Prediagnostic selenium status, selenoprotein gene variants and association with breast cancer risk in a European cohort study.

Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional 18 variants previously associated with Se concentrations were extracted from existing genotyping data within EPIC for 1564 case-control pairs. Multivariable-adjusted logistic regression models were used to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the association between Se status markers, SNP variants and BC risk. Overall, there was no statistically significant association of Se status with BC risk. However, higher GPX3 activity was associated with lower risk of premenopausal BC (4th versus 1st quartile, OR = 0.54, 95 % CI: 0.30-0.98, Ptrend = 0.013). While none of the genetic variant associations (P ≤ 0.05) retained significance after multiple testing correction, rs1004243 in the SELENOM selenoprotein gene and two SNPs in the related antioxidant TXN2 gene (rs4821494 and rs5750261) were associated with respective lower and higher risks of BC at a significance threshold of P ≤ 0.01. Fourteen SNPs in twelve Se pathway genes (P ≤ 0.01) in interaction with Se status were also associated with BC risk. Higher Se status does not appear to be associated with BC risk, although activity of the selenoenzyme GPX3 may be inversely associated with premenopausal BC risk, and SNPs in the Se pathway alone or in combination with suboptimal Se status may influence BC risk.

Selenium and viral infection: are there lessons for COVID-19?

Se is a micronutrient essential for human health. Sub-optimal Se status is common, occurring in a significant proportion of the population across the world including parts of Europe and China. Human and animal studies have shown that Se status is a key determinant of the host response to viral infections. In this review, we address the question whether Se intake is a factor in determining the severity of response to coronavirus disease 2019 (COVID-19). Emphasis is placed on epidemiological and animal studies which suggest that Se affects host response to RNA viruses and on the molecular mechanisms by which Se and selenoproteins modulate the inter-linked redox homeostasis, stress response and inflammatory response. Together these studies indicate that Se status is an important factor in determining the host response to viral infections. Therefore, we conclude that Se status is likely to influence human response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and that Se status is one (of several) risk factors which may impact on the outcome of SARS-CoV-2 infection, particularly in populations where Se intake is sub-optimal or low. We suggest the use of appropriate markers to assess the Se status of COVID-19 patients and possible supplementation may be beneficial in limiting the severity of symptoms, especially in countries where Se status is regarded as sub-optimal.

The Role of Selenium in Health and Disease: Emerging and Recurring Trends.

In this Special Issue of Nutrients, "The Role of Selenium in Health and Disease" covers diverse diseases in the 8 original research articles and 2 reviews, such as cardiovascular disorders (CVD), metabolic syndrome, obesity, cancer, and viral infection, and highlights novel potential biomarkers of disease risk and prognosis [...].

Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status.

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.

Association of Single Nucleotide Polymorphisms in Selenoprotein Genes with Cancer Risk.

Genetic association studies have linked genetic variants in the Selenium (Se) metabolism with the development of complex diseases such as cancer and helped unravel novel mechanisms underlying cancer development. The chapter describes the specificity of genetic variants in the Se metabolism, the approaches used in association studies, and the limitations of such approaches.

Modeling and gene knockdown to assess the contribution of nonsense-mediated decay, premature termination, and selenocysteine insertion to the selenoprotein hierarchy.

