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.

Early lifecycle UV-exposure calibrates adult vitamin D metabolism: Evidence for a developmentally originated vitamin D homeostat that may alter related adult phenotypes.

OBJECTIVES: Within the Developmental Origins of Adult Disease (DOHaD) model, early life environmental exposures can confer a long-term legacy on human health. This mechanism may be adaptive or maladaptive depending on lifestyle circumstances. This article examines the role of first trimester UV-exposure on late-life vitamin D levels, and potentially related adaptive and maladaptive phenotypes (height and osteoporosis respectively). METHODS: Six hundred and forty nine subjects were examined for vitamin D2 and D3 (HPLC) and height (stadiometer). Osteoporosis was assessed with an extensive medical history questionnaire. RESULTS: Solar irradiance over the first 90 days postconception correlated positively with late-life vitamin D3 (R2 = .0140; P = .0082; ß = .1075), but not vitamin D2 levels. It also correlated positively with female adult height (R2 = .170; P = .0103; ß = .1291) and negatively with the occurrence of female osteoporosis (P = .0495). All data were adjusted for age and gender as appropriate (unadjusted data also provided). From a contemporary perspective, vitamin D levels varied significantly according to season of blood sampling as might be predicted (P = .0009). CONCLUSIONS: Increased solar irradiance/UV exposure during the first trimester of pregnancy calibrates adult vitamin D metabolism, which is an important hormone in maintaining calcium balance. This may explain how very early lifecycle UV exposure can influence skeletal development (adult height) and modify risk for the skeletal degenerative disorder osteoporosis. The data demonstrate humans are tuned to the world (exposome) in ways we have not yet fully considered, and which are entrained at the earliest phase of the lifecycle.

Vitamin D and folate: A reciprocal environmental association based on seasonality and genetic disposition.

OBJECTIVES: The purpose of this study was (1) to elucidate any reciprocal seasonal relationship that might exist between red cell folate (RCF) and serum vitamin D3 Levels; (2) to explore whether folate-related gene variants that influence/alter DNA-thymidylate and methyl group biosynthesis modify any associations detected in objective 1; and (3) to consider whether these processes might influence reproductive success consistent with the "folate-vitamin D-UV hypothesis of skin pigmentation" evolutionary model. METHODS: A large (n = 649) Australian cross-sectional study population was examined. Polymerase chain reaction (PCR)/Restriction fragment length polymorphism (RFLP) analysis was used to genotype C677T-MTHFR, C1420T-SHMT, T401C-MTHFD and 2R > 3R-TS. RCF was measured by chemiluminescent immunoassay and vitamin D2 and D3 by HPLC. RESULTS: RCF and photosynthesized vitamin D3 , but not RCF and dietary vitamin D2 , exhibit a significant reciprocal association in spring and summer. Three folate genes (C677T-MTHFR, C1420T-SHMT, and 2R > 3R-TS) strengthen this effect in spring, and another (T401C-MTHFD) in summer. Effects are seasonal, and do not occur over the whole year. CONCLUSIONS: Findings are consistent with what might be required for the "folate-vitamin D-UV hypothesis of skin pigmentation" model. It suggests genetic influence in provision of one-carbon units by 5,10-methylene-H4 folate, may be an important factor in what appears to be a clear seasonal relationship between vitamin D3 and folate status.

UV-associated decline in systemic folate: implications for human nutrigenetics, health, and evolutionary processes.

OBJECTIVES: The purpose of this study was to examine whether UV exposure alters folate status according to C677T-MTHFR genotype, and to consider the relevance of this to human health and the evolutionary model of skin pigmentation. METHODS: Total Ozone Mapping Spectrometer (TOMS) satellite data were used to examine surface UV-irradiance, as a marker of UV exposure, in a large (n = 649) Australian cross-sectional study population. PCR/RFLP analysis was used to genotype C677T-MTHFR. RESULTS: Overall, cumulative UV-irradiance (42 and 120 days pre-clinic) was significantly negatively related to red cell folate (RCF) levels. When the cohort was stratified by MTHFR-C677T genotype, the relationship between UV-irradiance (42 days pre-clinic) and RCF remained significant only in the cohorts containing carriers of the T allele. Statistically significant z-score statistics and interaction terms from genotype and UV-irradiance (p-interaction) demonstrated that genotype did modify the effect of UV-irradiance on RCF, with the largest effect of UV being demonstrated in the 677TT-MTHFR subjects. CONCLUSIONS: Data provide strong evidence that surface UV-irradiance reduces long-term systemic folate levels, and that this is influenced by the C677T-MTHFR gene variant. We speculate this effect may be due to 677TT-MTHFR individuals containing more 5,10CH2 -H4 PteGlu, and that this folate form may be particularly UV labile. Since UV-irradiance lowers RCF in an MTHFR genotype-specific way, there are likely implications for human health and the evolution of skin pigmentation.

