Gene-nutrient Interactions Research Articles

Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study.

Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations. Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations. Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-β-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3β (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS). Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.

Lipid metabolism and Type VII secretion systems dominate the genome scale virulence profile of Mycobacterium tuberculosis in human dendritic cells.

BackgroundMycobacterium tuberculosis continues to kill more people than any other bacterium. Although its archetypal host cell is the macrophage, it also enters, and survives within, dendritic cells (DCs). By modulating the behaviour of the DC, M. tuberculosis is able to manipulate the host’s immune response and establish an infection. To identify the M. tuberculosis genes required for survival within DCs we infected primary human DCs with an M. tuberculosis transposon library and identified mutations with a reduced ability to survive.ResultsParallel sequencing of the transposon inserts of the surviving mutants identified a large number of genes as being required for optimal intracellular fitness in DCs. Loci whose mutation attenuated intracellular survival included those involved in synthesising cell wall lipids, not only the well-established virulence factors, pDIM and cord factor, but also sulfolipids and PGL, which have not previously been identified as having a direct virulence role in cells. Other attenuated loci included the secretion systems ESX-1, ESX-2 and ESX-4, alongside many PPE genes, implicating a role for ESX-5. In contrast the canonical ESAT-6 family of ESX substrates did not have intra-DC fitness costs suggesting an alternative ESX-1 associated virulence mechanism. With the aid of a gene-nutrient interaction model, metabolic processes such as cholesterol side chain catabolism, nitrate reductase and cysteine-methionine metabolism were also identified as important for survival in DCs.ConclusionWe conclude that many of the virulence factors required for survival in DC are shared with macrophages, but that survival in DCs also requires several additional functions, such as cysteine-methionine metabolism, PGLs, sulfolipids, ESX systems and PPE genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1569-2) contains supplementary material, which is available to authorized users.

Predisposing roles of paraoxonase-1 genetic variants in Korean ischemic stroke patients

Paraoxonase-1 (PON1), a high-density lipoprotein (HDL)-associated enzyme, is involved in the metabolism and detoxification of insecticides and pesticides. The aims of this study were to evaluate the role of PON1 gene polymorphisms (−107C > T, L55M, and Q192R) in patients susceptible to ischemic stroke and to determine the interactive relationship between PON1 gene polymorphisms and vascular risk factors regarding stroke occurrence. The PON1 polymorphisms were not significantly different between 471 stroke patients and 427 control subjects. When stratified by the size of the occluded vessel, the PON1 L55M polymorphism was associated with patients with small-vessel disease (LM + MM; AOR, 2.161; 1.204–3.880). In gene–environment or gene–nutrient interaction analysis, significant interactions associated with increased stroke risk were found. Of those significant interactions, the PON1 55LM + MM genotype with a plasma folate level <3.57 ng/ml accelerated the stroke prevalence 5.793-fold (AOR, 5.793; 95 % CI 1.575–21.306). Our study suggested that genetic associations of PON1 with ischemic stroke were affected by pathophysiological and environmental factors. Further studies are needed to elucidate the interactions of PON1 with other stroke risk factors in large populations.

α2‐Heremans‐Schmid glycoprotein (AHSG) polymorphism and HOMA‐IR in young Mexican adults

Circulating AHSG binds saturated fatty acids (SFA) and increases pro-inflammatory signal cascade via toll-like-4 receptor activation. The gene-nutrient interaction between SFA intake and polymorphisms in AHSG could contribute to the physiopathology of Metabolic Syndrome (MetS). We aim to identify if variations in AHSG relate to biomarkers of metabolic disease and SFA intake. Subjects were college applicants to the UASLP (18-25 years, n=414). Fasting blood was collected for analysis of biomarkers and genotyping. Dietary and health surveys were collected. HOMA-IR was calculated using glucose and insulin levels. Two single nucleotide polymorphisms (SNPs) in AHSG were genotyped (rs2518136 and rs4917). Both SNPs were in HWE and had minor allele frequencies greater than 10%. Mean HOMA-IR was lower in AHSG-rs2518136 T-allele carriers when compared to non-carriers (P<0.05, respectively). There was no interaction with AHSG SNPs and SFA intake. Neither SNPs were associated with BMI. Lower triglycerides values were ...

Mitochondria: hubs of cellular signaling, energetics and redox balance. A rich, vibrant, and diverse landscape of mitochondrial research.