The expression of selenoproteins, a specific group of proteins that incorporates selenocysteine, is hierarchically regulated by the availability of Se, with some, but not all selenoprotein mRNA transcripts decreasing in abundance with decreasing Se. Selenocysteine insertion into the peptide chain occurs during translation following recoding of an internal UGA stop codon. There is increasing evidence that this UGA recoding competes with premature translation termination, which is followed by nonsense-mediated decay (NMD) of the transcript. In this study, we tested the hypothesis that the susceptibility of different selenoprotein mRNAs to premature termination during translation and differential sensitivity of selenoprotein transcripts to NMD are major factors in the selenoprotein hierarchy. Selenoprotein transcript abundance was measured in Caco-2 cells using real-time PCR under different Se conditions and the data obtained fitted to mathematical models of selenoprotein translation. A calibrated model that included a combination of differential sensitivity of selenoprotein transcripts to NMD and different frequency of non-NMD related premature translation termination was able to fit all the measurements. The model predictions were tested using SiRNA to knock down expression of the crucial NMD factor UPF1 (up-frameshift protein 1) and selenoprotein mRNA expression. The calibrated model was able to predict the effect of UPF1 knockdown on gene expression for all tested selenoproteins, except SPS2 (selenophosphate synthetase), which itself is essential for selenoprotein synthesis. These results indicate an important role for NMD in the hierarchical regulation of selenoprotein mRNAs, with the exception of SPS2 whose expression is likely regulated by a different mechanism.

Transcriptomics and proteomics show that selenium affects inflammation, cytoskeleton, and cancer pathways in human rectal biopsies.

Epidemiologic studies highlight the potential role of dietary selenium (Se) in colorectal cancer prevention. Our goal was to elucidate whether expression of factors crucial for colorectal homoeostasis is affected by physiologic differences in Se status. Using transcriptomics and proteomics followed by pathway analysis, we identified pathways affected by Se status in rectal biopsies from 22 healthy adults, including 11 controls with optimal status (mean plasma Se = 1.43 µM) and 11 subjects with suboptimal status (mean plasma Se = 0.86 µM). We observed that 254 genes and 26 proteins implicated in cancer (80%), immune function and inflammatory response (40%), cell growth and proliferation (70%), cellular movement, and cell death (50%) were differentially expressed between the 2 groups. Expression of 69 genes, including selenoproteins W1 and K, which are genes involved in cytoskeleton remodelling and transcription factor NFκB signaling, correlated significantly with Se status. Integrating proteomics and transcriptomics datasets revealed reduced inflammatory and immune responses and cytoskeleton remodelling in the suboptimal Se status group. This is the first study combining omics technologies to describe the impact of differences in Se status on colorectal expression patterns, revealing that suboptimal Se status could alter inflammatory signaling and cytoskeleton in human rectal mucosa and so influence cancer risk.-Méplan, C., Johnson, I. T., Polley, A. C. J., Cockell, S., Bradburn, D. M., Commane, D. M., Arasaradnam, R. P., Mulholland, F., Zupanic, A., Mathers, J. C., Hesketh, J. Transcriptomics and proteomics show that selenium affects inflammation, cytoskeleton, and cancer pathways in human rectal biopsies.

Selenium and chronic diseases: a nutritional genomics perspective.

Mechanistic data have revealed a key role for selenium (Se) and selenoproteins in biological pathways known to be altered in multifactorial diseases, such as cellular maintenance, response to oxidative stress and correct protein folding. Although epidemiological studies indicate that low Se intake is linked to increased risk for various chronic diseases, supplementation trials have given confusing outcomes, suggesting that additional genetic factors could affect the relationship between Se and health. Genetic data support this hypothesis, as risk for several chronic diseases, in particular cancer, was linked to a number of single nucleotide polymorphisms (SNP) altering Se metabolism, selenoprotein synthesis or activity. Interactions between SNPs in selenoprotein genes, SNPs in related molecular pathways and biomarkers of Se status were found to further modulate the genetic risk carried by the SNPs. Taken together, nutritional genomics approaches uncovered the potential implication of some selenoproteins as well as the influence of complex interactions between genetic variants and Se status in the aetiology of several chronic diseases. This review discusses the results from these genetic associations in the context of selenoprotein functions and epidemiological investigations and emphasises the need to assess in future studies the combined contribution of Se status, environmental stress, and multiple or individual SNPs to disease risk.

Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort.

