PUBLIC HEALTH AND TRANSLATIONAL MEDICINE (P FRANKS, SECTION EDITOR)
Gene-Diet Interactions in Complex Disease: Current Findings
and Relevance for Public Health
Published online: 3 October 2012
# Springer Science+Business Media, LLC 2012
Abstract Rates of obesity and related complex diseases,
such as type 2 diabetes and cardiovascular disease, have
climbed sharply over the past decades, in parallel with shift
from principally more active lifestyle and nutritionally
dense tradition diet to sedentary lifestyle and more energy-
dense, western-pattern diet. During the past few years,
advances in genotyping technology and in particular a num-
ber of large-scale genome-wide association studies have
made great strides in unraveling the genetic basis of com-
plex diseases; and the growing inventory of genetic
variation is facilitating efforts to investigate gene-diet inter-
actions. Understanding gene-diet interaction has the poten-
tial to promote diet modifications on the basis of genetic
makeup. Several recent large-scale studies found reproduc-
ible evidence showing consumption of sugar sweetened
beverages or dietary patterns might modulate genetic pre-
disposition to obesity or cardiovascular disease. Analyses in
randomized trials also showed that genetic markers for
obesity, diabetes, or cardiovascular disease might modify
the metabolic response to weight-loss diets. However, little
of the knowledge about gene-diet interaction has been ap-
plied in public health practice; and opinion on how genetic
testing services are offered and interpreted is still divided.
This review will summarize recent findings regarding obe-
sogenic diet, genetic susceptibility, and gene-diet interac-
tions for obesity and related complex disorders and will
discuss the potential impact of these findings on public
coronary heart disease
genome-wide association study
body mass index
food frequency questionnaires
the homeostasis model
assessment-estimated insulin resistance index
single nucleotide polymorphismSNP
The prevalence of obesity and related complex diseases
such as type 2 diabetes and cardiovascular disease has been
rapidly increasing in the United States and worldwide, as
people gain access to the trappings of sedentary lifestyle and
obesogenic, Western-pattern diet [1, 2]. It also has been
noted considerable diversity exists in response to the diet
and lifestyle transition at individual levels, suggesting that
genetic makeup may also play a role in shaping the epidem-
ic pattern of these disorders. With recent revolutionary
advances in high-throughput genotyping technology, a large
body of genome-wide association studies (GWAS) emerged
and located hundreds of genomic variations related to risk of
obesity, type 2 diabetes, and cardiovascular disease in the past
few years [3••, 4, 5••, 6, 7]. In addition, recently emerging
evidence from gene-diet interaction analyses in large-scale
observational studies and randomized intervention trials
favors the idea that the epidemic of obesity and related com-
plex diseases may be not purely through lifestyle/diet or
L. Qi (*)
Department of Nutrition, Harvard School of Public Health,
665 Huntington Ave,
Boston, MA 02115, USA
Channing Division of Network Medicine,
Department of Medicine,
Brigham and Women’s Hospital and Harvard Medical School,
Boston, MA, USA
Curr Nutr Rep (2012) 1:222–227
genetics, but interactions of these factors [3••, 4]. However,
reproducible data supporting gene-diet interaction are still
sparse; and little of the knowledge about gene-diet interaction
has been applied in public health practice.
The aim of the present article is to review recent literature
about obesogenic diet behavior and studies of interaction
between genetic variation and diet in relation to obesity and
related complex diseases including type 2 diabetes and
cardiovascular disease. The review will particularly address
the public health implication of the findings on gene-diet
interaction, and discuss about the challenges lie in the stud-
ies and future directions.
