 gene is associated of n-6 fatty acids modulates effect of apolipoprotein A5
with postprandial hypertriacylglycerolemia; elevated small, gene on plasma fasting triglycerides, remnant lipoprotein
dense LDL concentrations; and oxidative stress in nonobese concentrations, and lipoprotein particle size: the Framing-
Korean men. Am J Clin Nutr 80, 832–840. ham Heart Study. Circulation 113, 2062–2070.
98. Kim JY, Kim OY, Koh SJ et al. (2006) Comparison of low- 103. Drenos F, Whittaker JC & Humphries SE (2007) The use of
fat meal and high-fat meal on postprandial lipemic response meta-analysis risk estimates for candidate genes in com-
in non-obese men according to the –1131T > C polymorphism bination to predict coronary heart disease risk. Ann Hum
of the apolipoprotein A5 (APOA5) gene (randomized cross- Genet 71, 611–619.
over design). J Am Coll Nutr 25, 340–347. 104. Yang Q, Khoury MJ, Friedman J et al. (2005) How many
99. Martin S, Nicaud V, Humphries SE et al. (2003) Contribu- genes underlie the occurrence of common complex diseases
Proceedings of the Nutrition Society

tion of APOA5 gene variants to plasma triglyceride deter- in the population? Int J Epidemiol 34, 1129–1137.
mination and to the response to both fat and glucose 105. Mardis ER (2006) Anticipating the 1,000 dollar genome.
tolerance challenges. Biochim Biophys Acta 1637, 217–225. Genome Biol 7, 112.