Suboptimal intakes of the micronutrient selenium (Se) are found in many parts of Europe. Low Se status may contribute to colorectal cancer (CRC) development. We assessed Se status by measuring serum levels of Se and Selenoprotein P (SePP) and examined the association with CRC risk in a nested case-control design (966 CRC cases; 966 matched controls) within the European Prospective Investigation into Cancer and Nutrition. Se was measured by total reflection X-ray fluorescence and SePP by immunoluminometric sandwich assay. Multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Respective mean Se and SePP levels were 84.0 µg/L and 4.3 mg/L in cases and 85.6 µg/L and 4.4 mg/L in controls. Higher Se concentrations were associated with a non-significant lower CRC risk (IRR = 0.92, 95% CI: 0.82-1.03 per 25 µg/L increase). However, sub-group analyses by sex showed a statistically significant association for women (p(trend) = 0.032; per 25 µg/L Se increase, IRR = 0.83, 95% CI: 0.70-0.97) but not for men. Higher SePP concentrations were inversely associated with CRC risk (p(trend) = 0.009; per 0.806 mg/L increase, IRR = 0.89, 95% CI: 0.82-0.98) with the association more apparent in women (p(trend) = 0.004; IRR = 0.82, 95% CI: 0.72-0.94 per 0.806 mg/L increase) than men (p(trend) = 0.485; IRR = 0.98, 95% CI: 0.86-1.12 per 0.806 mg/L increase). The findings indicate that Se status is suboptimal in many Europeans and suggest an inverse association between CRC risk and higher serum Se status, which is more evident in women.

Association between maternal micronutrient status, oxidative stress, and common genetic variants in antioxidant enzymes at 15 weeks׳ gestation in nulliparous women who subsequently develop preeclampsia.

Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Deficiencies of specific micronutrient antioxidant activities associated with copper, selenium, zinc, and manganese have previously been linked to preeclampsia at the time of disease. Our aims were to investigate whether maternal plasma micronutrient concentrations and related antioxidant enzyme activities are altered before preeclampsia onset and to examine the dependence on genetic variations in these antioxidant enzymes. Predisease plasma samples (15±1 weeks׳ gestation) were obtained from women enrolled in the international Screening for Pregnancy Endpoints (SCOPE) study who subsequently developed preeclampsia (n=244) and from age- and BMI-matched normotensive controls (n=472). Micronutrient concentrations were measured by inductively coupled plasma mass spectrometry; associated antioxidant enzyme activities, selenoprotein-P, ceruloplasmin concentration and activity, antioxidant capacity, and markers of oxidative stress were measured by colorimetric assays. Sixty-four tag-single-nucleotide polymorphisms (SNPs) within genes encoding the antioxidant enzymes and selenoprotein-P were genotyped using allele-specific competitive PCR. Plasma copper and ceruloplasmin concentrations were modestly but significantly elevated in women who subsequently developed preeclampsia (both P<0.001) compared to controls (median (IQR), copper, 1957.4 (1787, 2177.5) vs 1850.0 (1663.5, 2051.5) µg/L; ceruloplasmin, 2.5 (1.4, 3.2) vs 2.2 (1.2, 3.0) µg/ml). There were no differences in other micronutrients or enzymes between groups. No relationship was observed between genotype for SNPs and antioxidant enzyme activity. This analysis of a prospective cohort study reports maternal micronutrient concentrations in combination with associated antioxidant enzymes and SNPs in their encoding genes in women at 15 weeks׳ gestation that subsequently developed preeclampsia. The modest elevation in copper may contribute to oxidative stress, later in pregnancy, in those women that go on to develop preeclampsia. The lack of evidence to support the hypothesis that functional SNPs influence antioxidant enzyme activity in pregnant women argues against a role for these genes in the etiology of preeclampsia.

Detecting translational regulation by change point analysis of ribosome profiling data sets.