Mitochondria have become the cornerstone of cellular biology, opening new frontiers in health and disease. Poised at the convergence of most catabolic and anabolic pathways, mitochondria constitute the center of heterotrophic aerobic life, processing and generating key metabolites that feed into pathways leading to growth, division, and signaling. As such, mitochondria play the role of hubs in the overall metabolic network; thus their failure risks the collapse of most crucial cellular functions. The protagonist role of mitochondria is underscored by the existence of tightly regulated cellular processes that include autophagy/mitophagy and metabolically tuned morphological changes induced by fusion-fission dynamics. Mitochondria are also involved in a myriad of signaling cascades regulating cell survival vs. death. They provide the energy for the cell, a hub for biosynthetic processes and they contain a self-destructive arsenal of apoptotogenic factors that can be unleashed to promote apoptotic signaling. Consequently, it is no wonder that mitochondrial dysfunction is implicated in the aging phenomenon, and in numerous human maladies including metabolic disorders, cardiomyopathies, and neurodegeneration. Indeed, diseases characterized by altered gene-nutrient interactions, such as diabetes and cancer, exhibit elevated levels of reac

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice

Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions.Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism.Design: Folic acid–supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr+/+ and Mthfr+/− mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined.Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr+/− mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/− livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/− mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile.Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient.

Gene-gene, gene-environment, gene-nutrient interactions and single nucleotide polymorphisms of inflammatory cytokines

Inflammation plays a significant role in the etiology of type 2 diabetes mellitus (T2DM). The rise in the pro-inflammatory cytokines is the essential step in glucotoxicity and lipotoxicity induced mitochondrial injury, oxidative stress and beta cell apoptosis in T2DM. Among the recognized markers are interleukin (IL)-6, IL-1, IL-10, IL-18, tissue necrosis factor-alpha (TNF-α), C-reactive protein, resistin, adiponectin, tissue plasminogen activator, fibrinogen and heptoglobins. Diabetes mellitus has firm genetic and very strong environmental influence; exhibiting a polygenic mode of inheritance. Many single nucleotide polymorphisms (SNPs) in various genes including those of pro and anti-inflammatory cytokines have been reported as a risk for T2DM. Not all the SNPs have been confirmed by unifying results in different studies and wide variations have been reported in various ethnic groups. The inter-ethnic variations can be explained by the fact that gene expression may be regulated by gene-gene, gene-environment and gene-nutrient interactions. This review highlights the impact of these interactions on determining the role of single nucleotide polymorphism of IL-6, TNF-α, resistin and adiponectin in pathogenesis of T2DM.

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.

Regulation of Folate-Mediated One-Carbon Metabolism by Glycine N-Methyltransferase (GNMT) and Methylenetetrahydrofolate Reductase (MTHFR).

Folate-mediated one-carbon metabolism is an important therapeutic target of human diseases. We extensively investigated how gene-nutrient interactions may modulate human cancer risk in 2 major folate metabolic genes, MTHFR and GNMT. The biochemical impacts of MTHFR and GNMT on methyl group supply, global DNA methylation, nucleotide biosynthesis, DNA damage, and partitioning of the folate dependent 1-carbon group were carefully studied. The distinct model systems used included: EB virus-transformed lymphoblasts expressing human MTHFR polymorphic genotypes; liver-derived GNMT-null cell-lines with and without GNMT overexpression; and HepG2 cells with stabilized inhibition of MTHFR using shRNA, GNMT wildtype, heterozygotous (GNMT(het)) and knockout (GNMT(nul)) mice. We discovered that the MTHFR TT genotype significantly reduces folate-dependent remethylation under folate restriction, but it assists purine synthesis when folate is adequate. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in human hematological malignancies. GNMT affects transmethylation kinetics and S-adenosylmethionine (adoMet) synthesis, and facilitates the conservation of methyl groups by limiting homocysteine remethylation fluxes. Restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. The systematic series of studies gives new insights into the underlying mechanisms by which MTHFR and GNMT may participate in human tumor prevention.

Long-term effects of maternal citrulline supplementation on renal transcriptome prevention of nitric oxide depletion-related programmed hypertension: the impact of gene-nutrient interactions.

