Concept mapping One-Carbon Metabolism to model future ontologies for nutrient–gene–phenotype interactions

Abstract

Advances in the development of bioinformatic tools continue to improve investigators' ability to interrogate, organize, and derive knowledge from large amounts of heterogeneous information. These tools often require advanced technical skills not possessed by life scientists. User-friendly, low-barrier-to-entry methods of visualizing nutrigenomics information are yet to be developed. We utilized concept mapping software from the Institute for Human and Machine Cognition to create a conceptual model of diet and health-related data that provides a foundation for future nutrigenomics ontologies describing published nutrient-gene/polymorphism-phenotype data. In this model, maps containing phenotype, nutrient, gene product, and genetic polymorphism interactions are visualized as triples of two concepts linked together by a linking phrase. These triples, or ''knowledge propositions,'' contextualize aggregated data and information into easy-to-read knowledge maps. Maps of these triples enable visualization of genes spanning the One-Carbon Metabolism (OCM) pathway, their sequence variants, and multiple literature-mined associations including concepts relevant to nutrition, phenotypes, and health. The concept map development process documents the incongruity of information derived from pathway databases versus literature resources. This conceptual model highlights the importance of incorporating information about genes in upstream pathways that provide substrates, as well as downstream pathways that utilize products of the pathway under investigation, in this case OCM. Other genes and their polymorphisms, such as TCN2 and FUT2, although not directly involved in OCM, potentially alter OCM pathway functionality. These upstream gene products regulate substrates such as B12. Constellations of polymorphisms affecting the functionality of genes along OCM, together with substrate and cofactor availability, may impact resultant phenotypes. These conceptual maps provide a foundational framework for development of nutrient-gene/polymorphism-phenotype ontologies and systems visualization.

Maternal folate, one‐carbon metabolism and pregnancy outcomes

“…TCN2 polymorphism affects not only its expression but ultimately its plasma concentration and thus the availability of vitamin B12 to aid in re-methylation of Hcy (Oussalah et al, 2017). The C > G substitution alters the structure of the TCN2 protein affecting its affinity for vitamin B12, resulting in easier release from the bound TCN2 transporter (Afman, Lievers, van der Put, Trijbels, & Blom, 2002;Joslin, Green, German, & Lange, 2014) (Furness et al, 2013;Furness, Yasin, Dekker, Thompson, & Roberts, 2012). However, we found no direct association between low folate levels and some pregnancy complications.…”

“…TCN2 polymorphism affects not only its expression but ultimately its plasma concentration and thus the availability of vitamin B12 to aid in re‐methylation of Hcy (Oussalah et al, 2017). The C > G substitution alters the structure of the TCN2 protein affecting its affinity for vitamin B12, resulting in easier release from the bound TCN2 transporter (Afman, Lievers, van der Put, Trijbels, & Blom, 2002; Joslin, Green, German, & Lange, 2014) and thus reduced vitamin B12 transport into cells and ultimately higher Hcy levels compared with the CC genotype. This association conflicts with the findings from our study indicating the maternal TCN2 C776G (GG) genotype is associated with reduced risk for sPTB.…”