Xiaowei Ng

Preliminary evidence for involvement of the folate gene polymorphism 19bp deletion-DHFR in occurrence of autism.

Folate has long been implicated in both the metabolism of neurotransmitter molecules, and as an agonist with a direct effect upon neuronal tissue. Folates mediate transfer of one-carbon units into major biosynthetic pathways. From a developmental perspective, the most important reactions are de novo methionine and thymine synthesis, critical for DNA expression and elaboration, respectively. Dihydrofolate reductase (DHFR) is the sole enzyme responsible for maintaining the reduced state of the vitamin needed for these two pathways. Here, we report that the 19bp-deletion polymorphism of DHFR acts independently (OR 2.69, 95% CI; 1.00-7.28, p<0.05) and in concert with related folate polymorphisms as a significant risk factor for autism. Possible consequences of this are discussed in the context of the interaction between folate and the glutamatergic nervous system, an area of promising candidate genes for contributing to autism.

TAS2R38 bitter taste genetics, dietary vitamin C, and both natural and synthetic dietary folic acid predict folate status, a key micronutrient in the pathoaetiology of adenomatous polyps

Taste perception may influence dietary preferences and nutrient intakes contributing to diet-related disease susceptibility. This study examined bitter taste genetics and whether variation in the TAS2R38 gene at three polymorphic loci (A49P, V262A and I296V) could alter dietary and systemic folate levels and dietary vitamin C intake, and whether a nutrigenetic circuit existed that might link bitter taste, folate/antioxidant status and risk for a colonic adenomatous polyp. TAS2R38 diplotype predicted bitter taste (PROP) phenotype (p value <0.00001) and red cell folate status (p=0.0179) consistent with the diplotype that has the broadest range of bitter perception (AVI/PAV) also possessing the highest average red cell folate value. However, TAS2R38 diplotype did not predict dietary intake of methylfolic acid, pteroylmonoglutamic acid or total folic acid. Neither did it predict dietary intake of vitamin C. Despite this, intake of dietary folate predicts red cell folate with analysis pointing to a key nutrient-nutrient interaction between vitamin C intake and systemic folate status. Analysis of 38 patients with an adenomatous polyp and 164 controls showed that individually, dietary nutrient intake, nutrient status and taste diplotype did not influence polyp risk. However, red cell folate status (in individuals below the population median value) did interact with bitter taste diplotype (AVI/PAV) to predict polyp risk (p=0.0145). Furthermore, synthetic folic acid (below median intake) was statistically associated with adenoma occurrence (p=0.0215); individuals with adenomatous polyps had a 1.77× higher intake than controls. Additionally, stepwise regression taking account of all dietary nutrients showed a tight relationship between methylfolic acid (but not pteroylmonoglutamic acid) intake and red cell folate level in those with a low folate status and occurrence of an adenomatous polyp (p=0.0039). These findings point to a role for folate in the pathoaetiology of adenomatous polyps, with the natural and synthetic vitamers not necessarily having the same biological effect.

Methylation diet and methyl group genetics in risk for adenomatous polyp occurrence

Purpose The aim of this study is to explore whether a methylation diet influences risk for adenomatous polyps (AP) either independently, or interactively with one-carbon metabolism-dependent gene variants, and whether such a diet modifies blood homocysteine, a biochemical phenotype closely related to the phenomenon of methylation. Methods 249 subjects were examined using selective fluorescence, PCR and food frequency questionnaire to determine homocysteine, nine methylation-related gene polymorphisms, dietary methionine, 5-methyltetrahydrofolate, vitamins B6 and B12. Results 1). Both dietary methionine and 5-methyltetrahydrofolate intake are significantly associated with plasma homocysteine. 2). Dietary methionine is related to AP risk in 2R3R-TS wildtype subjects, while dietary B12 is similarly related to this phenotype in individuals heterozygous for C1420T-SHMT, A2756G-MS and 844ins68-CBS, and in those recessive for 2R3R-TS. 3). Dietary methionine has a marginal influence on plasma homocysteine level in C1420T-SHMT heterozygotes, while B6 exhibits the same effect on homocysteine in C776G-TCN2 homozygote recessive subjects. Natural 5-methyltetrahydrofolate intake is interesting: Wildtype A1298C-MTHFR, heterozygote C677T-MTHFR, wildtype A2756G-MS and recessive A66G-MSR individuals all show a significant reciprocal association with homocysteine. 4). Stepwise regression of all genotypes to predict risk for AP indicated A2756G-MS and A66G-MSR to be most relevant (p = 0.0176 and 0.0408 respectively). Results were corrected for age and gender. Conclusion A methylation diet influences methyl group synthesis in the regulation of blood homocysteine level, and is modulated by genetic interactions. Methylation-related nutrients also interact with key genes to modify risk of AP, a precursor of colorectal cancer. Independent of diet, two methylation-related genes (A2756G-MS and A66G-MSR) were directly associated with AP occurrence.

Folate Nutritional Genetics and Risk for Hypertension in an Elderly Population Sample

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.

Preliminary Evidence for Genetic Selection of 677T-MTHFR by Natural Annual Cycle of Folate Abundance

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 (677C→T-MTHFR). Methods: Blood was collected from 150 UK and 118 Australian subjects born prior to discretionary or mandatory use of SFA. 677C→T-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.

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

ABSTRACT 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.

Genetic Variation in Glutamate Carboxypeptidase II and Interaction with Dietary Natural Vitamin C May Predict Risk for Adenomatous Polyp Occurrence.

BACKGROUND The C1561T variant of the glutamate carboxypeptidase II (GCPII) gene is critical for natural methylfolylpolyglutamte (methylfolate) absorption, and has been associated with perturbations in folate metabolism and disease susceptibility. However, little is known on C1561T-GCPII as a risk factor for colorectal cancer. Therefore, this study examined whether C1561T-GCPII influences folate metabolism and adenomatous polyp occurrence. MATERIALS AND METHODS 164 controls and 38 adenomatous polyp cases were analysed to determine blood folate and plasma homocysteine (Hcy) level, dietary intake of natural methylfolate, synthetic pteroylglutamic acid (PteGlu), vitamin C and C1561T-GCPII genotype. RESULTS In controls and cases, 7.3 and 18.4 percent of subjects respectively, were found to have the CT genotype, increasing the risk for adenomatous polyp occurrence 2.86 times (95% CI:1.37-8.0, p=0.035). Total dietary folate, methylfolate and PteGlu intake and the level of erythrocyte folate and plasma Hcy did not predict the occurrence of an adenomatous polyp. However, dietary natural vitamin C intake was associated with adenomatous polyp risk within C1561T-GCPII CT genotype subjects (p=0.037). CONCLUSIONS The findings suggest that C1561T-GCPII variation may be associated with risk for adenomatous polyp, and vitamin C may modify risk by interacting with the variant gene, its expression product and/or folate substrates.