Obesogenic Diet Behavior and Genetic Susceptibility
The transition from traditional, more active lifestyle and
nutritionally dense tradition diet to an ‘obesogenic’ lifestyle
featured by Western-pattern diet behavior and reduced phys-
ical activity in the past 30 years is believed a major driving
force accounting for the epidemic of obesity and related
diseases such as type 2 diabetes and cardiovascular disease
[5••, 6]. A Western-pattern diet could be broadly defined by
high intakes of foods characterized by having a high energy
density as a result of a higher content of fat and a lower
content of starchy and fiber-rich food, together with a high
intake of sugar sweetened beverages; as well as low intakes
of whole grain products, vegetables and fruits [7, 8]. For
example, soft drinks and juices contain high concentrations
of sugar and little other nutrient benefits. According to
recent survey in the United States, between 1977 and
1996, the proportion of individuals consumption of average
total calories from sugar sweetened beverages more than
doubled, from 70 kcal to 189 kcal per day . In addition,
the fast-food culture is closely coupled to sugar sweetened
beverages. Fast food, defined by the United States Depart-
ment of Agriculture (USDA) as “food purchased in self-
service or carry-out eating places without wait service”,
is generally energy-dense, and tends to be high in fat,
saturated fat, and glycemic index, yet poor in fiber. In
the United States, consumption of fast food doubled
from 20 % in the 1970s to 40 % by 1995 [10, 11].
Increased intake of sugar sweetened beverages and fast
food not only add more energy, but may also corrupt
neural functions of brain systems involved in nutrient
sensing and regulation of energy balance ; which
may jointly drive the development of obesity and relat-
ed metabolic disorders . Several decent reviews
have revealed that unhealthy eating habits might pro-
mote weight gain and lead to elevated risk of obesity,
type 2 diabetes, or cardiovascular diseases [13–15].
Classical genetic research such as family and twin studies
have provided strong support for the genetic contribution to
development of obesity, type 2 diabetes and cardiovascular
disease; and the estimated heritability (a proportion of the
phenotypic variance accounted for by genetic factors) for
these complex disorders has shown a high proportion of the
risk (up to ~40–60 %) could be explained by genetic com-
ponents [16–18]. Extensive effort has been made to discover
the genomic loci related to these disorders; and such en-
deavor was recently accelerated by the breakthrough in
genotyping technology and application of large-scale
GWAS, which analyze millions of genetic variations spread-
ing across human genome for their associations with the
disease risk. Since the first wave of GWAS in 2007, the
identified genomic loci for obesity, type 2 diabetes and
cardiovascular disease have scaled up rapidly, reaching 30
to 50 for each disorder [19•, 20•]. While only a few of
genetic variants were found to confer relatively strong effect
on disease risk, such as the fat mass and obesity-associated
gene FTO for obesity [21, 22], the transcription factor 7-like
2 gene TCF7L2 for type 2 diabetes , and chromosome
9p21 for coronary heart disease [20•], most of the identified
genetic variants, however, are related to very moderate
effect and account for very small proportion of disease risk.
For example, the difference in BMI associated with a single
allele of established obesity genetic variant ranges from 0.06
to 0.39 kg/m2; and the variance explained ranges from 0.01
to 0.34 % . Even though, when the accumulative genetic
effects are considered, the difference in BMI between the
extreme groups is not trivia. Moreover, because the current-
ly identified genetic variants are all common in frequency,
their population-attributable risk is considerable.
Rationale for Studying Gene-Diet Interaction
A presentation of gene-diet interactions should involve the
concept of ‘thrifty genotype’ hypothesis, which was first
proposed by the American geneticist James Neel in relation
to an enhanced predisposition to type 2 diabetes and later
extended to obesity [24, 25]. According to the theory, feast-
or-famine conditions during human evolutionary develop-
ment naturally selected for people who could store excess
energy as body fat for later use. Thus, the ability to conserve
calories by storing more fat offers a genetic advantage for
selection of this genotype during periods of food scarcity.
