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5. NMR metabolomics-guided DNA methylation mortality predictors

Author

Bizzarri, Daniele, Reinders, Marcel J.T., Kuiper, Lieke, Beekman, Marian, Deelen, Joris, van Meurs, Joyce B.J., van Dongen, Jenny, Pool, René, Boomsma, D. I., Ghanbari, M., Franke, Lude, Geleijnse, J. M., Boersma, E., van Spil, W. E., van Greevenbroek, M. M.J., Stehouwer, C. D.A., van der Kallen, C. J.H., Arts, I. C.W., Rutters, F., Beulens, J. W.J., Muilwijk, M., Elders, P. J.M., 't Hart, L. M., Ikram, M. A., Netea, M. G., Kloppenburg, M., Ramos, Y. F.M., Bomer, N., Meulenbelt, I., Stronks, K., Snijder, M. B., Zwinderman, A. H., Heijmans, B. T., Lumey, L. H., Fu, J., Deelen, J., Mooijaart, S. P., Beekman, M., Bot, M., Trompet, S., van der Horst, I. C.C., So-Osman, C., Nelissen, R. G.H.H., Teunissen, C. E., van Dongen, J., Willemsen, A. H.M., Mei, H., Reinders, M. J.T., van den Akker, E. B., Bizzarri, Daniele, Reinders, Marcel J.T., Kuiper, Lieke, Beekman, Marian, Deelen, Joris, van Meurs, Joyce B.J., van Dongen, Jenny, Pool, René, Boomsma, D. I., Ghanbari, M., Franke, Lude, Geleijnse, J. M., Boersma, E., van Spil, W. E., van Greevenbroek, M. M.J., Stehouwer, C. D.A., van der Kallen, C. J.H., Arts, I. C.W., Rutters, F., Beulens, J. W.J., Muilwijk, M., Elders, P. J.M., 't Hart, L. M., Ikram, M. A., Netea, M. G., Kloppenburg, M., Ramos, Y. F.M., Bomer, N., Meulenbelt, I., Stronks, K., Snijder, M. B., Zwinderman, A. H., Heijmans, B. T., Lumey, L. H., Fu, J., Deelen, J., Mooijaart, S. P., Beekman, M., Bot, M., Trompet, S., van der Horst, I. C.C., So-Osman, C., Nelissen, R. G.H.H., Teunissen, C. E., van Dongen, J., Willemsen, A. H.M., Mei, H., Reinders, M. J.T., and van den Akker, E. B.

Abstract

Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

Published
2024

6. Urate-induced epigenetic modifications in myeloid cells

Author

Badii, M., Gaal, O. I., Cleophas, M. C., Klück, V., Davar, R., Habibi, E., Keating, S. T., Novakovic, B., Helsen, M. M., Dalbeth, N., Stamp, L. K., Macartney-Coxson, D., Phipps-Green, A. J., Stunnenberg, H. G., Dinarello, C. A., Merriman, T. R., Netea, M. G., Crişan, T. O., and Joosten, L. A. B.

Published
2021
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11. Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

Author

Sánchez-Maldonado, J. M., Campa, D., Springer, J., Badiola, J., Niazi, Y., Moñiz-Díez, A., Hernández-Mohedo, F., González-Sierra, P., Ter Horst, R., Macauda, A., Brezina, S., Cunha, C., Lackner, M., López-Nevot, M. A., Fianchi, L., Pagano, L., López-Fernández, E., Potenza, L., Luppi, M., Moratalla, L., Rodríguez-Sevilla, J. J., Fonseca, J. E., Tormo, M., Solano, C., Clavero, E., Romero, A., Li, Y., Lass-Flörl, C., Einsele, H., Vazquez, L., Loeffler, J., Hemminki, K., Carvalho, A., Netea, M. G., Gsur, A., Dumontet, C., Canzian, F., Försti, A., Jurado, M., and Sainz, J.