Maternal malnutrition can elicit gene expression leading to fetal programming. l-citrulline (CIT) can be converted to l-arginine to generate nitric oxide (NO). We examined whether maternal CIT supplementation can prevent NG-nitro-l-arginine-methyl ester (l-NAME, NO synthase inhibitor)-induced programmed hypertension and examined their effects on the renal transcriptome in male offspring using next generation RNA sequencing (RNA-Seq) technology. Pregnant Sprague-Dawley rats received l-NAME administration at 60mg/kg/day subcutaneously via osmotic minipump during pregnancy alone or with additional 0.25% l-citrulline solution in drinking water during the whole period of pregnancy and lactation. Male offspring were assigned to three groups: control, l-NAME, and l-NAME + CIT. l-NAME exposure induced hypertension in the 12-week-old offspring, which CIT therapy prevented. Identified differentially expressed genes in l-NAME and CIT-treated offspring kidneys, including Guca2b, Hmox1, Hba2, Hba-a2, Dusp1, and Serpine1 are related to regulation of blood pressure (BP) and oxidative stress. In conclusion, our data suggests that the beneficial effects of CIT supplementation are attributed to alterations in expression levels of genes related to BP control and oxidative stress. Our results suggest that early nutritional intervention by CIT has long-term impact on the renal transcriptome to prevent NO depletion-related programmed hypertension. However, our RNA-Seq results might be a secondary phenomenon. The implications of epigenetic regulation at an early stage of programming deserve further clarification.

Micronutrient, Genome Stabili ty and Degenerative Diseases: Nutrigenomics Concept of Disease Prevention - An Overview

Diet is a key factor in determining genomic stability is more important than previously imagined because it impacts on all relevant pathways like exposure to dietary carcinogens, DNA repair, DNA synthesis, epigenetic damage and apoptosis. Recent research focuses into how a single micronutrient deficiency is leading to genomic instability and development of degenerative diseases in various stages of life.The study aimed at finding the nutrigenomic mechanism of how a marginal deficiency of any single micronutrient is interrupting in DNA repairing, methylation and synthesis by taking nutrient-nutrient and nutrient-gene interaction into consideration. It also focuses on how recommended dietary allowance is important in achieving DNA integrity and genome stability to prevent degenerative diseases.Exhaustive review of research papers in genome health nutrigenomicsis involved in this study to explore, assimilate and analyze data to understand the importance of micronutrient in maintaining methylation of CpG sequence and preventing DNA oxidation or uracil misincorporation in DNA to stop disease occurrence in individuals.The study finds a direct link between micronutrient deficiency and increased epigenomic damage, resulting into elevated risk for adverse health outcomes during various stages of life like infertility, tumor development and cancer. The overview study concludes with a vision for a paradigm shift in disease prevention strategy based on diagnosis and micro-nutritional intervention of genome or epigenome damage on an individual basis, i.e. personalized prevention of degenerative diseases in genome health clinic.

Nutrigenetics and nutrigenomics insights into diabetes etiopathogenesis.

Diabetes mellitus (DM) is considered a global pandemic, and the incidence of DM continues to grow worldwide. Nutrients and dietary patterns are central issues in the prevention, development and treatment of this disease. The pathogenesis of DM is not completely understood, but nutrient-gene interactions at different levels, genetic predisposition and dietary factors appear to be involved. Nutritional genomics studies generally focus on dietary patterns according to genetic variations, the role of gene-nutrient interactions, gene-diet-phenotype interactions and epigenetic modifications caused by nutrients; these studies will facilitate an understanding of the early molecular events that occur in DM and will contribute to the identification of better biomarkers and diagnostics tools. In particular, this approach will help to develop tailored diets that maximize the use of nutrients and other functional ingredients present in food, which will aid in the prevention and delay of DM and its complications. This review discusses the current state of nutrigenetics, nutrigenomics and epigenomics research on DM. Here, we provide an overview of the role of gene variants and nutrient interactions, the importance of nutrients and dietary patterns on gene expression, how epigenetic changes and micro RNAs (miRNAs) can alter cellular signaling in response to nutrients and the dietary interventions that may help to prevent the onset of DM.

Emerging roles for folate and related B-vitamins in brain health across the lifecycle.