However, when individuals are faced with higher caloric
loads in a modern context, carrying the thrifty genotype
becomes a risk factor for obesity and related metabolic
disorders. As such, genetic variations caused by adaptation
to famine could have important health consequences in
modern society; and obesity and related metabolic disorders
may particularly affect those who are still adapted to former
famine conditions: i.e. who carry thrifty genotype. Although
the ‘thrifty genotype’ hypothesis was met with great skep-
ticism [26, 27], it may partly explain currently epidemic of
obesity and related diseases as consequence of interactions
Curr Nutr Rep (2012) 1:222–227223
between genomic makeup and changed environment. There
was a strong polarization of views that the changed envi-
ronment is the principal cause for recent epidemic of obesity
and related complex diseases. However, it is notable that,
despite decades of plentiful food supplies, ~70 % of the
population in the United States remains not obese, and
~30 % of the population remains lean . It appears people
vary in their inbuilt susceptibility, mainly determined by the
genetic architecture, to the obesogenic effects of environ-
mental factors such as diet.
Gene-Diet Interactions in Observational Studies
Gene–diet interaction occurs when the dietary effect on a
person's health is conditional on specific genotype [3••, 29,
30]. Although the topic of gene-diet interaction has been
extensively discussed, detection of such interaction in hu-
man studies was not fruitful in past decades, when most of
the findings were not reproducible [3••, 30, 31]. The previ-
ous studies are in general limited by relatively small sample
size and cross-sectional design. Although GWAS have dem-
onstrated the validity of studies with cross-sectional design
in identification of disease-predisposing variants, which are
less likely correlated with the potential confounders and free
of reverse causation, inherent bias of cross-sectional analy-
sis become paramount in testing gene-diet interaction. In
addition, lack of replication is another serious flaw in these
studies. An epidemiologic framework for evaluating gene-
diet interaction has yet to be well established. Even though,
several recent large-scale studies with prospective design
and replication have emerged to shed light on the potential
ways to plug gap in this fast-moving area.
A recent study [32••] tested interactions between CVD-
associated genetic variants on chromosome 9p21 and die-
tary patterns in two study samples, including 8,114 individ-
uals (3,820 MI cases) from the global INTERHEART study
and 19,129 individuals (1,014 incident cases of CVD) from
the prospective FINRISK study. It was found that a prudent
diet score (high in raw vegetables, fruits, green leafy vege-
tables, nuts, desserts, and dairy products) significantly in-
teract with 9p21 variants. The genetic effects appeared
strongest among those with the lowest prudent diet score
(odd ratio [OR]01.32, and 95 % confidence interval 1.18–
1.48). The findings were roughly replicated in FINRISK
study, in which stronger genetic effects on CVD were ob-
served in individuals with low intakes of vegetables and
fruits, which had the highest factor loadings for the prudent
diet score. In our recent analysis, we assessed interactions
between sugar sweetened beverage intake and obesity ge-
netic susceptibility (evaluated on the basis of 32 BMI-
associated loci) in relation to body mass index (BMI) and
obesity risk [33••]. We employed a two-stage design con-
sisting of three prospective cohorts – the Nurses’ Health
Study (NHS) and Health Professional Follow-up Study
(HPFS) in the discovery stage; and the Women Genome
Health Study (WGHS) in the replication stage. We observed
directionally consistent interaction between genetic suscep-
tibility and sugar sweetened beverage in NHS and HPFS. In
the combined samples of these cohorts, the increases in BMI
(kg/m2) per 10 risk alleles were 1.00 for sugar sweetened
beverage intake of <1 serving/month, 1.03 for 1–4 servings/
month, 1.39 for 2–6 servings/week, and 1.77 for ≥1 serv-
ings/day (P for interaction<0.001). The findings were suc-
cessfully replicated in the WGHS, in which per 10 risk
alleles were associated across the 4 categories of sugar
sweetened beverage intake with 1.39, 1.64, 1.90 and
2.53 kg/m2higher BMI (P for interaction00.001). Taken
together, these data provide reproducible evidence showing
that interplay between disease-contributing genetic variants
and diet may render certain individuals susceptible complex
Gene-Diet Interactions in Diet Intervention Trials
In observational studies, errors in dietary assessment may
seriously limit the study power. This is particularly damag-
ing when the size of gene-diet interaction is modest.