Ribo-Seq maps the location of translating ribosomes on mature mRNA transcripts. While during normal translation, ribosome density is constant along the length of the mRNA coding region, this can be altered in response to translational regulatory events. In the present study, we developed a method to detect translational regulation of individual mRNAs from their ribosome profiles, utilizing changes in ribosome density. We used mathematical modeling to show that changes in ribosome density should occur along the mRNA at the point of regulation. We analyzed a Ribo-Seq data set obtained for mouse embryonic stem cells and showed that normalization by corresponding RNA-Seq can be used to improve the Ribo-Seq quality by removing bias introduced by deep-sequencing and alignment artifacts. After normalization, we applied a change point algorithm to detect changes in ribosome density present in individual mRNA ribosome profiles. Additional sequence and gene isoform information obtained from the UCSC Genome Browser allowed us to further categorize the detected changes into different mechanisms of regulation. In particular, we detected several mRNAs with known post-transcriptional regulation, e.g., premature termination for selenoprotein mRNAs and translational control of Atf4, but also several more mRNAs with hitherto unknown translational regulation. Additionally, our approach proved useful for identification of new transcript isoforms.

Selenium and cancer: a story that should not be forgotten-insights from genomics.

Selenium (Se) is an essential micronutrient that is incorporated into selenoproteins. Although epidemiological studies suggest that low Se intake is associated with increased risk of various cancers, the results of supplementation trials have been confusing. These conflicting results may be due to different baseline Se status and/or genetic factors. In addition, mechanistic links between Se intake, selenoproteins and carcinogenesis are not clear. In this article, we discuss the functional significance of single-nucleotide polymorphisms (SNP) in selenoprotein genes and the evidence as to whether or not they influence risk of colorectal, prostate, lung or breast cancers. Both in vitro and in vivo studies have shown that a small number of SNPs in genes encoding glutathione peroxidases 1 and 4, selenoprotein P, selenoprotein S and 15-kDa selenoprotein have functional consequences. Data from case-control studies suggest that a variant at codon 198 in glutathione peroxidase 1 influences the effect of Se status on prostate cancer and risk, and it has also been associated with breast cancer and lung cancer risk, whereas variants in glutathione peroxidase 4, selenoprotein P and selenoprotein S may influence the risk of colorectal cancer. In addition, the results of gene microarray (transcriptomic) studies have identified novel selenoprotein biomarkers of Se status and novel downstream Se-targeted pathways. The work highlights the need to take baseline Se status and genetic factors into account in the design of future intervention trials.

Association between polymorphisms in glutathione peroxidase and selenoprotein P genes, glutathione peroxidase activity, HRT use and breast cancer risk.

Breast cancer (BC) is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases and 975 controls matched for age and hormone replacement therapy (HRT) use was genotyped for five functional single nucleotide polymorphisms (SNPs) in SEPP1, GPX1, GPX4 and the antioxidant enzyme SOD2 genes. The influence of genetic polymorphisms on breast cancer risk was assessed using conditional logistic regression. Additionally pre-diagnosis erythrocyte GPx (eGPx) activity was measured in a sub-group of the population. A 60% reduction in risk of developing overall BC and ductal BC was observed in women who were homozygous Thr carriers for SEPP1 rs3877899. Additionally, Leu carriers for GPX1 Pro198Leu polymorphism (rs1050450) were at ∼2 fold increased risk of developing a non-ductal BC. Pre-diagnosis eGPx activity was found to depend on genotype for rs713041 (GPX4), rs3877899 (SEPP1), and rs1050450 (GPX1) and on HRT use. Moreover, depending on genotype and HRT use, eGPx activity was significantly lower in women who developed BC later in life compared with controls. Furthermore, GPx1 protein levels increased in human breast adenocarcinoma MCF7 cells exposed to ß-estradiol and sodium selenite.In conclusion, our data provide evidence that SNPs in SEPP1 and GPX1 modulate risk of BC and that eGPx activity is modified by SNPs in SEPP1, GPX4 and GPX1 and by estrogens. Our data thus suggest a role of selenoproteins in BC development.

