March 2018
On
December 5, 2017, the Food Forum of the National Academies of Sciences,
Engineering, and Medicine hosted a public workshop in Washington, DC,
to review current knowledge in the field of nutrigenomics and to explore
the potential impact of personalized nutrition on health maintenance
and chronic disease prevention. This Proceedings of a Workshop—in Brief
highlights key points made by individual speakers during the workshop
presentations and discussions and is not intended to provide a
comprehensive summary of information shared during the workshop.1
The information summarized here reflects the knowledge and opinions of
individual workshop participants and should not be seen as a consensus
of the workshop participants, the Food Forum, or the National Academies
of Sciences, Engineering, and Medicine.
SETTING THE STAGE
In
her opening presentation, Patsy Brannon of Cornell University explained
how the first two steps of the risk assessment framework are central to
current, population based dietary guidance. First, a health outcome is
identified from a review of the literature and a synthesis of the
evidence and, second, the dose–response relationship between a nutrient,
or diet, and the health outcome is characterized. Using this
population-based approach, Dietary Reference Intakes (DRIs) are based on
distributions of nutrient intake. In the past, Brannon continued to
explain, it has been impossible to ascertain where in one of these
distributions an individual's needs fall. Therefore, it has been
impossible to provide specific nutrition recommendations for
individuals. “That's at the heart of the change of what nutrigenomics
opens up as a possibility,” she said.
The fact that there is a
distribution of responses to nutrient intakes, even in a healthy
population, raised the question for Brannon: Why do people vary? She
discussed how genetic, epigenetic, and nutrient–gene interactions drive
individual variation in nutritional kinetics and dynamics,2
elaborated on the complexity of these interrelationships, and
illustrated how this complexity is reflected in the variety of ways that
different authoritative bodies have defined nutrigenomics. In her
opinion, this complexity will need to be addressed as population-based
nutrition guidance transitions into personalized nutrition guidance (see
).
Complexities
of nutrigenomics, using cardiovascular disease (CVD) phenotypes as the
endpoints. NOTE: GRS = genetic risk score; NGS = next-generation
sequencing; SNP = single nucleotide polymorphism. SOURCE: Presented by
Patsy Brannon on December 5, 2017. (more...)
“Adding
to this complexity,” Brannon continued, “is the reality that consumer
and food behavior is very, very difficult to fully elucidate and
understand.” Health is not the only driving force and is likely not even
the major driving force in food choices. “Taste is often the primary
force,” she said, “and nutrigenomics is not going to change that
reality.”
In closing, Brannon opined that, because of these
complexities, rather than thinking about population-based and
personalized dietary guidance as an either-or situation, the two
approaches will likely need to be integrated.
NUTRIGENOMICS AND CHRONIC DISEASE ENDPOINTS
In
the first session, moderated by Naomi Fukagawa of the U.S. Department
of Agriculture, speakers discussed the interrelationships of diet,
genomics, and health outcomes, with a focus on chronic disease
endpoints.
To begin, José Ordovás of Tufts University discussed
both the genome and epigenome in relation to nutrition and disease risk.
According to Ordovás, the root of personalized therapies is newborn
screening. In the United States, each year, more than 1,000 babies are
born with congenital hypothyroidism (CH), one of several monogenic
diseases that require specific treatments. A cording to Ordovás, the
approximate cost of screening for CH is $20 million, compared to $400
million in benefits (i.e., costs avoided by having treated the disease).
Costs and benefits of such screening aside, he continued, “what we
know” is that the genome influences what therapies we need and how we
respond to pharmacological and diet treatments. As a less extreme
example than CH, he described what scientists have been learning about APOA23
and how earlier research had showed that individuals homozygous for the
less common C allele (CC genotype) ate more food, specifically fatty
foods, and as a result weighed more than individuals with TT and TC
genotypes. Yet, in later work, scientists discovered that under low
saturated fat conditions, genotype no longer mattered and that only when
consuming a high saturated fat diet, which Ordovás described as a diet
that stresses the physiology, do individuals with the CC genotype gain
more weight than individuals with either of the other two genotypes.
“This is a polymorphism that may have a significant impact in terms of
personalized recommendations,” he said. He emphasized that this later
finding has been replicated not only across populations worldwide, but
also across ethnicities.