Weighed diet records and multiple 24-h dietary recalls can
assess dietary intake with high accuracy. However, these
methods are usually not realistic in large population studies
due to heavy respondent burden and poor compliance; and
the most-widely used method for assessing long-term intake
in epidemiological studies is food frequency questionnaire
(FFQ) . However, erroneous self-reporting using FFQ
lowers the accuracy of the information and add huge amount
of noise in analysis of gene-diet interaction. In addition,
repeated dietary assessments may better capture long-term
variance in diet intakes. However, such data are not avail-
able in the majority of existing cohorts. As an alternative
approach, randomized intervention trials may offer an alter-
native setting for testing gene-diet interaction in longitudinal
manner. In a randomized intervention trial, dietary factors
are usually precisely defined and interventions are pre-
scribed. In addition, randomization procedure minimizes
the potential confounding effects that may seriously bias
gene-diet interactions. A unique strength for gene-diet inter-
action studies in diet intervention trials is that, they may
provide more direct evidence to instruct genetic-targeted
diet modifications in future public health practice. However,
most of existing diet intervention trials are relative small in
size, the power for detection of moderate gene-diet interac-
tions would be a major concern.
The Preventing Overweight Using Novel Dietary Strate-
gies (Pounds Lost) trial is a clinical trial including in total of
811 (BMI≥25 kg/m2) and obese (BMI≥30 kg/m2) adult
men and women who were randomly assigned to 1 of 4
224 Curr Nutr Rep (2012) 1:222–227
weight-loss diets varying in macronutrient contents (dietary
fat, protein and carbohydrates) for 2 years . Participants
were 30 to 70 years of age. At 6 months, participants assigned
their initial weight. The participants began to regain weight
after 12 months. By 2 years, weigh loss remained similar in
those who were assigned to diets with different components of
protein, fat, and carbohydrates (low vs high). We recently
tested hypothesis-driven gene-diet interactions in the Pounds
Lost trial. In one analysis [36•], we found significant interac-
tion between the insulin receptor substrate 1 gene IRS1 SNP
rs2943641 and carbohydrate intake in relation to changes in
insulin, HOMA-IR, and weight loss. In another analysis, we
observed significant modificationeffects forintervention vary-
body total percentage of fat mass, total adipose tissue mass,
visceral adipose tissue mass, and superficial adipose tissue
mass associated with FTO SNP rs1558902 [37•]. In addition,
we have reported interactions of diet fat with the gastric inhib-
itory polypeptide receptor gene GIPR genotype in relation to
insulin sensitivity [38•], and with the apolipoprotein A5 gene
APOA5 genotype in relation to lipid profiles [39•]. These data
clearly demonstrate considerable genetic heterogeneity in a
variety of metabolic parameters in response to diet interven-
tions, andlendsupportto personalized interventionsaccording
effects may be not clinically relevant.
Replication remains a major challenge in gene-diet studies
in the settings of clinical trials. The replication mechanisms
adopt by previous genetic analyses in large cohorts or case-
control studies are not applicable to intervention trials, be-
cause it is infeasible to hit upon trials with identical design.
Even though, collaborations among clinical trials addressing
similar diet interventions and outcomes own potential to be
cross-validated. For example, we are now running gene-diet
interaction tests in collaboration with another 2-year diet
intervention trial, the Dietary Intervention Randomized Con-
trolled Trial (DIRECT), which tests three different diets—
low-fat, Mediterranean, or low-carbohydrate—on weight loss
in 322 moderately obese participants . The similar design
of the DIRECT trial and the Pounds Lost trial builds excellent
basis for replicating gene-diet interactions.
