Vitomics: A novel paradigm for examining the role of vitamins in human biology.

The conventional view of vitamins reflects a diverse group of small molecules that facilitate critical aspects of metabolism and prevent potentially fatal deficiency syndromes. However, vitamins also contribute to the shaping and maintenance of the human phenome over lifecycle and evolutionary timescales, enabling a degree of phenotypic plasticity that operates to allow adaptive responses that are appropriate to key periods of sensitivity (i.e., epigenetic response during prenatal development within the lifecycle or as an evolved response to environmental challenge over a great many lifecycles). Individually, vitamins are important, but their effect is often based on nutrient-nutrient (vitamin-vitamin), nutrient-gene (vitamin-gene), and gene-gene interactions, and the environmental influence of shifting geophysical cycles, as well as evolving cultural practices. These ideas will be explored within what I refer to as the "adaptive vitome (vitomics)" paradigm.

The evolution of human skin pigmentation: A changing medley of vitamins, genetic variability, and UV radiation during human expansion.

This review examines putative, yet likely critical evolutionary pressures contributing to human skin pigmentation and subsequently, depigmentation phenotypes. To achieve this, it provides a synthesis of ideas that frame contemporary thinking, without limiting the narrative to pigmentation genes alone. It examines how geography and hence the quality and quantity of UV exposure, pigmentation genes, diet-related genes, vitamins, anti-oxidant nutrients, and cultural practices intersect and interact to facilitate the evolution of human skin color. The article has a strong focus on the vitamin D-folate evolutionary model, with updates on the latest biophysical research findings to support this paradigm. This model is examined within a broad canvas that takes human expansion out of Africa and genetic architecture into account. A thorough discourse on the biology of melanization is provided (includes relationship to BH4 and DNA damage repair), with the relevance of this to the UV sensitivity of folate and UV photosynthesis of vitamin D explained in detail, including the relevance of these vitamins to reproductive success. It explores whether we might be able to predict vitamin-related gene polymorphisms that pivot metabolism to the prevailing UVR exposome within the vitamin D-folate evolutionary hypothesis context. This is discussed in terms of a primary adaptive phenotype (pigmentation/depigmentation), a secondary adaptive phenotype (flexible metabolic phenotype based on vitamin-related gene polymorphism profile), and a tertiary adaptive strategy (dietary anti-oxidants to support the secondary adaptive phenotype). Finally, alternative evolutionary models for pigmentation are discussed, as are challenges to future research in this area.

Biophysical evidence to support and extend the vitamin D-folate hypothesis as a paradigm for the evolution of human skin pigmentation.

OBJECTIVE: To test the "vitamin D-folate hypothesis for the evolution of human skin pigmentation." METHODS: Total ozone mapping spectrometer (TOMS) satellite data were used to examine surface UV-irradiance in a large (n = 649) Australian cross-sectional study population. Genetic analysis was used to score vitamin D- and folate-related gene polymorphisms (n = 22), along with two pigmentation gene variants (IRF4-rs12203592/HERC2-rs12913832). Red cell folate and vitamin D3 were measured by immunoassay and HPLC, respectively. RESULTS: Ultraviolet radiation (UVR) and pigmentation genes interact to modify blood vitamin levels; Light skin IRF4-TT genotype has greatest folate loss while light skin HERC2-GG genotype has greatest vitamin D3 synthesis (reflected in both TOMS and seasonal data). UV-wavelength exhibits a dose-response relationship in folate loss within light skin IRF4-TT genotype (305 > 310 > 324 > 380 nm). Significant vitamin D3 photosynthesis only occurs within light skin HERC2-GG genotype, and is maximal at 305 nm. Three dietary antioxidants (vitamins C, E, and ß-carotene) interact with UVR and pigmentation genes preventing oxidative loss of labile reduced folate vitamers, with greatest benefit in light skin IRF4-TT subjects. The putative photosensitiser, riboflavin, did not sensitize red cell folate to UVR and actually afforded protection. Four genes (5xSNPs) influenced blood vitamin levels when stratified by pigmentation genotype; MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A-rs17216707, and VDR-ApaI-rs7975232. Lightest IRF4-TT/darkest HERC2-AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) has 0% occurrence. The opposing, commonest (39%) compound genotype (darkest IRF4-CC/lightest HERC2-GG) permits least folate loss and greatest synthesis of vitamin D3 . CONCLUSION: New biophysical evidence supports the vitamin D-folate hypothesis for evolution of skin pigmentation.

Diet and our genetic legacy in the recent anthropocene: a Darwinian perspective to nutritional health.