VDR gene methylation as a molecular adaption to light exposure: Historic, recent and genetic influences.

OBJECTIVES: The vitamin D receptor (VDR) is a member of the nuclear receptor family of transcription factors. We examined whether degree of VDR gene methylation acts as a molecular adaptation to light exposure. We explored this in the context of photoperiod at conception, recent UV irradiance at 305 nm, and gene-latitude effects. METHODS: Eighty subjects were examined for VDR gene-CpG island methylation density. VDR gene variants were also examined by PCR-RFLP. RESULTS: Photoperiod at conception was significantly positively related to VDR methylation density, explaining 17% of the variance in methylation (r2 = 0.17; P = .001). Within this model, photoperiod at conception and plasma 25(OH)D independently predicted methylation density at the VDR-CpG island. Recent UV exposure at 305 nm led to a fivefold increase in mean methylation density (P = .02). Again, UV exposure and plasma 25(OH)D independently predicted methylation density at the VDR-CpG island. In the presence of the BsmI mutant allele, methylation density was increased (P = .01), and in the presence of the TaqI or FokI mutant allele, methylation density was decreased (P = .007 and .04 respectively). Multivariate modelling suggests plasma 25(OH)D, photoperiod at conception, recent solar irradiance, and VDR genotype combine as independent predictors of methylation at the VDR-CpG island, explaining 34% of the variance in methylation (R2 = 0.34, P < .0001). CONCLUSIONS: Duration of early-life light exposure and strength of recent irradiance, along with latitudinal genetic factors, influence degree of VDR gene methylation consistent with this epigenetic phenomenon being a molecular adaptation to variation in ambient light exposure. Findings contribute to our understanding of human biology.

Vitamin D Receptor Polymorphisms Relate to Risk of Adenomatous Polyps in a Sex-Specific Manner.

Vitamin D receptor (VDR) gene polymorphisms may influence risk for adenomatous polyps (AP), a benign precursor to colon cancer, via modulation of vitamin D sensitive pathways, including cell proliferation and differentiation. However, results have been mixed and any association remains contentious. Failure to clinically exclude the presence of (AP in control cohorts may contribute to the lack of consensus. Therefore, we assessed the role of the FokI, BsmI, ApaI, and TaqI VDR polymorphisms in modifying risk for AP, adjusting for a range of dietary and lifestyle variables. Blood was collected from colonoscopy patients (n = 258) and VDR polymorphisms assessed by restriction fragment length polymorphism. Dietary habits were estimated from food frequency questionnaires. Odds ratios for AP were calculated by genotype, stratified by sex, and adjusted for age, lifestyle, and dietary factors. FokI was associated with modified risk for AP in males, whereas the BsmI/ApaI/TaqI haplotype was associated with modified risk in females. No interaction was found between VDR variants and vitamin D intake. This study offers novel insight into the potential for VDR genetics to contribute to risk for AP and is the first to demonstrate a sex-specific relationship between these polymorphisms and risk for AP.

The role of vitamins and minerals in modulating the expression of microRNA.

A growing number of studies in recent years have highlighted the importance of molecular nutrition as a potential determinant of health and disease. In particular, the ability of micronutrients to regulate the final expression of gene products via modulation of transcription and translation is now being recognised. Modulation of microRNA (miRNA) by nutrients is one pathway by which nutrition may mediate gene expression. miRNA, a class of non-coding RNA, can directly regulate gene expression post-transcriptionally. In addition, miRNA are able to indirectly influence gene expression potential at the transcriptional level via modulation of the function of components of the epigenetic machinery (DNA methylation and histone modifications). These mechanisms interact to form a complex, bi-directional regulatory circuit modulating gene expression. Disease-specific miRNA profiles have been identified in multiple disease states, including those with known dietary risk factors. Therefore, the role that nutritional components, in particular, vitamins and minerals, play in the modulation of miRNA profiles, and consequently health and disease, is increasingly being investigated, and as such is a timely subject for review. The recently posited potential for viable exogenous miRNA to enter human blood circulation from food sources adds another interesting dimension to the potential for dietary miRNA to contribute to gene modulation.

