Moderate alcohol consumption alters both leucocyte gene expression profiles and circulating proteins related to immune response and lipid metabolism in men

Moderate alcohol consumption has various effects on immune and inflammatory processes, which could accumulatively modulate chronic disease risk. So far, no comprehensive, integrative profiling has been performed to investigate the effects of longer-term alcohol consumption. Therefore, we studied the effects of alcohol consumption on gene expression patterns using large-scale profiling of whole-genome transcriptomics in blood cells and on a number of proteins in blood. In a randomised, open-label, cross-over trial, twenty-four young, normal-weight men consumed 100 ml vodka (30 g alcohol) with 200 ml orange juice or only orange juice daily during dinner for 4 weeks. After each period, blood was sampled for measuring gene expression and selected proteins. Pathway analysis of 345 down-regulated and 455 up-regulated genes revealed effects of alcohol consumption on various signalling responses, immune processes and lipid metabolism. Among the signalling processes, the most prominently changed was glucocorticoid receptor signalling. A network on immune response showed a down-regulated NF-¿B gene expression together with increased plasma adiponectin and decreased pro-inflammatory IL-1 receptor antagonist and IL-18, and acute-phase proteins ferritin and a1-antitrypsin concentrations (all P <0·05) after alcohol consumption. Furthermore, a network of gene expression changes related to lipid metabolism was observed, with a central role for PPARa which was supported by increased HDL-cholesterol and several apo concentrations (all P <0·05) after alcohol consumption. In conclusion, an integrated approach of profiling both genes and proteins in blood showed that 4 weeks of moderate alcohol consumption altered immune responses and lipid metabolis

Arginine intake and risk of coronary heart disease mortality in elderly men

From experimental studies, the hypothesis is derived that the amino acid arginine, the precursor of NO, could restore the impaired endothelial function and increased platelet activation observed in atherosclerosis. We investigated whether dietary intake of arginine is associated with reduced coronary heart disease risk in elderly persons. The study population consisted of 806 men aged 64 to 84 years at baseline who participated in the Zutphen Elderly Study, a population-based cohort followed up for 10 years. Information about habitual food consumption was collected by use of the cross-check dietary history method. Ninety (11.2€of the 806 men died from coronary heart disease. Mean±SD baseline arginine intake was 4.35±1.07 g/d. Meat was the main source of arginine intake (37.1Œ followed by bread (13.1€and milk and milk products (12.1Ž Arginine intake was not associated with coronary heart disease mortality. After adjustment for age, the relative risk (RR) for the medium tertile of arginine intake was 0.72 (95␌I 0.44 to 1.18), and the RR for the highest tertile was 0.71 (95␌I 0.43 to 1.19, P for trend=0.19) compared with the lowest tertile of arginine intake. After additional adjustment for history of coronary heart disease and diabetes mellitus, energy intake, body mass index, smoking habit, physical activity, and other relevant dietary and biological risk factors, the RR was 1.86 (95␌I 1.06 to 3.27) for the medium intake and 1.56 (95␌I 0.83 to 2.93) for the highest intake (P for trend=0.17). These results do not support the hypothesis that dietary arginine intake lowers the risk of coronary heart disease mortality

Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro

Background Many different mechanisms are involved in nutrient¿related prevention of colon cancer. In this study, a comprehensive assessment of the spectrum of possible biological actions of the bioactive compound quercetin is made using multiple gene expression analysis. Quercetin is a flavonoid that can inhibit proliferation of tumor cells and reduce the number of aberrant crypt foci, although increase of number of colon tumors was also reported. Aim of the study In order to elucidate possible mechanisms involved in its mode of action the effect of quercetin on expression of 4000 human genes in Caco¿2 cells was studied and related to functional effects. Methods Caco¿2 cells were exposed to 5 or 50 µM quercetin for 48 hours, differential expression of 4000 human genes was studied using microarrays and related to functional effects. Differentially expressed genes were categorized in seven functional groups: cell cycle and differentiation, apoptosis, tumor suppressor genes and oncogenes, cell adhesion and cell¿cell interaction, transcription, signal transduction and energy metabolism. Also, cell proliferation and cell cycle distribution were measured. Results Quercetin (5µM) downregulated expression of cell cycle genes (for example CDC6, CDK4 and cyclin D1), downregulated cell proliferation and induced cell cycle arrest in Caco¿2 cells. After exposure to 50 µM quercetin cell proliferation decreased to 51.3% of control, and further decrease of the percentage of cells in the G1 phase coincided with an increase of the percentage of cells in the sub¿G1 phase. Quercetin upregulated expression of several tumor suppressor genes. In addition, genes involved in signal transduction pathways like beta catenin/TCF signalling and MAPK signal transduction were influenced by quercetin. Conclusions This study shows that large¿scale gene expression analysis in combination with functional assays yields a considerable amount of information on (anti¿)carcinogenic potential of food components like querceti