Published
2020
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12. Genetic continuity, isolation, and gene flow in Stone Age Central and Eastern Europe

Author

Mattila, T. M. (Tiina M.), Svensson, E. M. (Emma M.), Juras, A. (Anna), Günther, T. (Torsten), Kashuba, N. (Natalija), Ala-Hulkko, T. (Terhi), Chyleński, M. (Maciej), McKenna, J. (James), Pospieszny, Ł. (Łukasz), Constantinescu, M. (Mihai), Rotea, M. (Mihai), Palincaș, N. (Nona), Wilk, S. (Stanisław), Czerniak, L. (Lech), Kruk, J. (Janusz), Łapo, J. (Jerzy), Makarowicz, P. (Przemysław), Potekhina, I. (Inna), Soficaru, A. (Andrei), Szmyt, M. (Marzena), Szostek, K. (Krzysztof), Götherström, A. (Anders), Storå, J. (Jan), Netea, M. G. (Mihai G.), Nikitin, A. G. (Alexey G.), Persson, P. (Per), Malmström, H. (Helena), Jakobsson, M. (Mattias), Mattila, T. M. (Tiina M.), Svensson, E. M. (Emma M.), Juras, A. (Anna), Günther, T. (Torsten), Kashuba, N. (Natalija), Ala-Hulkko, T. (Terhi), Chyleński, M. (Maciej), McKenna, J. (James), Pospieszny, Ł. (Łukasz), Constantinescu, M. (Mihai), Rotea, M. (Mihai), Palincaș, N. (Nona), Wilk, S. (Stanisław), Czerniak, L. (Lech), Kruk, J. (Janusz), Łapo, J. (Jerzy), Makarowicz, P. (Przemysław), Potekhina, I. (Inna), Soficaru, A. (Andrei), Szmyt, M. (Marzena), Szostek, K. (Krzysztof), Götherström, A. (Anders), Storå, J. (Jan), Netea, M. G. (Mihai G.), Nikitin, A. G. (Alexey G.), Persson, P. (Per), Malmström, H. (Helena), and Jakobsson, M. (Mattias)

Abstract

The genomic landscape of Stone Age Europe was shaped by multiple migratory waves and population replacements, but different regions do not all show similar patterns. To refine our understanding of the population dynamics before and after the dawn of the Neolithic, we generated and analyzed genomic sequence data from human remains of 56 individuals from the Mesolithic, Neolithic, and Eneolithic across Central and Eastern Europe. We found that Mesolithic European populations formed a geographically widespread isolation-by-distance zone ranging from Central Europe to Siberia, which was already established 10,000 years ago. We found contrasting patterns of population continuity during the Neolithic transition: people around the lower Dnipro Valley region, Ukraine, showed continuity over 4000 years, from the Mesolithic to the end of the Neolithic, in contrast to almost all other parts of Europe where population turnover drove this cultural change, including vast areas of Central Europe and around the Danube River.

Published
2023

21. Personalised immunotherapy in sepsis: a scoping review protocol

Author

Slim, Marleen A, primary, van Mourik, Niels, additional, Dionne, Joanna C, additional, Oczkowski, Simon J W, additional, Netea, M G, additional, Pickkers, Peter, additional, Giamarellos-Bourboulis, Evangelos J, additional, Müller, Marcella C A, additional, van der Poll, Tom, additional, Wiersinga, W Joost, additional, Vlaar, Alexander P J, additional, and van Vught, Lonneke A, additional

Published
2022
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23. Genetics and Not Shared Environment Explains Familial Resemblance in Adult Metabolomics Data

