Browsing publications of the working group of computational biology for individualized medicine ([CiiM] BIIM) by Authors
Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease.Chu, Xiaojing; Jaeger, Martin; Beumer, Joep; Bakker, Olivier B; Aguirre-Gamboa, Raul; Oosting, Marije; Smeekens, Sanne P; Moorlag, Simone; Mourits, Vera P; Koeken, Valerie A C M; et al. (BMC, 2021-07-06)Background: Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors. Result: We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target. Conclusion: This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.
Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.Ter Horst, Rob; van den Munckhof, Inge C L; Schraa, Kiki; Aguirre-Gamboa, Raul; Jaeger, Martin; Smeekens, Sanne P; Brand, Tessa; Lemmers, Heidi; Dijkstra, Helga; Galesloot, Tessel E; et al. (Lippincott, Williams & Wilkins, 2020-05-28)Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m2 and half with a BMI>30 kg/m2, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity.
Tissue alarmins and adaptive cytokine induce dynamic and distinct transcriptional responses in tissue-resident intraepithelial cytotoxic T lymphocytes.Zorro, Maria Magdalena; Aguirre-Gamboa, Raul; Mayassi, Toufic; Ciszewski, Cezary; Barisani, Donatella; Hu, Shixian; Weersma, Rinse K; Withoff, Sebo; Li, Yang; Wijmenga, Cisca; et al. (Elsevier, 2020-02-04)The respective effects of tissue alarmins interleukin (IL)-15 and interferon beta (IFNβ), and IL-21 produced by T cells on the reprogramming of cytotoxic T lymphocytes (CTLs) that cause tissue destruction in celiac disease is poorly understood. Transcriptomic and epigenetic profiling of primary intestinal CTLs showed massive and distinct temporal transcriptional changes in response to tissue alarmins, while the impact of IL-21 was limited. Only anti-viral pathways were induced in response to all the three stimuli, albeit with differences in dynamics and strength. Moreover, changes in gene expression were primarily independent of changes in H3K27ac, suggesting that other regulatory mechanisms drive the robust transcriptional response. Finally, we found that IL-15/IFNβ/IL-21 transcriptional signatures could be linked to transcriptional alterations in risk loci for complex immune diseases. Together these results provide new insights into molecular mechanisms that fuel the activation of CTLs under conditions that emulate the inflammatory environment in patients with autoimmune diseases.