Summary Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project we assessed the effect of environmental and non-genetic host factors, of the genetic make-up of the host, and of the intestinal microbiome, on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral and non-microbial metabolic stimuli in 534 healthy subjects. In this first study we show a strong impact of non-genetic host factors (e.g. age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies.

As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases. PAPERCLIP.

Average flavonoid intake may partly contribute to differences in coronary heart disease mortality across populations, but it does not seem to be an important determinant of cancer mortality.

At the end of the 1950s the Seven Countries Study was designed to investigate the relations between diet and cardiovascular diseases. Sixteen cohorts were selected in Finland, Greece, Italy, Japan, The Netherlands, United States, and Yugoslavia. During the 1960s food consumption data were collected from random samples of these cohorts by use of the record method. In Finland the intake of milk, potatoes, edible fats, and sugar products was very high. A similar but lower intake pattern was observed in The Netherlands. Fruit, meat, and pastry consumption was high in the United States; cereal and alcoholic drink consumption was high in Italy; and bread consumption high in Yugoslavians except for those in Belgrade. In Greece the intake of olive oil and fruit was high and the Japanese cohorts were characterized by a high consumption of fish, rice, and soy products. These differences in food consumption patterns have lessened during the past 25 y.