Author

Pool, Rene, Hagenbeek, Fiona A., Hendriks, Anne M., van Dongen, Jenny, Willemsen, Gonneke, de Geus, Eco, van Dijk, Ko Willems, Verhoeven, Aswin, Suchiman, H. Eka, Beekman, Marian, Slagboom, P. Eline, Harms, Amy C., Hankemeier, Thomas, Boomsma, Dorret, I, Beekman, M., Suchiman, H. E. D., Amin, N., Beulens, J. W., van der Bom, J. A., Bomer, N., Demirkan, A., van Hilten, J. A., Meessen, J. M. T. A., Pool, R., Moed, M. H., Fu, J., Onderwater, G. L. J., Rutters, F., So-Osman, C., van der Flier, W. M., van der Heijden, A. A. W. A., van der Spek, A., Asselbergs, F. W., Boersma, E., Elders, P. M., Geleijnse, J. M., Ikram, M. A., Kloppenburg, M., Meulenbelt, I, Mooijaart, S. P., Nelissen, R. G. H. H., Netea, M. G., Penninx, B. W. J. H., Stehouwer, C. D. A., Teunissen, C. E., Terwindt, G. M., 't Hart, L. M., van den Maagdenberg, A. M. J. M., van der Harst, P., van der Horst, I. C. C., van der Kallen, C. J. H., van Greevenbroek, M. M. J., van Spil, W. E., Wijmenga, C., Zwinderman, A. H., Zhernikova, A., Jukema, J. W., Wolf, J. J. H. Barkey, Cats, D., Mei, H., Slofstra, M., Swertz, M., van den Akker, E. B., Deelen, J., Reinders, M. J. T., Boomsma, D., I, van Duijn, C. M., Slagboom, P. E., Interne Geneeskunde, MUMC+: MA Interne Geneeskunde (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), MUMC+: MA Endocrinologie (9), MUMC+: MA Maag Darm Lever (9), MUMC+: MA Hematologie (9), MUMC+: MA Medische Oncologie (9), MUMC+: MA Nefrologie (9), MUMC+: MA Reumatologie (9), RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Molecular Neuroscience and Ageing Research (MOLAR), Cardiovascular Centre (CVC), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Medical Microbiology and Infection Prevention, Graduate School, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Obstetrics and Gynaecology, Cardiology, Public and occupational health, Gastroenterology and Hepatology, Paediatric Endocrinology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Epidemiology and Data Science, Obstetrics and gynaecology, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Anatomy and neurosciences, Anesthesiology, General practice, Internal medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Laboratory Medicine, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation, Amsterdam Reproduction & Development (AR&D), AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, Rheumatology, Gastroenterology and hepatology, APH - Aging & Later Life, and APH - Digital Health

Subjects
Male, Netherlands Twin Register (NTR), 0301 basic medicine, Shared environment, Metabolite, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Genome-wide association study, heritability, METABOLITES, Keywords: Classical twin design, chemistry.chemical_compound, 0302 clinical medicine, metabolite classes, Twins, Dizygotic, EPIDEMIOLOGY, Classical twin design, Genetics (clinical), Genetics, HERITABILITY, shared environment, Obstetrics and Gynecology, Phenotype, Quartile, Metabolome, Female, Adult, Dizygotic twin, POWER, TWIN, Environment, Biology, enrichment analysis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Metabolomics, AGE, Diseases in Twins, Humans, Family, GENOME-WIDE ASSOCIATION, Classical twin design [Keywords], Twins, Monozygotic, PROFILES, Heritability, Diet, Metabolomics data, 030104 developmental biology, chemistry, Pediatrics, Perinatology and Child Health, Gene-Environment Interaction, 030217 neurology & neurosurgery
Abstract

Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term ‘metabolomics’ refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.

Published
2020

24. Borrelia burgdorferi is a poor inducer of interferon-gamma: amplification induced by interleukin-12

Author

van de Schoor, F R, Vrijmoeth, H D, Brouwer, M A E, Ter Hofstede, H J M, Lemmers, H L M, Dijkstra, H, Boahen, C K, Oosting, M, Kullberg, B J, Hovius, J W, van den Wijngaard, C C, van de Veerdonk, F L, Netea, M G, and Joosten, L A B