Genetic-Targeted Public Health Practice
While waiting for additional evidence for gene-diet interac-
tions, it is time to consider an emerging important query:
How the findings of gene-diet interactions could be trans-
lated to public health practice? Obesity, type 2 diabetes, and
cardiovascular disease have been shown to be preventable
by changing lifestyles and/or diet habits [35, 41]. Because
the gene pool of a certain population has been relatively
constant for many generations, modifications of dietary
habits and lifestyles will remain a mainstream approach to
prevent obesity and related diseases in public health prac-
tice. Genetic variation is not only important in determining
an individual's susceptibility to diseases but also can influ-
ence the response to the diet modifications. The novel
knowledge of gene-diet interaction will provide a strong
scientific rationale for tailoring diet/lifestyle modifications
to a personalized manner, which is different from the tradi-
tional one-size-fits-all approach [42, 43]. Data collected for
gene-diet interactions would facilitate public health profes-
sionals to identify population subgroups with significantly
different responses to diet, and the greatest hope in this
context is the development of more efficient genetic-
targeted guideline of healthy diet for specific subpopula-
tions. In line with this idea, the National Human Genome
Research Institute recommends pursuing “genomic informa-
tion to improve behavior change interventions” as part of its
strategic vision for genomics . As high-throughput gen-
otyping and genome sequencing approaches are becoming
cheaper, to provide genetic information to individuals on
request will become feasible and grow to be a fertile ground
for health-related services. Notably, commercial activity has
been ahead of public health practice. The past few years
have seen a steady increase in the number of companies that
offer direct-to-consumer (DTC) genetic testing services
. It is still under tense debate whether individual gene
testing would be provided by a clinical setting or by com-
panies; and caution must be paid when interpreting results
of such tests and instructing combination of the genetic
information with an appropriate dietary regimen. In any
cases, discoveries of gene-diet interactions need to be
followed-up with functional and prospective validation be-
fore they can be applied to public health practice; and
involvement of geneticists, nutritionists, and other health-
care professionals is essential.
To reduce levels of obesity and related complex dis-
eases, interventions aimed at dietary modifications will not
be successful on their own. Supporting action on the
environment also is required at population levels. Our
obesogenic environment provides increased opportunities
for obtaining low-cost, energy-dense foods and sugared
drinks. For example, as of 2002, there were more than
170,000 fast food restaurants and three million soft drink
vending machines in the United States alone . Such an
obesogenic environment has considerably changed
people’s eating patterns. Other environmental factors, such
as physical, social, cultural, and economical factors, also
may affect dietary behavior . In addition, modern
sedentary activities also promote overconsumption of un-
healthy food. This is particularly the case with television
watching and short sleeping [48–50]. Future genetic-
targeted public health practice would take these high-
level factors into consideration as well.
Curr Nutr Rep (2012) 1:222–227225
Unhealthy diet is a key risk factor for obesity and related
complex diseases, such as type 2 diabetes and cardiovascu-
lar disease. In the past few years, genetic research has made
great strides in identification of genetic factors that contrib-
ute to these disorders. It is widely acknowledged that com-
plex diseases probably arise through a web of interplays
between genetic and environmental factors, including diet.
However, there is remarkably little evidence of gene-diet
interaction from human studies. Recent results from large-
scale studies highlight that dietary patterns or consumption
of sugar-sweetened beverages may modify the genetic pre-
disposition to cardiovascular risk or obesity. More well-
designed studies on gene-diet interactions are underway.
The advances in the field have raised a fundamental
question about how to incorporate the novel knowledge
about gene-diet interactions into genetic-targeted public
health practice. Advance in high-throughput genotyping
technology is facilitating offer of direct-to-consumer genetic
testing services, and raised great hope and expectations that
genetic testing will pave the way to personalized prevention.
In the light of such a trend, debates about how to establish
preventive genomics-based genetic testing in a medically
and socially responsible way have just begun. In addition,
curbing the epidemics of obesity and related disorders calls
for not only changes in diet habits but also changes in
policy, physical and social environment, as well as life-
styles. In the following years, public health practice will
not be able to ignore the impact of genetics and gene-diet
interactions, although it is still a long journey to better
appreciate their relevance to the practice of preventive
approaches for delaying onset of diseases, diminishing their
severity, and optimizing human health.
Health grants DK091718 and HL071981, American Heart Association
Scientist Development Award, United States – Israel Binational Sci-
ence Foundation (Grant 2011036), and the Boston Obesity Nutrition
Research Center (DK46200).
L. Qi is supported by National Institutes of
serving as a consultant and from Kellogg for lectures, including service
on speakers’ bureaus.
L. Qi has received compensation from GenoVive for
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