Nutrigenomics and the Future of Nutrition Proceedings of a Workshop (2018) / Chapter Skim
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3 Personalized Nutrition in the Real World
3 Personalized Nutrition in the Real World
Pages 29-60
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3 Personalized Nutrition in the Real World C ontinuing the session 1 discussion, four presenters discussed applica tions of nutrigenomics "in the real world." This chapter summarizes their presentations and the discussion that followed, with highlights provided in Box 3-1. EXPLORING PERSONAL, DENSE, DYNAMIC DATA CLOUDS AND THE FUTURE OF PERSONALIZED MEDICINE Nathan Price, Institute for Systems Biology, addressed personalized nutrition in the clinical setting.
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(Price) • Research has explained arginine deficiency syndromes, mostly in relation to sickle cell disease, an autosomal recessive inherited disease, but also trauma.
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To help launch this new scientific wellness industry, Price and his colleague, Leroy Hood, announced in 2014 a project called the 100K Wellness Project (Hood and Price, 2014)
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According to Price, there were a number of such cases. Scientific Wellness and Discovery: The Manifestation of Genetic Risk in the Body In addition to mining the data and returning new health disoveries c back to the Pioneer 100 Wellness Project participants, Price and his collaborators have been studying the nearly 4,000 correlations detected among the different types of data collected, including associations between the m icrobiome and metabolites, metabolites and proteins, proteins and lifestyle factors, and metabolites and genetic risk scores.
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Personalized Nutrition in the Real World Price reported that Arivale, which, as noted above, was launched after the successful completion of the Pioneer 100 Wellness Project, and which
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Price believes that "this kind of data can be the foundation for the future of personalized medicine." SICKLE CELL DISEASE: AN ARGININE DEFICIENCY SYNDROME WITH DISTINCTIVE NUTRITIONAL REQUIREMENTS Claudia Morris, Emory University School of Medicine, began by stating, "I am an emergency medicine physician. Most people scratch their
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Arginine is one of these amino acids. Morris explained that although she would be talking mainly about arginine deficiency and its role in sickle cell disease (SCD)
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The prolines play a role in collagen production and deposition, lung fibrosis, and airway remodeling, which Morris identified as the kinds of structural changes seen in pulmonary hypertension and asthma and as common complications in SCD. Arginine is semiessential, Morris continued, because the body has the ability to synthesize it through what is called "the intestinal renal axis." The amino acid L-glutamine is taken up in the diet, then converted into citrulline in the enterocytes of the small intestine, and the citrulline is converted into arginine in the kidney.
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Amino Acid Deficiencies: Sickle Cell Disease as a Model Morris defined SCD as an autosomal recessive inherited disease of the red blood cells. The genetic mutation responsible for SCD, she explained, is a single-point mutation, a substitution of valine for glutamic acid at the six position of the beta unit of the hemoglobin molecule, which causes the hemoglobin molecule to polymerize under stress or deoxygenation.
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Although she said she would go on to focus on pulmonary hypertension in particular, she noted that all of these clinical manifestations are hemolytic subphenotypes of both SCD and low arginine bioavailability. Also within the red blood cells, Morris noted, is lactase dehydrogenase (LDH)
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She noted that not all patients with SCD develop pulmonary hypertension -- only about 10 percent -- but that these results led her to pay more attention to pulmonary hypertension. Morris and her collaborators hypothesized, "if it is low, give it back." So they conducted a small study of arginine replacement and observed a greater than 15 percent decrease in pulmonary systolic pressures, as estimated by Doppler echocardiography (Morris et al., 2003)
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. That is, compared with thalassemia patients who were not at risk for pulmonary hypertension, those who were at risk had low arginine levels, high arginase activity, low arginine-to-ornithine ratios, and low global arginine bioavailability ratios.
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So, she stated, whether hepatic, immune, or from hemolyzed red blood cells during hemolysis or transfusion reactions -- that is, regardless of cellular origin -- the physiological effects and clinical consequences of excess extracellular arginase are similar. Arginine Deficiency and Trauma In addition to conditions involving endothelial dysfunctions such as SCD, Morris continued, are arginine deficiency–related conditions related to T cell dysfunction, trauma being one example.
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, decrease inflammation, help heal lung injury, reverse micro-vascular vaso-occlusion, and decrease mortality. However, what Morris finds interesting about a sickle cell mouse model is that mice do not have arginase in their red blood cells as do humans, yet they have increased arginase activity.