Abstract

Background Laboratory diagnosis of Lyme borreliosis (LB) is mainly based on serology, which has limitations, particularly in the early stages of the disease. In recent years there have been conflicting reports concerning a new diagnostic tool using the cytokine interferon-gamma (IFN-γ). Previous studies have generally found low concentrations of IFN-γ in early LB infection. The goal of this study is to investigate IFN-γ regulation during early LB and provide insights into the host response to B. burgdorferi. Methods We performed in vitro experiments with whole blood assays and peripheral blood mononuclear cells (PBMCs) of LB patients and healthy volunteers exposed to B. burgdorferi and evaluated the IFN-γ response using ELISA and related interindividual variation in IFN-γ production to the presence of single nucleotide polymorphisms. Results IFN-γ production of B. burgdorferi-exposed PBMCs and whole blood was amplified by the addition of IL-12 to the stimulation system. This effect was observed after 24 hours of B. burgdorferi stimulation in both healthy individuals and LB patients. The effect was highly variable between individuals, but was significantly higher in LB patients six weeks since the start of antibiotic treatment compared to healthy individuals. IL-12 p40 and IL-18 mRNA was upregulated upon exposure to B. burgdorferi, whereas IL-12 p35 and IFN-γ mRNA expression remained relatively unchanged. SNP Rs280520 in the downstream IL-12 pathway, Tyrosine Kinase 2, was associated with increased IFN-γ production. Conclusions This study shows that IL-12 evokes an IFN-γ response in B. burgdorferi exposed cells, and LB patients and healthy controls respond differently to this stimulation.

Published
2022

30. Sustained endothelial, coagulation and inflammatory cytokine activation without macrovascular dysfunction at 3 months after COVID-19: a reflection on SARS-CoV-2 induced thrombo-inflammation

Author

Willems, L H, primary, Nagy, M, additional, Ten Cate, H, additional, Spronk, H M H, additional, Groh, L A, additional, Leentjes, J, additional, Janssen, N A F, additional, Netea, M G, additional, Thijssen, D H J, additional, Hannink, G J, additional, Van Petersen, A S, additional, and Warle, M C, additional

Published
2021
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36. Additional file 1 of Urate-induced epigenetic modifications in myeloid cells

Author

Badii, M., Gaal, O. I., Cleophas, M. C., Klück, V., Davar, R., Habibi, E., Keating, S. T., Novakovic, B., Helsen, M. M., Dalbeth, N., Stamp, L. K., Macartney-Coxson, D., Phipps-Green, A. J., Stunnenberg, H. G., Dinarello, C. A., Merriman, T. R., Netea, M. G., Crişan, T. O., and Joosten, L. A. B.

Subjects
Data_FILES
Abstract

Additional file 1.

Published
2021
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37. Polymorphisms within the TNFSF4 and mapkapk2 loci influence the risk of developing invasive aspergillosis: A two-stage case control study in the context of the aspbiomics consortium

Author

Sanchez-Maldonado, J. M., Moniz-Diez, A., Ter Horst, R., Campa, D., Cabrera-Serrano, A. J., Martinez-Bueno, M., Garrido-Collado, M. P., Hernandez-Mohedo, F., Fernandez-Puerta, L., Lopez-Nevot, M. A., Cunha, C., Gonzalez-Sierra, P. A., Springer, J., Lackner, M., Alcazar-Fuoli, L., Fianchi, L., Aguado, J. M., Pagano, L., Lopez-Fernandez, E., Clavero, E., Potenza, L., Luppi, M., Moratalla, L., Solano, C., Sampedro, A., Cuenca-Estrella, M., Lass-Florl, C., Canzian, F., Loeffler, J., Li, Y., Einsele, H., Netea, M. G., Vazquez, L., Carvalho, A., Jurado, M., Sainz, J., Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Sanchez-Maldonado, J. M., Moniz-Diez, A., Ter Horst, R., Campa, D., Cabrera-Serrano, A. J., Martinez-Bueno, M., Garrido-Collado, M. P., Hernandez-Mohedo, F., Fernandez-Puerta, L., Lopez-Nevot, M. A., Cunha, C., Gonzalez-Sierra, P. A., Springer, J., Lackner, M., Alcazar-Fuoli, L., Fianchi, L., Aguado, J. M., Pagano, L., Lopez-Fernandez, E., Clavero, E., Potenza, L., Luppi, M., Moratalla, L., Solano, C., Sampedro, A., Cuenca-Estrella, M., Lass-Florl, C., Canzian, F., Loeffler, J., Li, Y., Einsele, H., Netea, M. G., Vazquez, L., Carvalho, A., Jurado, M., Sainz, J., Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD-plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD-B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16-cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.