Although the absolute complexity of the epigenome is smaller than the genome, with its 30 million CpG dinucleotides4
in various states of methylation, compared to the genome's more than
300 million base pairs, Ordovás remarked that it is much more difficult
to study in humans with respect to its importance in nutrition because
of its dynamic nature. Unlike the genome, the epigenome changes over
time and across organs and cell types. Yet, evidence in humans that
nutrition-related epigenetic changes can influence adult-onset chronic
diseases is beginning to emerge. Ordovás described some of what has been
learned about the consequences of fetal starvation during the Dutch
famine of 1944–1945 (the “Dutch Hunger Winter”), including obesity and
neurological disorders later in life and significant differences in the
epigenetic profiles of individuals who experienced fetal starvation
compared to those who did not. He provided additional examples as well,
including cases where both genetics and epigenetics ought to be taken
into consideration when predicting the impact of diet on health.
Otherwise, he said, recommending that everyone increase their intake of
the omega-3 fatty acid or EPA (eicosapentaenoic acid) for example, would
result in a positive effect in some individuals with respect to HDL
cholesterol, but a negative effect in others.
In closing, Ordovás
remarked that the microbiome also plays a role in nutrition and that
personalized nutrition will likely require combining not just an
individual's genomics and epigenomics, but his/her microbiome as well.
“I don't know that we'll ever get to perfect,” he concluded, meaning 100
percent personalized nutrition. However, paraphrasing an old Italian
proverb, he said, “perfection is the enemy of good.” There is enough
known now, in Ordovás's opinion, to begin putting the pieces of the
puzzle together in the right places and to control some of what he
described as the “snake oil” being sold by some commercial ventures.
“Why
can't we understand and cure the common metabolic and degenerative
diseases?” Douglas Wallace of the University of Pennsylvania began his
presentation on mitochondrial genetics and its relationship with disease
risk. He suspected that perhaps the problem is not the effort, given
the trillions of dollars that have been spent trying to understand
chronic disease in humans; rather it is the basic assumptions upon which
the scientific community is studying disease. Rather than focusing on
anatomy and Mendelian (i.e., nuclear) inheritance alone, Wallace
suggested also thinking about bioenergetics and non-Mendelian (i.e.,
mitochondrial) inheritance. He described how nuclear and mitochondrial
DNA have differentiated over evolutionary time, with today's
mitochondrial genome specializing in energy. The flow of energy across
the mitochondrial membrane is, he said, “absolutely critical” to life.
Wallace
explained how the different components of the mitochondrial “wiring
diagram” have co-evolved and how maternal inheritance of mitochondrial
DNA has ensured that these co-evolved components remain tightly coupled.
Through this tight coupling, energy production is more efficient than
it would be otherwise. However, although mitochondrial DNA does not
undergo sexual recombination, mitochondria are constantly replicating
and, as they replicate, mutations accumulate. As these mutations
accumulate, the different tissues in the body become mosaics of
different mitochondrial genotypes, Wallace continued to explain. And as
the number of mutant mitochondrial DNA increases, energy output
declines. Regardless of the type of mitochondrial mutation, when energy
output crosses a minimum energy threshold for that organ, disease
begins.
“Once we begin to think energetically,” Wallace said,
“then all the common diseases have the same etiology: a bioenergetics
defect.” He described results from several studies of mitochondrial
mutations, as well as mitochondrial heteroplasmy (cells with a mixed
population of mutant and normal mitochondria), in relation to a wide
range of disease and behavior phenotypes.
PERSONALIZED NUTRITION IN THE REAL WORLD
Shifting
the focus from research to personalized nutrition in the real world,
Nathan Price of the Institute for Systems Biology presented work under
way at Arivale, a wellness and personal coaching company he co-founded.
But first, he discussed the complexity of the relationship between
nutrition and disease at the molecular level; the many different systems
biology inputs that contribute to this complexity (e.g., genetics,
metabolic function, physical activity); and the estimated 90 percent of a
person's lifetime health that is attributed to genetics, behavior, or
the environment (as opposed to health care). He differentiated between
the health care industry and the wellness industry, the latter having a
mixed reputation, in his opinion, because of the many
non-scientifically-based approaches being applied. Price discussed how
he and a colleague proposed the 100K Wellness Project to increase
credibility in the wellness industry. The goal of scientific wellness,
he explained, is to predict and prevent disease before it happens; the
goal of the 100K Wellness Project is to collect a dense, dynamic dataset
for 100,000 individuals that can be watched over time for early warning
signs of disease.