Vitamin C-related nutrient-nutrient and nutrient-gene interactions that modify folate status.

PURPOSE: Folate-related nutrient-nutrient and nutrient-gene interactions modify disease risk; we therefore examined synergistic relationships between dietary folic acid, vitamin C and variant folate genes with respect to red cell folate status. METHODS: Two hundred and twelve subjects were examined using chemiluminescent immunoassay, PCR and food frequency questionnaire to determine red cell and serum folate, 14 folate gene polymorphisms, dietary folate (natural and synthetic) and vitamin C. RESULTS: When examined independently, synthetic PteGlu correlates best with red cell folate at higher levels of intake (p = 0.0102), while natural 5CH(3)-H(4)-PteGlu(n) correlates best with red cell folate at lower levels of intake (p = 0.0035). However, dietary vitamin C and 5CH(3)-H(4)-PteGlu(n) interact synergistically to correlate with red cell folate at higher levels of intake (p = 0.0005). No interaction between dietary vitamin C and PteGlu was observed. This 'natural' nutrient-nutrient interaction may provide an alternative to synthetic PteGlu supplementation that is now linked to adverse phenomena/health outcomes. On its own, vitamin C also correlates with red cell folate (p = 0.0150) and is strongly influenced by genetic variation in TS, MTHFR and MSR, genes critical for DNA and methionine biosynthesis that underpin erythropoiesis. Similarly, dietary vitamin C and 5CH(3)-H(4)-PteGlu(n) act synergistically to modify red cell folate status according to variation in folate genes: of note, heterozygosity for 2R3R-TS (p = 0.0181), SHMT (p = 0.0046) and all three MTHFR SNPs (p = 0.0023, 0.0015 and 0.0239 for G1793A, C677T and A1298C variants, respectively) promote a significant association with red cell folate. Again, all these genes are critical for nucleic acid biosynthesis. Folate variants with the strongest independent effect on folate status were C677T-MTHFR (p = 0.0004) and G1793A-MTHFR (p = 0.0173). CONCLUSIONS: 5CH(3)-H(4)-PteGlu(n) assimilation and variant folate gene expression products may be critically dependent on dietary vitamin C.

Photoperiod at conception predicts C677T-MTHFR genotype: A novel gene-environment interaction.

Data is presented, which suggest that the day length a woman experiences during the periconceptional period predicts the C677T-MTHFR genotype of her child. Logistic regression analysis involving 375 neonates born in the same geographical location within a three year period demonstrated that photoperiod (minutes) at conception predicts both genotype (P = 0.0139) and mutant allele carriage (P = 0.0161); the trend clearly showing that the 677T-MTHFR allele frequency increases as photoperiod increases. We propose a number of explanations, including a hypothesis in which a long photoperiod around conception decreases maternal systemic folate because of UVA induced dermal oxidative degradation of 5-methyl-H(4)folate, leading to a lower cellular 5,10-methylene-H(4)folate status. In this scenario, 5,10-methylene-H(4)folate would be more efficiently used for dTMP and DNA synthesis by 677T-MTHFR embryos than wildtype embryos giving the 677T-MTHFR embryos increased viability, and hence increasing mutant T-allele frequency. Alternate hypotheses include: increased seasonal availability of folate rich foods that genetically buffer any negative effect of 677T-MTHFR in embryos; seasonal oxidative stress lowering embryo-toxic homocysteine; an undefined hormonal effect of photoperiod on the neuroendocrine axis, which mediates genotype/embryo selection. The effect of photoperiod on genotype seems clear, but the speculative molecular mechanism underpinning the effect needs careful examination.

Independent and Interactive Influences of Environmental UVR, Vitamin D Levels, and Folate Variant MTHFD1-rs2236225 on Homocysteine Levels.