Published
2021

39. Author Correction: Heritability estimates for 361 blood metabolites across 40 genome-wide association studies (Nature Communications, (2020), 11, 1, (39), 10.1038/s41467-019-13770-6)

Author

Hagenbeek, Fiona A., Pool, René, van Dongen, Jenny, Draisma, H. M., Jan Hottenga, Jouke, Willemsen, Gonneke, Abdellaoui, Abdel, Fedko, Iryna O., den Braber, Anouk, Visser, Pieter Jelle, de Geus, Eco J.C.N., Willems van Dijk, Ko, Verhoeven, Aswin, Suchiman, H. Eka, Beekman, Marian, Slagboom, P. Eline, van Duijn, Cornelia M., Barkey Wolf, J. J.H., Cats, D., Amin, N., Beulens, J. W., van der Bom, J. A., Bomer, N., Demirkan, A., van Hilten, J. A., Meessen, J. M.T.A., Moed, M. H., Fu, J., Onderwater, G. L.J., Rutters, F., So-Osman, C., van der Flier, W. M., van der Heijden, A. A.W.A., van der Spek, A., Asselbergs, F. W., Boersma, E., Elders, P. M., Geleijnse, J. M., Ikram, M. A., Kloppenburg, M., Meulenbelt, I., Mooijaart, S. P., Nelissen, R. G.H.H., Netea, M. G., Penninx, B. W.J.H., Stehouwer, C. D.A., Teunissen, C. E., Terwindt, G. M., ‘t Hart, L. M., van den Maagdenberg, A. M.J.M., van der Harst, P., van der Horst, I. C.C., van der Kallen, C. J.H., van Greevenbroek, M. M.J., van Spil, W. E., Wijmenga, C., Zwinderman, A. H., Zhernikova, A., Jukema, J. W., Mei, H., Slofstra, M., Swertz, M., van den Akker, E. B., Deelen, J., Reinders, M. J.T., Harms, Amy C., Hankemeier, Thomas, Bartels, Meike, Nivard, Michel G., Boomsma, Dorret I., Neurology, APH - Health Behaviors & Chronic Diseases, ACS - Heart failure & arrhythmias, Epidemiology and Data Science, General practice, APH - Methodology, APH - Mental Health, Psychiatry, Clinical chemistry, APH - Aging & Later Life, APH - Personalized Medicine, APH - Digital Health, and ACS - Diabetes & metabolism

Abstract

The original version of the Supplementary Information associated with this Article included an incorrect Supplementary Data 1 file, in which additional delimiters were included in the first column for a number of rows, resulting in column shifts for some of these rows. The HTML has been updated to include a corrected version of Supplementary Data 1; the original incorrect version of Supplementary Data 1 can be found as Supplementary Information associated with this Correction. In addition, the original version of this Article contained an error in the author affiliations. An affiliation of Abdel Abdellaoui with Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2020