Nutrition plays a fundamental role in supporting the structural and functional development of the human brain from conception, throughout early infancy and extending into later life. A growing body of evidence suggests that folate and the metabolically related B-vitamins are essential for brain health across all age groups, owing to their specific roles in C1 metabolism and particularly in the production of S-adenosylmethionine, a universal methyl donor essential for the production of neurotransmitters. Emerging, though not entirely consistent, evidence suggests that maternal folate status throughout pregnancy may influence neurodevelopment and behaviour of the offspring. Furthermore optimal B-vitamin status is associated with better cognitive health in ageing. Of note, a recent clinical trial provided evidence that supplementation with folic acid and related B-vitamins over a 2-year-period reduced global and regional brain atrophy, as measured by MRI scan in older adults. In terms of potential mechanisms, the effects of these B-vitamins on cognitive health may be independent or may be mediated by nutrient-nutrient and/or relevant gene-nutrient interactions. Furthermore, a new area of research suggests that the in utero environment influences health in later life. Folate, an important cofactor in C1 metabolism, is indirectly involved in DNA methylation, which in turn is considered to be one of the epigenetic mechanisms that may underlie fetal programming and brain development. The present review will explore the evidence that supports a role for folate and the related B-vitamins in brain health across the lifecycle, and potential mechanisms to explain such effects.

Nutrient-Gene Interaction in Arsenic Metabolism

Arsenic (As) naturally occurs in water and its long-term exposure is linked with many health problems, including skin lesions and cancer. Nutrient intake and genetic polymorphisms involved in one-carbon metabolism, including the choline pathway, may explain inter-individual variation in As metabolism and elimination, possibly influencing susceptibility to As-related disease. To examine As metabolism and elimination efficiency in relation to intake of choline, betaine, and methionine, and choline dehydrogenase (CHDH) rs7626693 and betaine homocysteine methyltransferase (BHMT) rs3733890 genetic variants. Women (n=415) from As-exposed regions of Northern Mexico, were interviewed and provided biological samples. Nutrient intake was estimated using a validated semi-quantitative food frequency questionnaire. Urinary As species were determined with HPLC-ICP-MS and the relative proportions and ratios of As metabolism were calculated. Genetic polymorphisms were genotyped via allelic discrimination. Multivariate linear regression models were developed to evaluate the associations between nutrients, polymorphisms and urinary As parameters In gene-nutrient adjusted models, methionine was the only nutrient significantly associated with As metabolism. After adjusting for BHMT, methionine was associated with lower percentage of inorganic As (%iAs) and higher percentage of dimethylarsinic acid (%DMA) and total methylation index (DMA/iAs). Among women with the GG+AG genotypes of BHMT, methionine was additionally associated with lower percentage of monomethylarsonic acid (%MMA) and higher secondary methylation index (DMA/MMA). A statistically significant interaction between methionine and BHMT was detected. Conclusion. Nutrients may play a role in As metabolism, particularly within certain genetic variant subgroups, via one-carbon and choline pathways. Differences in nutrient intake and genetic polymorphisms may jointly influence As metabolism and elimination efficiency.

Abstract 2197: Interaction between genetic variants in one-carbon metabolism and folate biomarkers on colorectal cancer risk: The Women's Health Initiative observational cohort

