Editorial
See corresponding articles on page 165 and 176.
From nutrigenomics to personalizing diets: are we ready for precision
medicine?
Ruth JF Loos
Department of Environmental Medicine and Public Health, The Charles Bronfman Institute for Personalized Medicine, and The Mindich Child Health and
Development Institute, The Icahn School of Medicine at Mount Sinai, New York City, NY
Since the completion of the human genome project >15 y
ago, a plethora of genetic variants have been identified that
affect people’s susceptibility to disease (1). With a growing
understanding of the genetic basis of diseases and of their risk
factors, the hope and expectation is that genetics will soon
revolutionize health care. Knowing a patient’s genome would
enable us to predict risk of future disease more accurately and
to prescribe personalized treatment and prevention strategies,
as opposed to the traditional “one-size-fits-all” approach. More
than 3 y ago, President Obama launched the Precision Medicine
Initiative as a bold new effort to support researchers, patients, and
health care providers to work together towards the development
of individualized care that takes into account people’s unique
characteristics. Although environment and lifestyle were both
considered when personalizing care, a strong emphasis was
placed on the importance of people’s genomes.
Long before the Precision Medicine Initiative, however,
online genomic companies had already been offering genetic
testing directly-to-consumers (DTC). Their business model is
straightforward: customers send saliva and pay a few hundred
dollars for DNA extraction and for the genotyping of thousands
of genetic variants across their genome. Four to 6 wk later,
they receive a “personalized” report that informs them of
their genetic predispositions—all without involving health care
providers or genetic counselors. The conditions covered by the
DTC companies vary from specific life-changing diseases (e.g.,
Parkinson disease, phenylketonuria, celiac disease) to general
traits of appearance, senses, and behavior (e.g., eye and hair color,
wake-up time, taste preference). A key question, however, is
whether there is sufficient scientific evidence for “personalized”
recommendations.
Several DTC companies focus on diet, nutrition, physical
performance, and fitness. They claim that, based on the
customers’ genotype data, they can design “genetically matched
diets” to help them lose weight more easily, determine what
nutrients their body favors during exercise, and what type of
training is most effective, among other things. However, scientists
have urged caution because, for many of these outcomes, research
has not generated the evidence to support such bold claims and
customers do not have sufficient insight to interpret the reports
(2–4).
Am J Clin Nutr 2019;109:1–2. Printed in USA. © 2019 American Society for Nutrition. All rights reserved.
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Most popular DTC genetic testing companies aim to provide
personalized recommendations on common multifactorial out-
comes (e.g., to lose weight, improve health, nutrition, fitness,
or performance), which are only partially determined by genetic
variation. Lifestyle, environment, sociodemographic factors,
and other nongenetic factors are equally—or sometimes even
more—important. Thus, even the best genetic test will never
predict a multifactorial outcome perfectly, nor will it allow
for a personalized tailoring of treatment strategies. In addition,
the genetic contribution is polygenic, meaning that multiple—
sometimes hundreds or more—genetic variants play a role, all
with small effects. Although detailed information is hard to
find, most DTC companies seem to base their recommendations
on only 1, or just a few, genetic variants, which can result
in incomplete or potentially misleading reports. Furthermore,
a common misconception is that a genetic variant can predict
a disease when it is associated with the disease. However,
many genome-wide association study–identified genetic variants
show highly significant associations with a trait, but explain
only a fraction of the susceptibility to a disease. Therefore,
it is no surprise that the predictive ability of 1, or even 100,
variants combined is very limited, and insufficient to inform
individuals about their future risk of disease. Finally, another
common mistake is made when results from cross-sectional
studies are interpreted as if they were longitudinal. For example,
a genetic variant may be associated with higher body weight
when consuming a high-fat diet (cross-sectional), but this does
not mean that a person carrying that given variant will lose weight
when they reduce their fat intake (longitudinal). Evidence from
longitudinal studies is critical for genetic testing companies, in
particular when their focus is on improving (i.e., changing over
time) their customers’ health, fitness, performance, etc. Although
Supported by National Human Genome Research Institute grant
U01HG007417 and National Institute of Diabetes and Digestive and
Kidney Diseases grants R01DK110113 and R01DK107786.