44. LifeTime and improving European healthcare through cell-based interceptive medicine

Author

Rajewsky, N., Almouzni, G., Gorski, S. A., Aerts, S., Amit, I., Bertero, M. G., Bock, C., Bredenoord, A. L., Cavalli, G., Chiocca, S., Clevers, H., De Strooper, B., Eggert, A., Ellenberg, J., Fernández, X. M., Figlerowicz, M., Gasser, S. M., Hubner, N., Kjems, J., Knoblich, J. A., Krabbe, G., Lichter, P., Linnarsson, S., Marine, J. -C, Marioni, J., Marti-Renom, M. A., Netea, M. G., Nickel, D., Nollmann, M., Novak, H. R., Parkinson, H., Piccolo, S., Pinheiro, I., Pombo, A., Popp, C., Reik, W., Roman-Roman, S., Rosenstiel, P., Schultze, J. L., Stegle, O., Tanay, A., Testa, G., Thanos, D., Theis, F. J., Torres-Padilla, M. -E, Valencia, A., Vallot, C., van Oudenaarden, A., Vidal, M., Voet, T., Alberi, L., Alexander, S., Alexandrov, T., Arenas, E., Bagni, C., Balderas, R., Bandelli, A., Becher, B., Becker, M., Beerenwinkel, N., Benkirame, M., Beyer, M., Bickmore, W., Biessen, E. E. A. L., Blomberg, N., Blumcke, I., Bodenmiller, B., Borroni, B., Boumpas, D. T., Bourgeron, T., Bowers, S., Braeken, D., Brooksbank, C., Brose, N., Bruining, H., Bury, J., Caporale, N., Cattoretti, G., Chabane, N., Chneiweiss, H., Cook, S. A., Curatolo, P., de Jonge, M. I., Deplancke, B., de Witte, P., Dimmeler, S., Draganski, B., Drews, A. -D, Dumbrava, C., Engelhardt, S., Gasser, T., Giamarellos-Bourboulis, E. J., Graff, C., Grün, D., Gut, I., Hansson, O., Henshall, D. C., Herland, Anna, Heutink, P., Heymans, S. R. B., Heyn, H., Huch, M., Huitinga, I., Jackowiak, P., Jongsma, K. R., Journot, L., Junker, J. P., Katz, S., Kehren, J., Kempa, S., Kirchhof, P., Klein, C., Koralewska, N., Korbel, J. O., Kühnemund, M., Lamond, A. I., Lauwers, E., Le Ber, I., Leinonen, V., Tobon, A. L., Lundberg, E., Lunkes, A., Maatz, H., Mann, M., Marelli, L., Matser, V., Matthews, P. M., Mechta-Grigoriou, F., Menon, R., Nielsen, A. F., Pagani, M., Pasterkamp, R. J., Pitkanen, A., Popescu, V., Pottier, C., Puisieux, A., Rademakers, R., Reiling, D., Reiner, O., Remondini, D., Ritchie, C., Rohrer, J. D., Saliba, A. -E, Sanchez-Valle, R., Santosuosso, A., Sauter, A., Scheltema, R. A., Scheltens, P., Schiller, H. B., Schneider, A., Seibler, P., Sheehan-Rooney, K., Shields, D., Sleegers, K., Smit, G., Smith, K. G. C., Smolders, I., Synofzik, M., Tam, W. L., Teichmann, S., Thom, M., Turco, M. Y., van Beusekom, H. M. M., Vandenberghe, R., den Hoecke, S. V., Van de Poel, I., der Ven, A., van der Zee, J., van Lunzen, J., van Minnebruggen, G., Van Paesschen, W., van Swieten, J., van Vught, R., Verhage, M., Verstreken, P., Villa, C. E., Vogel, J., von Kalle, C., Walter, J., Weckhuysen, S., Weichert, W., Wood, L., Ziegler, A. -G, Zipp, F., Community, LifeTime, Rajewsky, N., Almouzni, G., Gorski, S. A., Aerts, S., Amit, I., Bertero, M. G., Bock, C., Bredenoord, A. L., Cavalli, G., Chiocca, S., Clevers, H., De Strooper, B., Eggert, A., Ellenberg, J., Fernández, X. M., Figlerowicz, M., Gasser, S. M., Hubner, N., Kjems, J., Knoblich, J. A., Krabbe, G., Lichter, P., Linnarsson, S., Marine, J. -C, Marioni, J., Marti-Renom, M. A., Netea, M. G., Nickel, D., Nollmann, M., Novak, H. R., Parkinson, H., Piccolo, S., Pinheiro, I., Pombo, A., Popp, C., Reik, W., Roman-Roman, S., Rosenstiel, P., Schultze, J. L., Stegle, O., Tanay, A., Testa, G., Thanos, D., Theis, F. J., Torres-Padilla, M. -E, Valencia, A., Vallot, C., van Oudenaarden, A., Vidal, M., Voet, T., Alberi, L., Alexander, S., Alexandrov, T., Arenas, E., Bagni, C., Balderas, R., Bandelli, A., Becher, B., Becker, M., Beerenwinkel, N., Benkirame, M., Beyer, M., Bickmore, W., Biessen, E. E. A. L., Blomberg, N., Blumcke, I., Bodenmiller, B., Borroni, B., Boumpas, D. T., Bourgeron, T., Bowers, S., Braeken, D., Brooksbank, C., Brose, N., Bruining, H., Bury, J., Caporale, N., Cattoretti, G., Chabane, N., Chneiweiss, H., Cook, S. A., Curatolo, P., de Jonge, M. I., Deplancke, B., de Witte, P., Dimmeler, S., Draganski, B., Drews, A. -D, Dumbrava, C., Engelhardt, S., Gasser, T., Giamarellos-Bourboulis, E. J., Graff, C., Grün, D., Gut, I., Hansson, O., Henshall, D. C., Herland, Anna, Heutink, P., Heymans, S. R. B., Heyn, H., Huch, M., Huitinga, I., Jackowiak, P., Jongsma, K. R., Journot, L., Junker, J. P., Katz, S., Kehren, J., Kempa, S., Kirchhof, P., Klein, C., Koralewska, N., Korbel, J. O., Kühnemund, M., Lamond, A. I., Lauwers, E., Le Ber, I., Leinonen, V., Tobon, A. L., Lundberg, E., Lunkes, A., Maatz, H., Mann, M., Marelli, L., Matser, V., Matthews, P. M., Mechta-Grigoriou, F., Menon, R., Nielsen, A. F., Pagani, M., Pasterkamp, R. J., Pitkanen, A., Popescu, V., Pottier, C., Puisieux, A., Rademakers, R., Reiling, D., Reiner, O., Remondini, D., Ritchie, C., Rohrer, J. D., Saliba, A. -E, Sanchez-Valle, R., Santosuosso, A., Sauter, A., Scheltema, R. A., Scheltens, P., Schiller, H. B., Schneider, A., Seibler, P., Sheehan-Rooney, K., Shields, D., Sleegers, K., Smit, G., Smith, K. G. C., Smolders, I., Synofzik, M., Tam, W. L., Teichmann, S., Thom, M., Turco, M. Y., van Beusekom, H. M. M., Vandenberghe, R., den Hoecke, S. V., Van de Poel, I., der Ven, A., van der Zee, J., van Lunzen, J., van Minnebruggen, G., Van Paesschen, W., van Swieten, J., van Vught, R., Verhage, M., Verstreken, P., Villa, C. E., Vogel, J., von Kalle, C., Walter, J., Weckhuysen, S., Weichert, W., Wood, L., Ziegler, A. -G, Zipp, F., and Community, LifeTime

