In IN-CONTROL 1, we built a cohort of 300 subjects with overweight or obesity for deep phenotyping of clinical parameters for cardiometabolic disease, genomics, microbiome, and extensive phenotyping of the immune system (see figure);


The main observations that we did in this cohort, were that we identified novel circulating inflammatory markers that were highly associated the presence of carotid atherosclerosis, over and above know inflammatory markers such as high-sensitive CRP (van den Munckhof, submitted). In addition, using multi-omics and cross-omics approaches, we identified novel layers of regulation of inflammation and how this might contribute to the development of cardiovascular diseases (ten Horst, submitted; Frishberg et al, submitted).

Combining data of our cohort with cohorts from Groningen resulted in an improved insight into the role of the microbiome in inflammation, metabolism, and cardiovascular diseases (Kurilshikov, van den Munckhof et al, Circ Res 2019; van den Munckhof, et al, Obes Rev 2018).

In IN-CONTROL II we will now decipher in more depth the mechanisms that induce inflammation in these subjects, focusing on trained immunity, clonal hematopoiesis, and immune cell senescence in relation to increased CVD risk based on the proteomic panel. Subsequently, we will design and test novel therapies based on these mechanisms in WP4. Trained immunity indicates the nonspecific immunological memory leading to hyperinflammation and is mediated by metabolic and epigenetic reprogramming. Brief exposure of monocytes to oxidized LDL and lipoprotein (a) induces a persistent pro-atherogenic monocyte phenotype, as well as a four-week WTD in murine models, due to epigenetic reprogramming of myeloid bone marrow progenitors. Interestingly, statins partly prevent the inappropriate induction of trained immunity. In addition, clonal hematopoiesis impacts on the inflammatory potential of myeloid cells. Clonal hematopoiesis is a hallmark of aging and results from somatic mutations in hematopoietic stem cells which gives an advantage to mutant cells, driving their clonal expansion. Epigenetic regulators, including Tet2 and Dnmt3a, drives these effects, and individuals with clonal hematopoiesis have an increased risk for atherosclerotic CVD through increased secretion of pro-inflammatory cytokines. With ultra-sensitive sequencing, more that 20% of subjects aged 60-69 appear to carry clonal hematopoiesis-driver mutations. With epigenetic reprogramming at the center of trained immunity, we hypothesize that clonal hematopoiesis influences induction of trained immunity.


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