Actionable Variation in Human Genes to Enhance Metabolic Efficiency
Abstract
Nutritional vitamin deficiencies result in severe disorders such as anemia, cardiovascular defects, neurological malfunction, and atrophy (among others). At the cellular level, many metabolic pathways are compromised by nutritional deficiencies such as: increased DNA damage (folate, B12, niacin deficiency), decreased neuronal connectivity (thiamine, B6 deficiency), redox imbalances which lead to oxidative stress (riboflavin deficiency). Some of these gross phenotypes are due to dietary inadequacies and studies related to this contributed to establishing the Recommended Daily Allowance (RDA), which approximates the amount of each vitamin and mineral needed to prevent loss of health for the average person under an average range of experiences. However, some metabolic imbalance is due to single enzyme deficiencies (as is the case for MTHFR above). When the RDAs were established in the middle of the 20th century it was not possible to describe or incorporate individual genetic variation in the recommendations. From our initial studies, we now know that certain nonsynonymous substitutions in enzymes require significantly higher levels of their vitamin cofactors for normal performance. Hence the RDA is inadequate to the needs of some individuals, especially warfighters and athletes, who are asked to perform at the upper extremes of human capacity. Objectives of the Study: Our first objective is to bring greater value to the growing catalog of human genetic variation by identifying which of these variants result in suboptimum performance of individual enzymes. The second objective is to determine which of the suboptimum variations are amenable to metabolic tuning and which are not. This will be accomplished by leveraging the resources and lessons learned from our previous work with folate metabolism and vitamin B6 utilization. Our goal is to extend those results to a greater number of enzymes amenable to this strategy of functional remediation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 25, 2023
- Accession Number
- AD1229258
Entities
People
- Jasper D. Rine
Organizations
- University of California, Berkeley