Elevated homocysteine (Hcy) levels are a risk factor for vascular diseases. Recently, increases in ultraviolet radiation (UVR) have been linked to decreased Hcy levels. This relationship may be mediated by the status of UVR-responsive vitamins, vitamin D and folate, and/or genetic variants influencing their levels; however, this has yet to be examined. Therefore, the independent and interactive influences of environmental UVR, vitamin D and folate levels and related genetic variants on Hcy levels were examined in an elderly Australian cohort (n = 619). Red blood cell folate, 25-hydroxyvitamin D (25(OH)D), and plasma Hcy levels were determined, and genotyping for 21 folate and vitamin D-related variants was performed. Erythemal dose rate accumulated over six-weeks (6W-EDR) and four-months (4M-EDR) prior to clinics were calculated as a measure of environmental UVR. Multivariate analyses found interactions between 6W-EDR and 25(OH)D levels (pinteraction = 0.002), and 4M-EDR and MTHFD1-rs2236225 (pinteraction = 0.006) in predicting Hcy levels. The association between 6W-EDR and Hcy levels was found only in subjects within lower 25(OH)D quartiles (<33.26 ng/mL), with the association between 4M-EDR and Hcy occurring only in subjects carrying the MTHFD1-rs2236225 variant. 4M-EDR, 6W-EDR, and MTHFD1-rs2236225 were also independent predictors of Hcy. Findings highlight nutrient-environment and gene-environment interactions that could influence the risk of Hcy-related outcomes.

The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification.

The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased risk of colon cancer although it may increase the risk of breast cancer. This polymorphism is associated with changes in intracellular folate cofactors, which may affect DNA methylation and synthesis via altered one-carbon transfer reactions. We investigated the effect of this mutation on DNA methylation and uracil misincorporation and its interaction with exogenous folate in further modulating these biomarkers of one-carbon transfer reactions in an in vitro model of the MTHFR 677T mutation in HCT116 colon and MDA-MB-435 breast adenocarcinoma cells. In HCT116 cells, the MTHFR 677T mutation was associated with significantly increased genomic DNA methylation when folate supply was adequate or high; however, in the setting of folate insufficiency, this mutation was associated with significantly decreased genomic DNA methylation. In contrast, in MDA-MB-435 cells, the MTHFR 677T mutation was associated with significantly decreased genomic DNA methylation when folate supply was adequate or high and with no effect when folate supply was low. The MTHFR 677T mutation was associated with a nonsignificant trend toward decreased and increased uracil misincorporation in HCT116 and MDA-MB-435 cells, respectively. Our data demonstrate for the first time a functional consequence of changes in intracellular folate cofactors resulting from the MTHFR 677T mutation in cells derived from the target organs of interest, thus providing a plausible cellular mechanism that may partly explain the site-specific modification of colon and breast cancer risks associated with the MTHFR C677T mutation.

Folic acid fortification: a double-edged sword.

PURPOSE OF REVIEW: To examine the impact of folic acid fortification, including its use as a functional food component, on human health. RECENT FINDINGS: There is a consensus view that folic acid supplementation has numerous health benefits, many of which are significant in their impact. However, emerging evidence suggests that increased population exposure to folic acid may also have a negative impact with respect to certain developmental and degenerative disorders. As examples, presently much attention is focused on the role of folic acid fortification augmenting colon cancer risk, whereas earlier in the life cycle, the vitamin may additionally influence insulin resistance. Without question, conditions that are influenced by folic acid are both diverse and many - from concerns relating to cognitive decline, breast cancer and vascular disease through to preconceptional issues where maternal folate levels might conceivably alter the phenotype of offspring via epimutations. SUMMARY: The highly complex and critical biological importance of folic acid-related molecular nutrition makes it a difficult micronutrient to deploy as a simple intervention at a population level - it has far too many biochemical spheres of influence to predict effects in a generalized way. Additionally, several gene variants and other nutrients are interactive factors. It is, therefore, hardly surprising that the scientific community does not have a true consensus view on whether mandatory fortification is appropriate as a population measure. This latter point not withstanding, any ultimate decisions on fortification should be well rooted in scientific fact rather than political expediency.

Maternal undernutrition programmes atherosclerosis in the ApoE*3-Leiden mouse.