Address correspondence to RJFL (e-mail: ruth.loos@mssm.edu).
Abbreviations used: DTC, directly-to-consumers; GRS, genetic risk score;
LA, linoleic acid; n–3 FA, omega-3 fatty acid; TG, triglyceride.
First published online January 23, 2019; doi: https://doi.org/10.1093/
ajcn/nqy364.
1
2 Editorial
there are rather few studies that examine the genetic underpinning
of changes in response to dietary intervention, The American
Journal of Clinical Nutrition’s current edition reports on 2 studies
that did exactly that (5, 6).
The first study (5) aimed to develop a genetic risk score (GRS)
to accurately predict whose triglyceride (TG) concentrations
would decrease in response to omega-3 fatty acid (n–3 FA)
supplementation. The 208 participants of the Canadian Fatty Acid
Sensor population were divided into “responders,” whose TG
concentrations decreased after a 6-wk n–3 FA supplementation,
and “non-responders,” whose TG concentrations increased or did
not change. The GRS, representing a person’s innate likelihood
to benefit from n–3 FA supplementation (i.e., to be a “responder”)
or not, explained almost 50% of the variation in TG response
and had an almost perfect discriminatory ability (area under the
receiver operator curve = 0.94). Specifically, knowing a person’s
GRS allows us to determine with great accuracy whether they
will benefit from a 6-wk n–3 FA supplementation or not, at least
among the Fatty Acid Sensor participants. However, when the
same GRS was used in the European FINGEN study, in which
310 participants underwent a 12-wk n–3 FA supplementation,
the findings were remarkably different. The GRS explained only
3.7% of variation in TG response and did not allow identifying
who would benefit from supplementation (area under the receiver
operator curve = 0.64). This shows that a genetic test may work
in one population but not necessarily in another population of
different sex, age, ancestry, diet, baseline values, etc.
The second study (6) examined whether the beneficial effect
of dietary linoleic acid (LA) on health is attenuated by people’s
Fatty Acid Desaturase 1 (FADS1) genotype (rs174550). Cross-
sectionally, in 1337 Finnish men of the Metabolic Syndrome in
Men (METSIM) study, higher plasma LA concentrations were
associated with lower glucose concentrations, but only among
carriers of the rs174550 T-allele, not in CC homozygotes. In
a subsequent 4-wk dietary intervention, the effects of an LA-
enriched diet on a range of metabolic markers were examined
in 26 individuals with the TT genotype and 33 individuals
with the CC genotype. Although changes in lipid mediator and
inflammatory marker concentrations in response to the 4-wk
LA-enriched diet differed by FADS1 genotype, the differences
between genotypes were generally small.
Both studies support the notion that a person’s genotype may
influence their response to changes in diet, but the results do
not provide evidence that genotype data can be used to predict
their response or tailor their diet. For a genetic variant or a
GRS to be useful in precision medicine, their effect sizes would
need to be large and their penetrance high. They would need to
be studied in the context of people’s full genetic background,
not in isolation. Furthermore, they should also be studied in
a longitudinal setting (to study response to intervention) and,
importantly, observations will need to be validated across a
diversity of populations. Given the importance of nongenetic
factors (lifestyle, environment, demographics, etc.) in many of
the health outcomes covered by the DTC companies, precision
medicine that focuses solely on people’s genome is doomed to
fail. Inaccurate “genotype-specific” recommendations may be
misleading and have potentially negative consequences. It is clear
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that to predict disease accurately, or to personalize treatment,
an integrated approach that accounts for people’s unique genetic
and nongenetic characteristics is needed. Research efforts such as
the Accumulating Data to Optimally Predict Obesity Treatment
project, which aims to understand interindividual variability in
response to obesity treatment (7), are needed for other common
disease outcomes. In the meantime, it seems that genotype-based
recommendations from DTC genetic testing companies are likely
as effective as the “one-size-fits-all” recommendations.
The sole author was responsible for all aspects of this manuscript. The
author reports no conflicts of interest.
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