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Role of phytochemicals in colon cancer prevention. A nutrigenomics approach

Specific food compounds, especially from fruits and vegetables, may protect against development of colon cancer. In this thesis effects and mechanisms of various phytochemicals in relation to colon cancer prevention were studied through application of large-scale gene expression profiling. Expression measurement of thousands of genes can yield a more complete and in-depth insight into the mode of action of the compounds. Effects of quercetin (a flavonoid present in e.g. apples and onions), curcumin (a spice used e.g. in curries) and resveratrol (present e.g. in grapes) were studied in cultured colon cancer cells. These studies confirmed some hypothesized mechanisms of action of these compounds (e.g. effects on cell cycle) and yielded new interesting leads (e.g. effects on proteasome genes, DNA repair genes, tubulin genes). In addition, expression profiles of a panel of 14 human cell lines derived from colonic tissue were compared and related to expression profiles of human colon biopsies from normal and tumor tissue. Changes in expression profiles of a subset of colon cancer-specific genes (as a biomarker set) in cultured colon cancer cells could be useful to translate in vitro results to the in vivo situation. In addition to the in vitro studies, effects of wheat bran, curcumin,rutinand benzyl isothiocyanate on colon carcinogenesis were studied in a rat model. Wheat bran and curcuminshoweda protective effect (lower tumor multiplicity after 8 months compared to the control group). Expression profiles of differentially expressed genes in small intestinal tissue at intermediate time points were predictive of colon tumor development at the end of the study, confirming a correlation between effects in small intestine and colon. In summary, the studies in this thesis demonstrate the potential of large-scale expression profiling in nutrition studies. These studies also demonstrated that although the technological advancements in large-scale gene expression analysis allow for the collection of 'whole genome' results, the challenge for the coming years will be to further exploit these data. Only when advances in the bioinformatics field lead to easier interpretation of large amounts of data from nutrigenomics studies, the large potential of nutrigenomics can become reality

High-protein and high-carbohydrate breakfasts differentially change the transcriptome of human blood cells

Background: Application of transcriptomics technology in human nutrition intervention studies would allow for genome-wide screening of the effects of specific diets or nutrients and result in biomarker profiles. Objective: The aim was to evaluate the potential of gene expression profiling in blood cells collected in a human intervention study that investigated the effect of a high-carbohydrate (HC) or a high-protein (HP) breakfast on satiety. Design: Blood samples were taken from 8 healthy men before and 2 h after consumption of an HP or an HC breakfast. Both breakfasts contained acetaminophen for measuring the gastric emptying rate. Analysis of the transcriptome data focused on the effects of the HP or HC breakfast and of acetaminophen on blood leukocyte gene expression profiles. Results: Breakfast consumption resulted in differentially expressed genes, 317 for the HC breakfast and 919 for the HP breakfast. Immune response and signal transduction, specifically T cell receptor signaling and nuclear transcription factor κB signaling, were the overrepresented functional groups in the set of 141 genes that were differentially expressed in response to both breakfasts. Consumption of the HC breakfast resulted in differential expression of glycogen metabolism genes, and consumption of the HP breakfast resulted in differential expression of genes involved in protein biosynthesis. Conclusions: Gene expression changes in blood leukocytes corresponded with and may be related to the difference in macronutrient content of the breakfast, meal consumption as such, and acetaminophen exposure. This study illustrates the potential of gene expression profiling in blood to study the effects of dietary exposure in human intervention studies. © 2006 American Society for Nutrition