Poor quality of nutrition during fetal development is associated with adverse health outcomes in adult life. Epidemiological studies suggest that markers of fetal undernutrition are predictive of risk of the metabolic syndrome and CHD. Here we show that feeding a low-protein diet during pregnancy programmed the development of atherosclerosis in ApoE*3-Leiden mice. ApoE*3-Leiden mice carry a mutation of human ApoE*3 rendering them prone to atherosclerosis when fed a diet rich in cholesterol. It was noted that fetal exposure to protein restriction led to a greater degree of dyslipidaemia in mice when fed an atherogenic diet, with low-protein-exposed ApoE*3 mice having elevated total plasma cholesterol (34 % higher; P < 0.001) and TAG (39 % higher; P < 0.001) relative to offspring exposed to a control diet in utero. The low-protein group developed more severe atherosclerotic lesions within the aortic arch (2.61-fold greater lesion area; P < 0.001). Analysis of a targeted gene array suggested a potential role for members of the LDL receptor superfamily, along with similar programmed suppression of the mRNA expression of hepatic sterol regulatory element-binding protein-1c. This indicates that disordered lipid metabolism may play a role in the fetal programming of atherosclerosis in this model. Whereas earlier studies have shown early programming of cardiovascular risk factors, these results demonstrate for the first time that the interaction of prenatal undernutrition with a postnatal atherogenic diet increases the extent of atherosclerotic disease.

Photobiology of vitamins.

This review explores contemporary ideas about the relationship between light exposure and vitamin biology. Nutritional biochemistry has long recognized the relationship between vitamins A and D and light exposure, but in recent years other vitamins have also been implicated in photoresponsive biological mechanisms that influence health, well-being, and even evolutionary processes. Interactions between light and vitamins can modify genotype-phenotype relationships across the life cycle, providing a basis for interesting new explanations relevant to wide aspects of human biology. This review examines both well-established and emerging ideas about vitamin photobiology in the context of the following: (1) light responsiveness of vitamin D (photosynthesized in skin), vitamin A (linked to vision), and vitamin B3 (needed to repair genomic damage); (2) vulnerability of folate and vitamins B1, B2, B12, and D to ultraviolet (UV) light (all potentially degraded); (3) protective/filtering actions of carotenoids and vitamins C and E, which act as antioxidants and/or natural sunscreens, against UV light; (4) role of folate, carotenoids, and vitamins A, B3, C, D, and E in UV-related genomic regulation, maintenance, and repair; (5) role of folate and vitamins A, B2, B12, and D in a range of light-signaling and light-transduction pathways; and (6) links between folate and vitamin D and the evolution of UV light-adaptive phenotypes.

A potential sex dimorphism in the relationship between bitter taste and alcohol consumption.

BACKGROUND: Bitterness is an innate aversive taste important in detecting potentially toxic substances, including alcohol. However, bitter compounds exist in many foods and beverages, and can be desirable, such as in beer. TAS2R38 is a well-studied bitter taste receptor with common polymorphisms. Some have reported relationships between TAS2R38 genotypes, bitter taste phenotype and alcohol intake, however results have been mixed. These mixed results may be explained by the varying taste properties of different alcoholic beverages or a sex dimorphism in responses. METHODS: Bitter taste phenotype was assessed using PROP taste test and TAS2R38-P49A genotype was assessed by RFLP-PCR. Alcohol intake was assessed by food frequency questionnaire and classified by beverage type (beer, wine, spirits or mixed drinks). The relationships between bitter taste phenotype and carriage of the P allele of the TAS2R38-A49P gene and alcohol intake were assessed adjusted for and stratified by sex, and the interaction between taste and sex was evaluated. RESULTS: The relationship between alcohol intake and bitter taste phenotype varied by beverage type, with significant results for beer, spirits and mixed drinks, but not wine. When stratified, results varied by sex, and were only significant in males. Significant interactions were found for taster phenotype and sex (total alcohol intake and intake of beer and spirits). Results were similar for carriage of the TAS2R38-P49A P allele. CONCLUSIONS: Sex-specific interactions between bitter taste phenotype, TAS2R38 genotype and alcohol intake may explain variance in previous studies and may have implications for sex-specific disease risk and public health interventions.

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.

Genomic characterization of the chromosomal breakpoints of t(4;14) of multiple myeloma suggests more than one possible aetiological mechanism.

