http://nova.newcastle.edu.au/vital/access/services/Feed ${session.getAttribute("locale")} 5 http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:10304 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-H₄folate, leading to a lower cellular 5,10-methylene-H₄folate status. In this scenario, 5,10-methylene-H₄folate 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. 2012-03-13T03:40:02.277Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:6984 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. 2012-01-30T05:03:36.530Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:6997 Background/Aims: 118 elderly participants (65–90 years) were assessed for any relationship between folate, related genes and hypertension. Methods: Six B-vitamin-related SNPs were genotyped in 80 normotensive and 38 hypertensive subjects. Results: Of six polymorphisms (677C>T-MTHFR, 1298A>C-MTHFR, 80G>A-RFC, 2756A>G-MS, 66A>G- MSR, 19bpDHFR and 1561C>T-GCPII), only 677C>T-MTHFR was a significant risk for hypertension: OR 1.89; 95% CI 1.07–3.32 (χ² p = 0.038). Additionally, hypertensive subjects had a significantly lower intake of dietary folate than normotensive individuals (p = 0.0221), although this did not markedly alter blood metabolite levels. Several significant linear associations between dietary folate and related blood metabolites were found in normotensive subjects (p<0.001 for Hcy, red cell and serum folate) and were as predicted on an a priori basis – generally weaker associations existed in hypertensive subjects (p<0.05 for serum folate). This was true for data examined collectively or by genotype. Multiple regression analysis for diastolic or systolic blood pressure showed significant interaction for gender and folate intake (p = 0.014 and 0.019, respectively). In both cases this interaction occurred only in females, with higher folate intake associated with decreased blood pressure. Regressing diastolic blood pressure and 677C>T-MTHFR genotype showed significance (males; p = 0.032) and borderline significance (all subjects). Conclusion: Dietary folate and 677C>T-MTHFR genotype may modify blood pressure. 2012-01-30T05:03:33.112Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:7268 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. 2011-02-21T04:50:06.092Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:1899 Background: Although single nucleotide polymorphisms may be potentially important pharmacogenetic determinants of cancer therapy, functional evidence regarding their relevance is currently lacking. The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with changes in cellular composition of folates. We hypothesized that this polymorphism may modulate the cytotoxic effect of 5-fluorouracil (5FU) and methotrexate (MTX), two commonly used chemotherapeutic agents for colon and breast cancers, because the modes of action of 5FU and MTX are critically dependent on cellular composition of folates. Methods: Human HCT116 colon and MDA-MB-435 breast cancer cells were stably transfected with wild-type or mutant 677T human MTHFR cDNA. MTHFR enzyme activity and thermolability, intracellular folate composition, growth rate, and catalytic thymidylate synthase activity were determined. In vitro chemosensitivity to 5FU and MTX was determined using the sulforhodamine B assay. In vivo chemosensitivity of HCT116 cells to 5FU was determined in nude mice. Results: Compared with cells expressing the wild-type MTHFR, HCT116 and MDA-MB-435 cells expressing the mutant 677T MTHFR had decreased MTHFR activity, MTHFR thermolability, changed intracellular folate distribution, accelerated cellular growth rate, and increased thymidylate synthase activity. The MTHFR 677T mutation increased chemosensitivity of colon and breast cancers to 5FU, but decreased chemosensitivity of breast cancer cells to MTX. In nude mice, xenografts expressing the mutant 677T MTHFR grew faster, but were more sensitive to 5FU, than xenografts expressing the wild-type protein. Conclusions: Our data provide evidence that the MTHFR C677T polymorphism affects the concentration and intracellular distribution of folates and changes the growth and chemosensitivity of colon and breast cancer cells. The MTHFR C677T polymorphism may be a useful pharmacogenetic determinant for providing rational and effective tailored chemotherapy. 2010-04-27T06:58:21.744Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:1465 We live in a health-conscious age — many of us supplement our diet with essential micronutrients through the discretionary use of multivitamin pills or judicious selection of foods that have a health benefit beyond that conferred by the nutrient content alone — the so-called 'functional foods'. Indeed, the citizens of some nations have little choice, with a mandatory fortification policy in place for certain vitamins. But do we ever stop to consider the consequences of an increased exposure to micronutrients? We examine this issue in relation to the B-group vitamin folic acid, and ask whether supplementation with this vitamin could introduce a strong genetic selection pressure — one that has the side effect of increasing the prevalence of some of the most significant, human life-threatening diseases. Are we affecting our genetics — is this a case of human evolution in progress by altering our diet? 2010-04-27T06:52:13.391Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:1162 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. 2010-04-27T06:37:55.651Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:319 The story of folate nutrition is one of the most important in contemporary preventive medicine. In order to provide the ultimate answer as to why your children should eat their greens, and clear their plates - read on. 2010-04-27T05:49:13.876Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:626 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). [chi]2; p = 0.022 (Yates corrected [chi]2; 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. 2010-04-27T05:41:28.774Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:4945 Background/Aims: Folic acid mediates transfer of one-carbon units into methionine and DNA-thymine biosynthesis. Discretionary and mandatory use of synthetic folic acid (SFA) to reduce spina bifida is on the increase. We show that historically, the seasonal cycle of abundance of folate-rich foods may have regulated embryo viability by acting as a selection factor for a significant polymorphism within a gene encoding 5,10-methylenetetrahydrofolate reductase (677CT→MTHFR). Methods: Blood was collected from 150 UK and 118 Australian subjects born prior to discretionary or mandatory use of SFA. 677CT→MTHFR genotype was determined using PCR. Results: The highest prevalence for 677T→MTHFR occurred 9 months post-harvest in UK subjects and was significantly higher at this time of year (July-Sept.) compared with Jan.-Mar. (OR = 2.0, 95% CI 1.03-3.87, p = 0.039) and Oct.-Dec. (OR = 2.2, 95% CI 1.12-4.31, p = 0.021). This effect was not detected in an Australian population subject to more moderate seasonality. Conclusions: Dietary folate may confer significant genetic buffering within populations dependent upon seasonal food sources that modify an individual's vitamin status at the time of conception. 2010-04-27T04:34:47.826Z ]]>