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Exploiting Single Nucleotide Polymorphisms for Extreme Performance

Description:

TECHNOLOGY AREA(S): Human Systems 

OBJECTIVE: To enhance cognitive and physical performance in warfighters by exploiting single nucleotide polymorphisms 

DESCRIPTION: American soldiers are an elite and highly motivated group of individuals. They face severe cognitive and physical loads while in combat and while preparing for combat. The Army prepares soldiers with both physical and cognitive training. Individual soldiers usually also prepare themselves for training and combat by consuming considerable quantities of nutritional supplements, including vitamins and minerals. Standards for vitamins and minerals were developed in the 1940s and have changed little since then. National recommendations vary widely across the developed world, reflecting the paucity of underlying science. Most importantly, national standards were developed to reflect the needs of an average individual and take no account of genetic variation that dramatically influences needs at an individual level. Furthermore, indiscriminate overconsumption to attempt to compensate for this lack of knowledge leads to both health and performance problems. Advances in DNA sequencing technology have revealed a surprising level of genetic variation between individual humans, with any two humans differing by an average of 3 million single nucleotide polymorphisms. While some polymorphisms are neutral, many others have a metabolic and physiological impact. Over 600 human genes encode critical enzymes that require a vitamin or mineral cofactor. Proper function of these 600 enzymes requires appropriate levels of individual vitamin or mineral cofactors; too much or too little leads to loss of function and downstream metabolic, physiological, and phenotypic effects. Single nucleotide polymorphisms within the exons, promoters and splice sites of these genes alter the amount of the vitamin or mineral cofactor that an individual needs. A typical human has functional polymorphisms in two or more of these critical 600 genes, that alter the amount of cofactor needed for proper enzymatic function. Because of advances in sequencing technologies these polymorphisms can now be rapidly identified and biochemically interrogated. The results of these interrogations of individual single nucleotide polymorphisms can be used to tailor intake of supplements to individual genotypes. The impact of this on the Future Army will be enhanced warfighter cognitive and physical performance. With the advent of inexpensive genome and exome sequencing it is becoming unconscionable to not exploit this new capability. The missing link between individual genomic information and improved performance capabilities is the functional interrogation of single nucleotide polymorphisms in key enzymes that require vitamin or mineral cofactors for proper function. The objective of this SBIR is to functionally interrogate single nucleotide polymorphisms in a subset of the 600 genes that encode critical enzymes that require a vitamin or mineral cofactor in order to identify those variants that affect enzymatic function but that can be remediated with vitamin or mineral supplementation in order to enable enhanced cognitive and physical performance and to protect warfighters from performance-degrading factors. Metabolic tuning through dietary cofactors (i.e. vitamins and minerals) is safe, efficacious, inexpensive, and easy to deliver. 

PHASE I: In phase I the investigators will demonstrate that they have the capability to rapidly, efficiently and rigorously screen comprehensive libraries of human polymorphisms in metabolically important genes whose enzymatic activity is cofactor sensitive. They will demonstrate this by determining, for one common human polymorphism, the impact of the polymorphism and the impact of individually tailored nutritional intervention. Furthermore they will quantify the impact of the polymorphism and the intervention on performance in a young healthy population that is similar demographically to U.S. soldiers. For example, recent work by Manousaki et al (AJHG 2017) confirms other reports that single nucleotide polymorphisms in the human CYPR2R1 gene have large effects on 25-hydroxyvitamin D levels, and individuals with just one synonymous coding variant have a significantly increased risk of vitamin D insufficiency (p = 1.26 x 10-12). Other investigators have previously shown that vitamin D deficiency depresses the immune response to infections, and is also associated with increased mortality from cardiovascular disease, diabetes, multiple sclerosis and some cancers. While cancer, diabetes and stroke are outside the scope of this SBIR topic, 5% of male and 20% of female soldiers develop stress fractures during basic training. A successful phase I could be screening soldiers entering basic training for CYPR2R1 polymorphisms that affect vitamin D levels, prescribing dietary (vitamin) interventions for soldiers with CYPR2R1 polymorphisms that suppress serum vitamin D levels, and documenting the return on investment of this intervention on the incidence of stress fractures in basic training. However, a successful phase I could also instead focus on a different gene and its polymorphisms and quantify the effect of those polymorphisms and tailored interventions on soldier performance and readiness. A demographically similar population may be used instead of U.S. soldiers. 

PHASE II: By the end of phase II the investigators will have comprehensively characterized common polymorphisms in at least fifteen cofactor-dependent enzymes with well-established metabolic importance and impact on human performance. They will characterize the impact of these polymorphisms as well as the impact of remediation. They will provide DoD with qualitative and quantitative measures of the biological, physiological, and economic costs and benefits of assaying these polymorphisms in warfighters. The deliverable is the dataset which will provide the content for immediate implementation for genotyping assays to identify individuals with suboptimal enzymatic activity. The performer will have designed a low cost accurate screening test for individual humans and low cost recommendations for individually tailored nutritional recommendations of FDA approved over the counter supplements to optimize performance capabilities. By the end of phase II the results will be ready for large scale commercial production. The analysis should cost less than $100 per soldier and the analysis should be complete within 24 hours of receiving a soldier’s sample. 

PHASE III: The ability to use tailored regimens of over the counter FDA approved vitamins and minerals in conjunction with precise knowledge of the molecular effects of individual genetic polymorphisms will radically advance human performance capabilities. Today many warfighters seek to be physically and mentally better prepared by consuming vast quantities of vitamins, herbs, and other substances, often with no scientific basis whatsoever and almost certainly with no knowledge of their own genetic variance and biochemical needs. This SBIR will change this behavior from anecdote driven to scientifically based. It is anticipated that civilian athletes, scholars, scientists and engineers, as well as any civilian seeking improve physical or cognitive capabilities will embrace the opportunity for informed nutritional intervention in order to safely and economically enhance and preserve cognitive and physical performance capabilities. 

REFERENCES: 

1: Hustad, S., Midttun, O., Schneede, J., Vollset, S.E., Grotmol, T., and Ueland, P.M. The methylenetetrahydrofolate reductase 677C-T polymorphism as a modulate of a B vitamin network with major effects on homocysteine metabolism. 2007. Am J Hum Genet 80(5): 846-55.

2:  Manousaki, D., et al. Low-frequency synonymous coding variation in CYP2R1 has large effects of vitamin D levels and risk of multiple sclerosis. 2017. Am J. Hum Genet 101(2): 227-238.

3:  Roussotte, F.F., Hua, X., Narr, K.L., Small, G.W., Thompson, P.M., Alzheimer’s Disease Neuroimaging Initiative. The C677T variant in MTHFR modulates associates between brain integrity, mood, and cognitive functioning in old age. 2017. Bio Psychiatry Cogn Neurosci Neuroimaging 2(3): 280-288.

4:  Troesch, B., Weber, P., and Mohajeri, M.H. Potential links between impaired one-carbon metabolism due to polymorphisms, inadequate B-vitamin status, and the development of Alzheimer’s disease. 2016. Nutrients 8(12): 803.

KEYWORDS: Genetic, Variation, Polymorphisms, Metabolism, Performance, Health, Cognition, Cognitive, Biochemistry 

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