Using FISH-based techniques, rearrangements of the immunoglobulin heavy-chain (IgH) locus at 14q32 have been found in the majority of cases of multiple myeloma (MM). Some of these IgH translocations are recurrent and we have characterized the genomic breakpoints of seven t(4;14) translocations from MM patients, using a combination of vectorette and conventional polymerase chain reaction methods, the aim being to understand the molecular mechanism leading to MM. Conventionally, the chromosome 14q32 breakpoints in these reciprocal translocations are believed to be located in the IgH mu switch (S) region and a further downstream S region with deletion of intervening DNA occurring as a result of aberrant class switch recombination (CSR); this was seen in five of the cases analysed. However, in two patients it was possible to demonstrate that the rearranged hybrid switch region sequence was joined to DNA from chromosome 4p16, suggesting that IgH translocations can occur in B cells that have already undergone legitimate CSR. The complex nature of these rearrangements leads us to speculate that primary IgH translocations may occur at different time points in the development in MM plasma cells, either at the time of physiological CSR or at a later stage, possibly involving a different mechanism.

G80A reduced folate carrier SNP modulates cellular uptake of folate and affords protection against thrombosis via a non homocysteine related mechanism.

Dietary folate is absorbed in the jejunum by the 'Reduced Folate Carrier' binding protein. This protein also sequesters extracellular folate for use by many cells in the body. As several biosynthetic pathways require folate for critical life processes, any change in the properties of this protein could lower folate bioavailability, cellular levels of the vitamin, and thus influence health. Since folate lowers thrombogenic homocysteine, we examined the prevalence of a common genetic polymorphism encoding the Reduced Folate Carrier (G80A RFC) to see if it acts as a risk factor for thrombotic vascular disease via an effect on homocysteine disposition in a cohort of 156 patients. The odds ratio indicates a significant protective effect of the mutant A allele against thrombosis: OR = 0.56(95% CI; 0.34-0.92). chi2; p = 0.022 (Yates corrected chi2; p = 0.031). The polymorphism had no impact on homocysteine, but did increase the level of extracellular to intracellular folate as might be predicted by the biological role of the expressed protein. This, and not homocysteine level, may be what affords protection against thrombosis.

Vitamin D: Beyond Metabolism.

Interest in vitamin D and the VDR gene is increasing as putative roles in human health and evolutionary processes are explored. This review looks beyond the classic biochemistry that links vitamin D to calcium homeostasis; it explores how vitamin D interacts with light in a broader perspective than simple skin photosynthesis. It examines how the vitamin influences circadian rhythm, and how it may have helped drive the evolution of skin pigmentation. To this end, the nutrient-nutrient relationship with folate is also explored. The VDR gene is additionally examined as a factor in the evolutionary selection of skin depigmentation at higher latitudes to allow vitamin D synthesis. Evidence is given to show that VDR polymorphisms exhibit a latitudinal gradient in allele prevalence consistent with such a paradigm. Overall, the review examines new evo-devo ideas that link light-sensitive vitamins to human health/phenotype, both within and across the lifecycle.

Gene-Nutrient Interaction between Folate and Dihydrofolate Reductase in Risk for Adenomatous Polyp Occurrence: A Preliminary Report.

Folate and related gene variants are significant risk factors in the aetiology of colorectal cancer. Dihydrofolate reductase (DHFR) is critical in the metabolism of synthetic folic acid (pteroylmonoglutamatamic, PteGlu) to tetrahydrofolate following absorption. Therefore, the 19bp deletion variant of DHFR may lead to the alteration of folate-related colorectal disease susceptibility. This study examined the association between PteGlu and 19bp del-DHFR, and adenomatous polyp (AP) occurrence, an antecedent of colorectal cancer. A total of 199 subjects (162 controls and 37 AP cases) were analysed to determine dietary intake of total folate, natural methylfolate and synthetic PteGlu, level of erythrocyte folate and plasma homocysteine (tHcy), and genotype of 19bp del-DHFR. Dietary folate intake, erythrocyte folate, tHcy and 19bp del-DHFR variants did not independently predict the occurrence of AP. However, a gene-nutrient interaction was observed when subjects were stratified according to dietary folate intake. In subjects with a folate intake above the median value due to significant dietary PteGlu content, the presence of the 19bp-deletion allele decreased the risk for AP (OR=0.35, 95% CI: 0.13-0.97). However, such association was not evident in individuals with a folate intake below the median value. In conclusion, the finding suggests that folate nutrition and 19bp del-DHFR variation may interact to modify AP risk.