In the meantime, Price and colleagues have
completed a 9-month feasibility study, the Pioneer 100 Wellness Project,
which involved 108 participants who underwent detailed laboratory tests
at three different times and received personal wellness coaching for
the duration of the study. Data were collected on hundreds of
metabolites and markers and the investigators also provided participants
with wellness coaching. Regarding the coaching, Price referred to other
workshop speakers' emphases on the critical role of behavior change in
personalized nutrition. Over the course of the study, participants
showed improvements in a number of clinical markers, such as a 12
percent improvement in inflammation by 6 months (i.e., inflammation was
reduced). Price noted that participants who have stayed with the
program, through participation in Arivale's scientific wellness program,
have shown continued improvements. In addition to mining the data and
returning new health discoveries back to the study participants, Price
and colleagues have also been studying the nearly 4,000 correlations
detected among the different data types (e.g., associations between
metabolites in the blood and genetic risk scores). “These data types had
never before been measured simultaneously on a population of people,”
he said.
Continuing the focus on the potential for nutrigenomics
in the real world, next, Claudia Morris of Emory University shared her
research on arginine deficiency syndromes, mostly in relation to sickle
cell disease and trauma. She described both as having distinct
nutritional requirements that develop because of metabolic abnormalities
that may benefit from arginine replacement therapy. Arginine, a
conditionally essential amino acid (i.e., it becomes indispensable under
stress or critical illness, but is otherwise non-essential) is an
obligate substrate for nitric oxide (NO) production. NO, in turn, is a
potent vasodilator with multiple functions. Morris stressed that a drop
in an amino acid does not necessarily translate into a clinically
significant deficiency. For a nutritional deficiency to occur, a
biological process that is dependent on that nutrient has to be
compromised, that compromise has to lead to an abnormal physiological
response that is causative of a poor outcome, and those poor outcomes
need to be reversible when the nutrient is replaced. In the case of
pulmonary hypertension in sickle cell disease, Morris demonstrated how
low arginine bioavailability meets these criteria: it leads to
endothelial dysfunction (i.e., the compromised biological process),
which may lead to pulmonary hypertension (i.e., the abnormal
physiological response), which is associated with increased mortality in
patients with sickle cell disease (i.e., the poor outcome) and may be
reversible with arginine supplementation.
Patients with sickle
cell disease have also been shown to have lowered arginine-to-ornithone
ratios, which, in turn, have been associated with higher risk for
pulmonary hypertension. Morris and colleagues observed decreases in
pulmonary hypertension among sickle cell patients treated with arginine
similar to what has been reported for some of the pulmonary hypertension
medications on the market. She described how arginine deficiency also
has been shown to play a role in other diseases, including
cardiovascular disease. In one study, the arginine-to-ornithone ratio
was more predictive of cardiovascular disease than cholesterol.
Although
the potential benefit of arginine therapy for sickle cell disease, as
well as for trauma, has been demonstrated in mice and humans, most of
these studies are limited by methodological weaknesses, according to
Morris. Additionally there is a paucity of data in children. There are
other therapeutic strategies to consider as well, such as arginine
precursors (e.g., glutamine) and combination therapies that target
multiple mechanisms. Morris concluded by calling for more research,
including the identification of sub-populations that would likely
benefit the most from arginine replacement therapy.
“We have heard
a lot of evidence that has tremendous promise,” David Alpers of the
Washington University School of Medicine in St. Louis began, but said,
“we are just in the early stages of where we can utilize this
information.” Nutrigenomic studies are difficult not only because they
are complex, but also because proving causation from associations is
especially challenging in the field of nutrition. There are many
components in the diet that interact and which, together, cause multiple
metabolic changes in the body. Additionally, except for diseases caused
by single gene defects, it is very difficult to isolate which
components of a disease phenotype are related to nutrition and which to
other factors. In the clinic, Alpers said, “usually by the time we see a
well-developed chronic disease, the effects of the disease itself are
more potent than that of nutritional deficiencies.” Because of these
difficulties, many scientific approaches to studying links between
genomics and nutritional phenotypes have relied on in vitro and in vivo
animal studies. For example, turmeric and garlic extracts and other
nutrient components have been shown to play potent roles in preventing
some cancer changes in cells or in animals. But most of these findings
have not been translated to human data. Alpers further stated that the
human data that do exist, for example, studies on omega-3 fatty acid
supplementation, are not as suggestive as they are in animal studies. In
sum, Alpers expects a long lag before strong human data are available
and nutrigenomics can be commercially implemented.