Nutrient-gene research tends to focus on human disease, although such interactions are often a by-product of our evolutionary heritage. This review explores health in this context, reframing genetic variation/epigenetic phenomena linked to diet in the framework of our recent evolutionary past. This "Darwinian/evolutionary medicine" approach examines how diet helped us evolve among primates and to adapt (or fail to adapt) our metabolome to specific environmental conditions leading to major diseases of civilization. This review presents updated evidence from a diet-gene perspective, portraying discord that exists with respect to health and our overall nutritional, cultural, and activity patterns. While Darwinian theory goes beyond nutritional considerations, a significant component within this concept does relate to nutrition and the mismatch between genes, modern diet, obesogenic lifestyle, and health outcomes. The review argues that nutritional sciences should expand knowledge on the evolutionary connection between food and disease, assimilating it into clinical training with greater prominence.

Synergy of genes and nutrients: the case of homocysteine.

PURPOSE OF REVIEW: Folic acid is now considered an important functional food component: it lowers potentially toxic homocysteine, prevents birth defects and modulates the risk of several cancers. The complexity of interactions involved, however, means we still have much to learn about the role of folate and homocysteine in both health and disease. RECENT FINDINGS: This review examines the emergence of homocysteine as a public health issue, and places this in context by exploring recent developments in the field of homocysteine as a vasculo, neuro and embryotoxic thiol. The paper also examines the homocysteine nexus in relation to mood disorders and cancer. It ends with an assessment of the issues associated with government-mandated folate fortification. SUMMARY: Folate fortification as a population measure may mask B12 deficiency, affect antiepileptic drug seizure control, and influence the genetic selection of a potentially deleterious genotype, albeit over a number of generations. It is likely that only large studies with a comprehensive battery of endpoints that fully address the complexity of nutrient-gene and gene-gene interactions will be able to answer all the necessary questions fully.

G80A reduced folate carrier SNP influences the absorption and cellular translocation of dietary folate and its association with blood pressure in an elderly population.

The functional consequences of the G80A RFC SNP on the expressed reduced folate carrier protein were evaluated by looking at the relationship between intake of folate, plasma folate and cellular stores of the vitamin. The effect on homocysteine was also examined. Homocysteine is a thiol that is known to be inversely associated with folate, and which is considered to be both thrombo- and athrogenic. At high levels, homocysteine may also interfere with nitric oxide mediated vasodilation, cause oxidative injury to, and proliferation of the vascular endothelium, and alter the elastic properties of the vascular wall, contributing to increased blood pressure. Participants (119; 52 male, 67 female) from a NSW retirement village were assessed. Independent of gender, the assimilation of folate from dietary sources into red cells showed a significant association for GG (r=0.399; p=0.022) and GA (r=0.564; p<0.0001) subjects, but not homozygous recessive (AA) individuals (r=0.223; p=0.236). The same genotype based pattern of significance was shown for the association between dietary folate and plasma folate (GG: r=0.524; p=0.002, GA: r=0.408; p=0.002). No genotype-related pattern of significance was shown for the association between dietary folate and homocysteine. When examined by gender, some differences were apparent; one-way ANOVA showed that genotype influenced diastolic blood pressure in males (p=0.019), while only females showed a significant correlation between dietary folate and blood pressure within specific genotypes (Systolic pressure GA: r=-0.372; p=0.025, carriage of A: r=0.-0.357; p=0.011. Diastolic pressure GA: r=-0.355; p=0.034, carriage of A: r=0.-0.310; p=0.029). The G80A RFC SNP had an impact on the absorption and cellular translocation of dietary folate and its association with blood pressure in an elderly population.

Temporal evaluation of methionine synthase and related metabolites in the MAC15A mouse adenocarcinoma animal model.

Methionine dependence is unique to cancer cells and defined as the inability to grow in a methionine-deprived environment even if supplemented with the metabolic precursor homocysteine. Cobalamin-dependent methionine synthase (MS) catalyses the formation of methionine and tetrahydrofolate from homocysteine and methyltetrahydrofolate, thus linking the methionine and folate pathways. The apparent altered methionine metabolism in methionine-dependent cancer cells suggests a role for MS, although results to date are conflicting. We have analysed key metabolites of the MS-associated transmethylation, transsulphuration and folate pathways of the methionine-dependent MAC15A tumour model as a function of tumour progression over a 10-day period. MS activity increased 2-fold from day 1 to day 10. Cysteine, homocysteine, S-adenosylmethionine and S-adenosylhomocysteine levels in tumour cytosolic fractions decreased as a function of tumour progression. Plasma cysteine levels also decreased, whilst the distribution of folates in erythrocytes was altered, with a maximum increase in methyltetrahydrofolate observed by day 5. The increasing MS activity and decreasing cysteine levels suggest an increasing methionine requirement by the tumour, whilst the induction of enzyme activity indicates that MS is not defective in the methionine-dependent MAC15A tumour. The decrease in tumour S-adenosylmethionine and S-adenosylhomocysteine levels suggests that methionine is required for some function other than cellular methylation, e.g., incorporation into protein. Overall, the results support a theory of methionine conservation in response to tumour growth, where the methionine-dependent MAC15A tumour has a higher than normal methionine requirement.