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This occurs in such cases as critical illness, trauma, and hemolysis. • SCD and trauma represent arginine deficiency syndromes, and they pose a distinct nutritional requirement that develops because of their metabolic abnormalities.
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. • The global arginine bioavailability ratio may be a novel biomarker of arginine deficiency, and as such warrants further study.
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He pointed out, however, that in nutrition, particularly in nutrigenomics, where the goal is to prevent disease in relatively healthy people, it is very difficult to narrow an association down to one cause and one effect because there are so many components to the diet and because those components interact, causing multiple metabolic changes to the diet. He added that this complexity extends even to inherited diseases caused by single genetic changes, such as what Morris had discussed.
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, but one without the necessary clinical data at present. Alpers observed further that with human data, some genetic factors that can be detected -- such as human leukocyte antigen (HLA)
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First, many currently available personalized Internet services provide people with information based on an analysis of their dietary patterns, although, according to Alpers, none of these services have anything to do with genomics (Gibney and Walsh, 2013)
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The third and final trend Alpers discussed is personalized nutrition based on genomic data. He observed that at present, most of the information in this area comes from observational studies linking SNPs to dietary patterns.
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It will be difficult but it will occur slowly. We just need to be patient." IS GENETIC TESTING FOR PERSONALIZED NUTRITION READY FOR PRIME TIME?
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He and his collaborators found that in fast metabolizers (CYP1A2 AA) , moderate coffee consumption was associated with a lower risk of myocardial infarction, whereas in slow metabolizers (CYP1A2 AC + CC)
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among fast metabolizers but a strong increased risk among slow metabolizers. In addition to these observational studies, El-Sohemy and his team conducted a randomized controlled intervention trial of endurance performance in athletes.
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panel said coffee can be part of a healthy diet. That might be true for only half of us." According to El-Sohemy, the journalist cited some of the work on fast versus slow metabolizers and wondered why these one-size-fits-all recommendations are still be being issued when the science suggests otherwise (Whoriskey, 2015)
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He pointed out that if a study population comprised only 60 percent fast metabolizers and 40 percent slow metabolizers, the fast metabolizer effect would still predominate. "We need to move away from these kinds of sudies," he argued.
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El-Sohemy and his collaborators decided to put this notion to the test and conduct a randomized controlled trial comparing DNA-based dietary advice with standard recommendations (Nielsen and El-Sohemy, 2012)
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, showing again that while not everyone changes behavior in response to receiving genetic information, providing people with the right kind of information can be a very useful way to get at least some people to change their eating habits. What Do the Skeptics Say?
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Unintended Consequences of Information Provided to Consumers Session moderator Naomi Fukagawa asked the speakers to reflect on the potential unintended consequences of providing consumers with genetic information and on ways to achieve a balance such that dietary recommendations do not end up being punitive -- that is, with people feeling guilty about their dietary choices when they know they have an SNP that increases their risk for a particular health outcome. Douglas Wallace replied that providing genetic information without genetic counseling can be highly problematic.
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"But I think there is still a huge amount of unknown information that we need to really understand this in any causal way," he said. When Morck asked about potential stem cell stimulation in particular, Wallace replied that in fact, some of the most interesting studies have involved introducing mutations into the nuclear-encoded mitochondrial DNA polymerase that increased mitochondrial DNA mutation rates and caused premature aging.
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"So that is an enormously important part of the whole equation," he said, "which usually isn't looked into very often in this particular setting." Behavior and Coaching An audience member asked about the longitudinal follow-up of the coaching that Price had described, wondering whether he and his team had followed participants beyond 6 months to see whether they continued to show improvement either with or without continued coaching. Price replied that many of the Pioneer 100 Wellness Project participants had entered Arivale's commercial program.
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Treating Specific Nutritional Deficiencies In response to a question about when the field will begin treating the type of very specific nutritional deficiencies discussed by Morris -- that is, those with clear causality constructs -- Morris reframed the question as, Are we really replacing a nutritional deficiency, or is arginine, or glutamine, working and functioning as a drug that works for everyone? Her personal experience in patients with SCD was that glutamine supplementation had the greatest effect on those who were the most glutamine deficient and that glutamine deficiency in those patients' red blood cells was correlated strongly with their tricuspid regurgitant jet velocity on Doppler echo cardiography (a measure of pulmonary hypertension risk)
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Morris was involved with a phase II study that showed that administering arginine to these children during a pain crisis had an impact on pain outcomes. Finally, when Morris and her collaborators gave arginine to SCD p atients at baseline, they saw no effect on NO bioavailability.
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