Abstract Folate-mediated one-carbon metabolism (FOCM) is important in the development of colorectal cancer (CRC), but gene-nutrient interactions in this relationship have not been comprehensively evaluated. We investigated whether folate modified the association of genetic variants of FOCM with CRC risk. Among 821 Caucasian case/control matched pairs in the Women's Health Initiative observational cohort (1993-2008), we genotyped 453 single nucleotide polymorphisms (SNPs) tagging 227 independent loci in 30 genes in FOCM pathways (AARS, ADH1B, ADH1C, BHMT, BHMT2, CBS, DHFR, DNMT1, DNMT3A, DNMT3B, EHMT1, EHMT2, FOLH1, FOLR1, GGH, GNMT, MAT1A, MAT2B, MTHFD1, MTHFD2, MTHFR, MTR, MTRR, PON1, PRDM2, SHMT1, SHMT2, SLC19A1, TCN2, and TYMS). Folate concentrations in plasma and red blood cell (RBC) were measured by radioassays. Multivariable conditional logistic regression was used to estimate odds ratios, and likelihood ratio tests were performed to test the differences in the associations of SNPs with CRC among plasma/RBC folate tertile categories. Nominal P-values were reported for non-synonymous and candidate SNPs. For tagSNPs, we used the Benjamini and Hochberg method to control false discovery rate (FDR) at the gene level. When comparing homozygous variants with wild-types, we observed higher risks of CRC associated with genetic variants in folate absorption and uptake in the presence of low (tertile 1) plasma folate concentrations: GGH (rs16930073, flanking 3′UTR, P-interaction=0.006), FOLH1 (rs10839236, intron, candidate, P=0.018; rs2299650, intron, P=0.016), and FOLR1 (rs651646, intron, P=0.021). In other FOCM pathways (methionine/S-adenosylmethionine reactions, vitamin B12 transport, and DNA methylation), plasma/RBC folate also modified important non-synonymous and candidate SNPs in relation to CRC risk: MTRR (C524T [p.S202L], P=0.045), CBS (rs1801181 [p.A360A], P=0.035), TCN2 (C776G [p.R232P], P=0.040), DNMT1 (A201G [p.I311L], P=0.016), DNMT3A (rs11695471 [intron 22 A&amp;gt;T], candidate, P=0.002), and DNMT3B (283T&amp;gt;C, 5′ near gene, p=0.043). In addition, interactions with plasma/RBC folate were observed for several variants in paraoxonase 1 (PON1), an enzyme generating homocysteine from homocysteine thiolactone: p.L55M (P=0.021), rs8491 (3′UTR, P=0.037), rs854548 (3′ near gene, P=0.033), rs854551 (3′UTR, P=0.045), and rs3917527 (intron, P=0.006). All significant interactions with tagSNPs remained as “noteworthy” at the FDR 25% level. In conclusion, our observations highlight the importance of folate status when investigating FOCM-related genetic influences on CRC risk in postmenopausal women. Citation Format: Ting-Yuan D. Cheng, Karen W. Makar, Marian L. Neuhouser, Joshua W. Miller, Xiaoling Song, Elissa C. Brown, Shirley A.A. Beresford, Yingye Zheng, David J. Duggan, Elizabeth M. Poole, Nina Habermann, Reka Toth, Lynn B. Bailey, Marie A. Caudill, Cornelia M. Ulrich. Interaction between genetic variants in one-carbon metabolism and folate biomarkers on colorectal cancer risk: The Women's Health Initiative observational cohort. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2197. doi:10.1158/1538-7445.AM2014-2197

Nutrigenetic associations with cardiovascular disease.

It is becoming increasingly evident that not all people respond equally to diet. Nutrigenetics and nutrigenomics is the study of how genes affect dietary response or how nutrients affect gene expression. Understanding gene-nutrient interactions has become essential in many areas of study to account for variation in results. Identifying subgroups or individuals who might benefit from more targeted recommendations has also been a result of studying these interactions. This review summarizes findings from genetic polymorphisms in apolipoprotein E, fatty acid desaturase, lipoxygenase-5, peroxisome proliferator-activated receptors, apolipoprotein A1, apolipoprotein A2, apolipoprotein A5, and methylenetetrahydrofolate reductase associated with cardiovascular disease.

Approaches for the identification of genetic modifiers of nutrient dependent phenotypes: examples from folate.

By combining the sciences of nutrition, bioinformatics, genomics, population genetics, and epidemiology, nutrigenomics is improving our understanding of how diet and nutrient intake can interact with or modify gene expression and disease risk. In this review, we explore various approaches to examine gene–nutrient interactions and the modifying role of nutrient consumption, as they relate to nutrient status and disease risk in human populations. Two common approaches include the use of SNPs in candidate genes to identify their association with nutritional status or disease outcomes, or genome-wide association studies to identify genetic polymorphisms associated with a given phenotype. Here, we examine the results of various gene–nutrient interaction studies, the association of genetic polymorphisms with disease expression, and the identification of nutritional factors that modify gene-dependent disease phenotypes. We have focused on specific examples from investigations of the interactions of folate, B-vitamin consumption, and polymorphisms in the genes of B-vitamin dependent enzymes and their association with disease risk, followed by an examination of the strengths and limitations of the methods employed. We also present suggestions for future studies, including an approach from an on-going large scale study, to examine the interaction of nutrient intake and genotypic variation and their impact on nutritional status.