Abstract

LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade., QC 20201117Correction in: Nature, Volume 587, Issue 7834, Pages 377 - 386, 19 November 2020. DOI: 10.1038/s41586-021-03287-8, Scopus ID: 2-s2.0-85102698588

Published
2020
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45. Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

Author

Sánchez-Maldonado, J M, Campa, D, Springer, J, Badiola, J, Niazi, Y, Moñiz-Díez, A, Hernández-Mohedo, F, González-Sierra, P, Ter Horst, R, Macauda, A, Brezina, S, Cunha, C, Lackner, M, López-Nevot, M A, Fianchi, Luana, Pagano, Livio, López-Fernández, E, Potenza, L, Luppi, M, Moratalla, L, Rodríguez-Sevilla, J J, Fonseca, J E, Tormo, M, Solano, C, Clavero, E, Romero, A, Li, Y, Lass-Flörl, C, Einsele, H, Vazquez, L, Loeffler, J, Hemminki, K, Carvalho, A, Netea, M G, Gsur, A, Dumontet, C, Canzian, F, Försti, A, Jurado, M, Sainz, J, Fianchi, L, Pagano, L (ORCID:0000-0001-8287-928X), Sánchez-Maldonado, J M, Campa, D, Springer, J, Badiola, J, Niazi, Y, Moñiz-Díez, A, Hernández-Mohedo, F, González-Sierra, P, Ter Horst, R, Macauda, A, Brezina, S, Cunha, C, Lackner, M, López-Nevot, M A, Fianchi, Luana, Pagano, Livio, López-Fernández, E, Potenza, L, Luppi, M, Moratalla, L, Rodríguez-Sevilla, J J, Fonseca, J E, Tormo, M, Solano, C, Clavero, E, Romero, A, Li, Y, Lass-Flörl, C, Einsele, H, Vazquez, L, Loeffler, J, Hemminki, K, Carvalho, A, Netea, M G, Gsur, A, Dumontet, C, Canzian, F, Försti, A, Jurado, M, Sainz, J, Fianchi, L, and Pagano, L (ORCID:0000-0001-8287-928X)

Abstract

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Published
2020

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