The impact of folate on health and disease, particularly pregnancy complications and congenital malformations, has been extensively studied. Mandatory folic acid fortification therefore has been implemented in multiple countries, resulting in a reduction in the occurrence of neural tube defects. However, emerging evidence suggests increased folate intake may also be associated with unexpected adverse effects. This literature review focuses on contemporary issues of concern, and possible underlying mechanisms as well as giving consideration the future direction of mandatory folic acid fortification. Folate fortification has been associated with the presence of unmetabolized folic acid (PteGlu) in blood, masking of vitamin B12 deficiency, increased dosage for anti-cancer medication, photo-catalysis of PteGlu leading to potential genotoxicity, and a role in the pathoaetiology of colorectal cancer. Increased folate intake has also been associated with twin birth and insulin resistance in offspring, and altered epigenetic mechanisms of inheritance. Although limited data exists to elucidate potential mechanisms underlying these issues, elevated blood folate level due to the excess use of PteGlu without consideration of an individual's specific phenotypic traits (e.g. genetic background and undiagnosed disease) may be relevant. Additionally, the accumulation of unmetabolized PteGlu may lead to inhibition of dihydrofolate reductase and other enzymes. Concerns notwithstanding, folic acid fortification has achieved enormous advances in public health. It therefore seems prudent to target and carefully monitor high risk groups, and to conduct well focused further research to better understand and to minimize any risk of mandatory folic acid fortification.

Dietary patterns are a risk factor for metabolic syndrome (MetS). The prevalence of MetS has increased in Korea, and this condition has become a public health issue. Therefore, the present cross-sectional study aimed to identify the associations between dietary patterns and the risk of MetS among Korean women. The data of 5189 participants were analyzed to determine dietary intake and lifestyle. A principal components analysis was employed to determine participant dietary patterns with regard to 106 food items. MetS was diagnosed using the National Cholesterol Education Program, Adult Treatment Panel III. Logistic regression analyses were applied to evaluate the associations between dietary pattern quintiles and MetS and to generate odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for potential confounders. Three dietary patterns were identified: “traditional,” “western,” and “prudent.” The “prudent” dietary pattern consisted of a high intake of fruits and fruit products as well as nuts, dairy, and a low consumption of grains; this pattern was negatively associated with the risk of MetS. The highest quintile of the “prudent” dietary pattern was significantly less likely to develop MetS (OR: 0.5, 95% CI: 0.36–0.68, P for trend <0.001) compared with the lowest quintile. This pattern was also negatively associated with all of the MetS diagnostic criteria: abdominal obesity (OR: 0.52, 95% CI: 0.41–0.65), blood pressure (OR: 0.72, 95% CI: 0.59–0.87), triglycerides (OR: 0.67, 95% CI: 0.52–0.85), fasting glucose (OR: 0.64, 95% CI: 0.43–0.95), and high-density lipoprotein cholesterol (OR: 0.53, 95% CI: 0.42–0.68). However, the “traditional” and “western” dietary patterns were not associated with the risk of MetS. The “prudent” dietary pattern was negatively associated with the risk of developing MetS among Korean women.

The human TAS2R38 gene encodes a bitter taste receptor that regulates the bitterness perception and differentiation of ingested nutritional/poisonous compounds in the oral cavity and gastrointestinal tract. TAS2R38 gene variants are associated with alterations in individual sensitivity to bitter taste and food intake; hence, these genetic variants may modify the risk for diet-related diseases, including cancer. However, little is known about the association between TAS2R38 polymorphisms and gastric cancer susceptibility. The present case-control study examined the influence of TAS2R38 polymorphisms on food intake and determined whether they predict gastric cancer risk in Koreans. A total of 1,580 subjects, including 449 gastric cancer cases, were genotyped for TAS2R38 A49P, V262A, I296V and diplotypes. Dietary data were analysed to determine the total consumption of energy, fibre, vegetables, fruits, sweets, fats, alcohol and cigarettes. TAS2R38 diplotype was not associated with food, alcohol or cigarette consumption, either independent or dependent of gastric cancer phenotype. However, the PAV/AVI diplotype significantly increased gastric cancer risk (adjusted odds ratio: 1.513; 95% confidence interval: 1.148–1.994) independent of dietary intake. Findings suggest that TAS2R38 may be associated with the risk for gastric cancer in Koreans, although the TAS2R38 diplotype did not influence dietary intake.