Interactions between differential fatty acids and inflammatory stressors—impact on metabolic health

Current interest in obesity has established a clear link between diets high in fat and metabolic complications such as Type 2 Diabetes. Dietary fats and their metabolites act as stressors to induce a pro-inflammatory immune response which dysregulates many essential metabolic functions. Recent research suggests that different dietary fats may have varying inflammatory potentials. However the molecular mechanisms involved in the cross talk between dietary fat composition and the ‘immuno-metabolism’ remain enigmatic. It is probable that lipids, and their derivatives, differentially regulate IL-1β activation and inflammatory signaling via the NLRP3 inflammasome complex. Also from the translational perspective, certain nutrient sensitive genotypes and potential gene nutrient interactions offer the possibility to reduce inflammation through personalized nutrition approaches.

Riboflavin lowers blood pressure in hypertensive people with the MTHFR677TT genotype

Hypertension, defined as a systolic/diastolic blood pressure of 140/90 mmHg or greater, is estimated to carry a 3-fold increased risk of developing cardiovascular disease (CVD), while treating hypertension significantly reduces CVD events, and stroke in particular. Among the many risk factors involved, there is much recent interest in the role of genetic factors that might predispose to hypertension. Evidence from genome-wide association studies has identified an association between blood pressure and the gene encoding the folate-metabolising enzyme, methylenetetrahydrofolate reductase (MTHFR), while recent meta-analyses of observational studies show an increased risk of hypertension in people homozygous for the 677C→T polymorphism in MTHFR. Riboflavin (vitamin B2) in the form of FAD acts as a cofactor for MTHFR and we have been studying its modulating role in relation to this polymorphism. The variant enzyme is known from molecular studies to become inactive as a result of having an increased propensity to dissociate from FAD, but our earlier work suggested that supplementation with low-dose riboflavin could stabilise MTHFR activity in vivo in homozygous individuals. In recent years we showed that CVD patients with the relevant MTHFR 677TT genotype (compared to CC or CT genotypes) had significantly higher blood pressure, and that blood pressure was highly responsive to riboflavin intervention, specifically in the TT genotype group [1]. Further investigations confirmed this gene-nutrient interaction in hypertensive patients (with and without overt CVD), and furthermore showed that the blood pressure lowering effect of riboflavin in the TT genotype group was independent of the number and type of antihypertensive drugs that they were taking [2]. Although the precise mechanism linking this polymorphism to hypertension remains to be established, it would appear that the biological perturbation that leads to higher blood pressure in individuals with the MTHFR 677TT genotype is modifiable by correcting the variant MTHFR enzyme through enhancing riboflavin status. Thus riboflavin, targeted specifically at this genetically at-risk group, may offer a personalized non-drug approach to managing hypertension.

Genetic associations with micronutrient levels identified in immune and gastrointestinal networks.

The discovery of vitamins and clarification of their role in preventing frank essential nutrient deficiencies occurred in the early 1900s. Much vitamin research has understandably focused on public health and the effects of single nutrients to alleviate acute conditions. The physiological processes for maintaining health, however, are complex systems that depend upon interactions between multiple nutrients, environmental factors, and genetic makeup. To analyze the relationship between these factors and nutritional health, data were obtained from an observational, community-based participatory research program of children and teens (age 6–14) enrolled in a summer day camp in the Delta region of Arkansas. Assessments of erythrocyte S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), plasma homocysteine (Hcy) and 6 organic micronutrients (retinol, 25-hydroxy vitamin D3, pyridoxal, thiamin, riboflavin, and vitamin E), and 1,129 plasma proteins were performed at 3 time points in each of 2 years. Genetic makeup was analyzed with 1 M SNP genotyping arrays, and nutrient status was assessed with 24-h dietary intake questionnaires. A pattern of metabolites (met_PC1) that included the ratio of erythrocyte SAM/SAH, Hcy, and 5 vitamins were identified by principal component analysis. Met_PC1 levels were significantly associated with (1) single-nucleotide polymorphisms, (2) levels of plasma proteins, and (3) multilocus genotypes coding for gastrointestinal and immune functions, as identified in a global network of metabolic/protein–protein interactions. Subsequent mining of data from curated pathway, network, and genome-wide association studies identified genetic and functional relationships that may be explained by gene–nutrient interactions. The systems nutrition strategy described here has thus associated a multivariate metabolite pattern in blood with genes involved in immune and gastrointestinal functions.Electronic supplementary materialThe online version of this article (doi:10.1007/s12263-014-0408-4) contains supplementary material, which is available to authorized users.