Meanwhile, he
continued, there are many personalized Internet services currently
available to consumers that provide individuals with information based
on an analysis not of their genomes, but of their dietary patterns. Many
of these services are mobile phone based, which Alpers predicts will
become a potent method for modifying behavior when nutrigenomics does
become commercially implemented. Also available are personalized
programs based on phenotypic data, for example, wrist-watch
accelerometers that monitor and deliver physical activity information.
Alpers acknowledged that these programs work in terms of the immediate
feedback they provide, but reiterated that what is missing is whether
the information provided, if used by the recipient, will actually change
a disease phenotype. Finally, in fact, there are some personalized
nutrition services already available that rely on genomic data; however,
most of the information comes from observational studies linking single
nucleotide polymorphisms (SNPs) to dietary patterns. “That's not really
enough in itself,” Alpers said, as those links have yet to be
translated into changes in disease phenotypes.
In closing, Alpers
remarked, “the concept of genomics for personalized nutrition is a
sound one, and many of the strategies are in place. What is missing is
the data that translate those strategies or the preclinical work to
actual clinical outcomes.”
The final speaker of this session,
Ahmed El-Sohemy of the University of Toronto and founder of
Nutrigenomix, Inc., remarked that, while he agreed with many of Alpers's
comments, he would also be presenting evidence to show that many of
Alpers' criticisms “are actually not true.” He acknowledged, however,
that the field is not without controversy, as what is being offered is
quite varied and some of what is being offered is not rooted in robust
scientific evidence. But where there have been enough observational
studies linking nutritional factors with health outcomes, the responses
are variable. El-Sohemy emphasized the importance of understanding
genetic differences that help to explain these variable responses.
Without this understanding, he argued, “outlier” individuals could
actually be harmed by advice that benefits others. As an example, he
described coffee intake and how the risk of myocardial infarction
associated with coffee intake depends on whether one is a fast
metabolizer or a slow metabolizer based on the CYP1A2 genotype. The CYP1A2
genotype has also been shown to modify the association between coffee
intake and several other health outcomes, El-Sohemy continued to
describe. While questions remain about the economic and social aspects
of genetic testing, including the cost and accessibility of such
testing, in terms of the science, referring to the CYP1A2
studies, El-Sohemy said, “I think these are some really good examples of
proof of concept at how an individual SNP, a single SNP, can modify the
association between a dietary component and a variety of different
health outcomes.”
El-Sohemy went on to describe some of the ways
that nutrigenomics is portrayed in the media and what he perceived as
problems in how information is communicated. He provided an example of
an article where a pediatrician who was asked during an interview about
the variability of diet response and he was unaware of the evidence that
suggests that people respond differently to different diets. Per
El-Sohemy, not only does such evidence exist, but it is “pretty robust”
and has been replicated. He was referring to evidence showing that a
person's response (i.e., change in fat mass) to a low protein versus a
high protein diet depends on an individual's FTO gene variant.
Specifically, people with an AA genotype lost a considerably greater
amount of fat mass on a high protein diet, compared to a low protein
diet. In contrast, individuals with the TT or TA genotypes showed no
difference in loss of fat mass on a low protein versus a high protein
diet. Bringing to mind Brannon's prediction in her opening presentation
that the future likely will bring an integration of population-based and
individualized dietary guidance, as opposed to completely transitioning
into individualized dietary guidance, El-Sohemy asked: How can this
kind of personalized dietary advice (e.g., regarding FTO
genotype) be balanced with public health recommendations for
populations? He described the results of a randomized clinical trial
showing that people who were provided with DNA-based dietary advice had a
greater understanding of the recommendations, compared to people who
did not receive the advice; were motivated to change their eating
habits; and showed greater compliance 1 year later. This finding has
been replicated, according to El-Sohemy, suggesting that providing
people with personal information can be a very useful tool for
motivating them to change their eating habits.
More at link.