Bitterness-sensing protein taste receptor type-2 member 38 (TAS2R38, T2R38) mediates taste perception and various physiological responses, including energy- and adiposity-related mechanisms. This study examined whether the genetic variant rs10246939 C > T in TAS2R38 was associated with food intake and body size as well as obesity risk. Data from the Korean Multi-Rural Communities Cohort study (1338 males and 2229 females) were analyzed to obtain the intake of six food groups, alcohol consumption, smoking status and anthropometric measurements, including height, weight, waist and hip circumference, and body mass index (BMI), according to the rs10246939 genotype. Findings suggested that females with the TT genotype consumed more fruit (adjusted p = 0.025) and had significantly higher body weights (adjusted p = 0.046) and BMIs (adjusted p = 0.003) than individuals with other genotypes. Having the TT genotype also increased the risk of obesity by 1.75-fold (95% confidence interval: 1.31–2.36) in females. The genetic variation had a minimal influence on the males’ dietary intake, but tended to increase the adiposity risk. In conclusion, TAS2R38 rs10246939 variation was associated with Koreans’ dietary intake and increased their risk of obesity. Although more detailed statistical analyses in the larger cohort are required, current study suggested that, as a genetic predictive marker, TAS2R38 bitterness receptor variations may have a large implication in obesity prevention and treatment.

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.

Background and objectives: Vitamin D and folate are highly UV sensitive, and critical for maintaining health throughout the lifecycle. This study examines whether solar irradiance during the first trimester of pregnancy influences vitamin D receptor (VDR) and nuclear folate gene variant occurrence, and whether affected genes influence late-life biochemical/clinical phenotypes. Methodology: 228 subjects were examined for periconceptional exposure to solar irradiance, variation in vitamin D/folate genes (polymerase chain reaction (PCR)), dietary intake (food frequency questionnaire (FFQ)) and important adult biochemical/clinical phenotypes. Results: Periconceptional solar irradiance was associated with VDR-BsmI (P = 0.0008^wk7), TaqI (P = 0.0014^wk7) and EcoRV (P = 0.0030^wk6) variant occurrence between post-conceptional weeks 6–8, a period when ossification begins. Similar effects were detected for other VDR gene polymorphisms. Periconceptional solar irradiance was also associated with 19 bp del-DHFR (P = 0.0025^wk6), and to a lesser extent C1420T-SHMT (P = 0.0249^wk6), a folate-critical time during embryogenesis. These same genes were associated with several late-life phenotypes: VDR-BsmI, TaqI and ApaI determined the relationship between dietary vitamin D and both insulin (P < 0.0001/BB, 0.0007/tt and 0.0173/AA, respectively) and systolic blood pressure (P = 0.0290/Bb, 0.0299/Tt and 0.0412/AA, respectively), making them important early and late in the lifecycle. While these and other phenotype associations were found for the VDR variants, folate polymorphism associations in later-life were limited to C1420T-SHMT (P = 0.0037 and 0.0297 for fasting blood glucose and HbA1c levels, respectively). We additionally report nutrient–gene relationships with body mass index, thiol/folate metabolome, cognition, depression and hypertension. Furthermore, photoperiod at conception influenced occurrence of VDR-Tru9I and 2R3R-TS genotypes (P = 0.0120 and 0.0360, respectively). Conclusions and implications: Findings identify environmental and nutritional agents that may interact to modify gene–phenotype relationships across the lifecycle, offering new insight into human ecology. This includes factors related to both disease aetiology and the evolution of skin pigmentation.