Matrix correlations for high-dimensional data: The modified RV-coefficient

Motivation: Modern functional genomics generates high-dimensional datasets. It is often convenient to have a single simple number characterizing the relationship between pairs of such high-dimensional datasets in a comprehensive way. Matrix correlations are such numbers and are appealing since they can be interpreted in the same way as Pearson's correlations familiar to biologists. The high-dimensionality of functional genomics data is, however, problematic for existing matrix correlations. The motivation of this article is 2-fold: (i) we introduce the idea of matrix correlations to the bioinformatics community and (ii) we give an improvement of the most promising matrix correlation coefficient (the RV-coefficient) circumventing the problems of high-dimensional data. Results: The modified RV-coefficient can be usedin high-dimensional data analysis studies as an easy measure of common information of two datasets. This is shown by theoretical arguments, simulations and applications to two real-life examples from functional genomics, i.e. a transcriptomics and metabolomics example. © The Author 2008. Published by Oxford University Press. All rights reserved

Do aberrant crypt foci have predictive value for the occurrence of colorectal tumours? Potential of gene expression profiling in tumours

The effects of different dietary compounds on the formation of aberrant crypt foci (ACF) and colorectal tumours and on the expression of a selection of genes were studied in rats. Azoxymethane-treated male F344 rats were fed either a control diet or a diet containing 10% wheat bran (WB), 0.2% curcumin (CUR), 4% rutin (RUT) or 0.04% benzyl isothiocyanate (BIT) for 8 months. ACF were counted after 7, 15 and 26 weeks. Tumours were scored after 26 weeks and 8 months. We found that the WB and CUR diets inhibited the development of colorectal tumours. In contrast, the RUT and BIT diets rather enhanced (although not statistically significantly) colorectal carcinogenesis. In addition, the various compounds caused different effects on the development of ACF. In most cases the number or size of ACF was not predictive for the ultimate tumour yield. The expression of some tumour-related genes was significantly different in tumours from the control group as compared to tumours from the treated groups. It was concluded that WB and CUR, as opposed to RUT and BIT, protects against colorectal cancer and that ACF are unsuitable as biomarker for colorectal cancer. Effects of the different dietary compounds on metalloproteinase 1 (TIMP-1) expression correlated well with the effects of the dietary compounds on the ultimate tumour yield

Do aberrant crypt foci have predictive value for the occurrence of colorectal tumours? Potential of gene expression profiling in tumours

The effects of different dietary compounds on the formation of aberrant crypt foci (ACF) and colorectal tumours and on the expression of a selection of genes were studied in rats. Azoxymethane-treated male F344 rats were fed either a control diet or a diet containing 10% wheat bran (WB), 0.2% curcumin (CUR), 4% rutin (RUT) or 0.04% benzyl isothiocyanate (BIT) for 8 months. ACF were counted after 7, 15 and 26 weeks. Tumours were scored after 26 weeks and 8 months. We found that the WB and CUR diets inhibited the development of colorectal tumours. In contrast, the RUT and BIT diets rather enhanced (although not statistically significantly) colorectal carcinogenesis. In addition, the various compounds caused different effects on the development of ACF. In most cases the number or size of ACF was not predictive for the ultimate tumour yield. The expression of some tumour-related genes was significantly different in tumours from the control group as compared to tumours from the treated groups. It was concluded that WB and CUR, as opposed to RUT and BIT, protects against colorectal cancer and that ACF are unsuitable as biomarker for colorectal cancer. Effects of the different dietary compounds on metalloproteinase 1 (TIMP-1) expression correlated well with the effects of the dietary compounds on the ultimate tumour yield. © 2004 Elsevier Ltd. All rights reserved. Chemicals / CAS: benzyl isothiocyanate, 622-78-6; curcumin, 458-37-7; rutoside, 153-18-4, 22519-99-9; Anticarcinogenic Agents; DNA Primers; DNA, Complementary; RNA, Neoplasm; Tissue Inhibitor of Metalloproteinase-1; Tumor Markers, Biologica