Polymorphisms in thioredoxin reductase and selenoprotein K genes and selenium status modulate risk of prostate cancer.

Increased dietary intake of Selenium (Se) has been suggested to lower prostate cancer mortality, but supplementation trials have produced conflicting results. Se is incorporated into 25 selenoproteins. The aim of this work was to assess whether risk of prostate cancer is affected by genetic variants in genes coding for selenoproteins, either alone or in combination with Se status. 248 cases and 492 controls from an EPIC-Heidelberg nested case-control study were subjected to two-stage genotyping with an initial screening phase in which 384 tagging-SNPs covering 72 Se-related genes were determined in 94 cases and 94 controls using the Illumina Goldengate methodology. This analysis was followed by a second phase in which genotyping for candidate SNPs identified in the first phase was carried out in the full study using Sequenom. Risk of high-grade or advanced stage prostate cancer was modified by interactions between serum markers of Se status and genotypes for rs9880056 in SELK, rs9605030 and rs9605031 in TXNRD2, and rs7310505 in TXNRD1. No significant effects of SNPs on prostate cancer risk were observed when grade or Se status was not taken into account. In conclusion, the risk of high-grade or advanced-stage prostate cancer is significantly altered by a combination of genotype for SNPs in selenoprotein genes and Se status. The findings contribute to explaining the biological effects of selenium intake and genetic factors in prostate cancer development and highlight potential roles of thioredoxin reductases and selenoprotein K in tumour progression.

The influence of selenium and selenoprotein gene variants on colorectal cancer risk.

Colorectal cancer (CRC) is a major cause of mortality throughout the world and risk of CRC is known to be modulated by nutritional factors. Low intake of the micronutrient selenium (Se) has been implicated as a risk factor in CRC, and in this article we describe the biochemical functions of selenium in selenoproteins, review the evidence for an association of selenium status with CRC and adenoma risk and describe the genetic epidemiological data on selenoprotein genes and CRC risk. Epidemiological evidence linking Se intake to CRC risk is limited but there is strong evidence for a link to adenoma risk. Two studies show an association between a genetic variant in the selenoprotein S gene and CRC risk. Selenium intake modulates selenoprotein expression in the colon, especially selenoproteins W, H, M, 15 kDa selenoprotein and glutathione peroxidase 1, and downstream targets such as endoplasmic reticulum stress response, oxidative stress and inflammatory pathways. We hypothesis that Se, through the selenoproteins, plays a key role in the ability of colonic epithelial cells to respond to microbial and oxidative challenges and that a combination of low Se intake and SNP in selenoprotein genes can impair that role and so lead to increased risk of pre-neoplastic lesions. There is a need for both further studies of selenoprotein function in the colon and major genetic epidemiological and intervention studies.

Marginal selenium deficiency down-regulates inflammation-related genes in splenic leukocytes of the mouse.

Moderate selenium deficiency may lead to an impaired capacity to cope with health challenges. Functional effects of suboptimal selenium intake are not fully known, and biomarkers for an insufficient selenium supply are inadequate. We therefore fed mice diets of moderately deficient or adequate selenium intake for 6 weeks. Changes in global gene expression were monitored by microarray analysis in splenic leukocytes. Genes for four selenoproteins, Sepw1, Gpx1, Selh and Sep15, were the most significantly down-regulated in moderate selenium deficiency, and this was confirmed by quantitative polymerase chain reaction (qPCR). Classification of significantly affected genes revealed that processes related to inflammation, heme biosynthesis, DNA replication and transcription, cell cycle and transport were affected by selenium restriction. Down-regulation by moderate selenium deficiency of specific genes involved in inflammation and heme biosynthesis was confirmed by qPCR. Myeloperoxidase and lysozyme activities were decreased in selenium-restricted leukocytes, providing evidence for functional consequences. Genes for 31 nuclear factor (NF)-κB targets were down-regulated in moderate selenium deficiency, indicating an impaired NF-κB signaling. Together, the observed changes point to a disturbance in inflammatory response. The selenoproteins found here to be sensitive to selenium intake in murine leukocytes might also be useful as biomarkers for a moderate selenium deficiency in humans.

Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar.

Micronutrients are essential for optimal human health. However, in some cases, raising intake by supplementation has not proven to be beneficial and there is even some evidence that supplementation may increase disease risk, highlighting the importance of assessing the functional status of micronutrients. Techniques such as gene microarrays and single-nucleotide polymorphism analysis have the potential to examine effects of micronutrient intake on patterns of gene expression and inter-individual variation in micronutrient metabolism. Recent genomic research related to selenium (Se) provides examples illustrating how studies of functional single-nucleotide polymorphism and gene expression patterns can reveal novel biomarkers of micronutrient function. Both in vitro and in vivo experiments show that there are functionally relevant polymorphisms in genes encoding glutathione peroxidases 1, 3 and 4, selenoprotein P, selenoprotein S and the 15 kDa selenoprotein. Disease association studies investigating these gene variants have so far been relatively small but an association of a polymorphism in the selenoprotein S gene with colorectal cancer risk has been replicated in two distinct populations. Future disease association studies should examine effects of multiple variants in combination with nutritional status. Gene microarray studies indicate that changes in Se intake alter expression of components of inflammatory, stress response and translation pathways. Our hypothesis is that Se intake and genetic factors have linked effects on stress response, inflammation and apoptotic pathways. Combining such data in a systems biology approach has the potential to identify both biomarkers of micronutrients status and sub-group populations at particular risk.

Trace elements and ageing, a genomic perspective using selenium as an example.

Trace elements are key regulators of metabolic and physiological pathways known to be altered during the ageing process and therefore have the capacity to modulate the rate of biological ageing. Optimal intake is required to maintain homeostasis and to increase cell protection. Deficiencies are associated with specific illnesses. However the contribution of commonly observed life-long sub-optimal intakes of trace elements to the development and severity of age-related chronic diseases is less appreciated. Additionally, reduce intake of several trace elements has been shown to be particularly challenging for elderly people. This review will use selenium as an example to illustrate how a trace element can influence ageing and how the Omics technologies could help to study the effect of trace elements on the ageing process. Although transcriptomics and proteomics approaches in animal models have so far enabled us to identify downstream targets of trace elements in pathways related to age-related diseases processes, future approaches of combining nutrigenomics with longevity studies in humans will help us to identify mechanisms whereby trace elements affect the ageing process.

The Micronutrient Genomics Project: a community-driven knowledge base for micronutrient research.

Micronutrients influence multiple metabolic pathways including oxidative and inflammatory processes. Optimum micronutrient supply is important for the maintenance of homeostasis in metabolism and, ultimately, for maintaining good health. With advances in systems biology and genomics technologies, it is becoming feasible to assess the activity of single and multiple micronutrients in their complete biological context. Existing research collects fragments of information, which are not stored systematically and are thus not optimally disseminated. The Micronutrient Genomics Project (MGP) was established as a community-driven project to facilitate the development of systematic capture, storage, management, analyses, and dissemination of data and knowledge generated by biological studies focused on micronutrient-genome interactions. Specifically, the MGP creates a public portal and open-source bioinformatics toolbox for all "omics" information and evaluation of micronutrient and health studies. The core of the project focuses on access to, and visualization of, genetic/genomic, transcriptomic, proteomic and metabolomic information related to micronutrients. For each micronutrient, an expert group is or will be established combining the various relevant areas (including genetics, nutrition, biochemistry, and epidemiology). Each expert group will (1) collect all available knowledge, (2) collaborate with bioinformatics teams towards constructing the pathways and biological networks, and (3) publish their findings on a regular basis. The project is coordinated in a transparent manner, regular meetings are organized and dissemination is arranged through tools, a toolbox web portal, a communications website and dedicated publications.