Publications by authors named "Olivier B Bakker"

8 Publications

  • Page 1 of 1

An integrative genomics approach identifies KDM4 as a modulator of trained immunity.

Eur J Immunol 2021 Nov 25. Epub 2021 Nov 25.

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

Innate immune cells are able to build memory characteristics via a process termed trained immunity. Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/eji.202149577DOI Listing
November 2021

Evolution of cytokine production capacity in ancient and modern European populations.

Elife 2021 09 7;10. Epub 2021 Sep 7.

Department of Internal Medicine and Radboud Center for Infectious diseases (RCI), Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.

As our ancestors migrated throughout different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits that influence the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.
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http://dx.doi.org/10.7554/eLife.64971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423439PMC
September 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease.

Genome Biol 2021 07 6;22(1):198. Epub 2021 Jul 6.

Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584, CT, Utrecht, the Netherlands.

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.
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http://dx.doi.org/10.1186/s13059-021-02413-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259168PMC
July 2021

Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells.

Sci Rep 2021 04 29;11(1):9252. Epub 2021 Apr 29.

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease.
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http://dx.doi.org/10.1038/s41598-021-86612-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085175PMC
April 2021

Deconvolution of bulk blood eQTL effects into immune cell subpopulations.

BMC Bioinformatics 2020 Jun 12;21(1):243. Epub 2020 Jun 12.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background: Expression quantitative trait loci (eQTL) studies are used to interpret the function of disease-associated genetic risk factors. To date, most eQTL analyses have been conducted in bulk tissues, such as whole blood and tissue biopsies, which are likely to mask the cell type-context of the eQTL regulatory effects. Although this context can be investigated by generating transcriptional profiles from purified cell subpopulations, current methods to do this are labor-intensive and expensive. We introduce a new method, Decon2, as a framework for estimating cell proportions using expression profiles from bulk blood samples (Decon-cell) followed by deconvolution of cell type eQTLs (Decon-eQTL).

Results: The estimated cell proportions from Decon-cell agree with experimental measurements across cohorts (R ≥ 0.77). Using Decon-cell, we could predict the proportions of 34 circulating cell types for 3194 samples from a population-based cohort. Next, we identified 16,362 whole-blood eQTLs and deconvoluted cell type interaction (CTi) eQTLs using the predicted cell proportions from Decon-cell. CTi eQTLs show excellent allelic directional concordance with eQTL (≥ 96-100%) and chromatin mark QTL (≥87-92%) studies that used either purified cell subpopulations or single-cell RNA-seq, outperforming the conventional interaction effect.

Conclusions: Decon2 provides a method to detect cell type interaction effects from bulk blood eQTLs that is useful for pinpointing the most relevant cell type for a given complex disease. Decon2 is available as an R package and Java application (https://github.com/molgenis/systemsgenetics/tree/master/Decon2) and as a web tool (www.molgenis.org/deconvolution).
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http://dx.doi.org/10.1186/s12859-020-03576-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291428PMC
June 2020

Integrating GWAS with bulk and single-cell RNA-sequencing reveals a role for LY86 in the anti-Candida host response.

PLoS Pathog 2020 04 6;16(4):e1008408. Epub 2020 Apr 6.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Candida bloodstream infection, i.e. candidemia, is the most frequently encountered life-threatening fungal infection worldwide, with mortality rates up to almost 50%. In the majority of candidemia cases, Candida albicans is responsible. Worryingly, a global increase in the number of patients who are susceptible to infection (e.g. immunocompromised patients), has led to a rise in the incidence of candidemia in the last few decades. Therefore, a better understanding of the anti-Candida host response is essential to overcome this poor prognosis and to lower disease incidence. Here, we integrated genome-wide association studies with bulk and single-cell transcriptomic analyses of immune cells stimulated with Candida albicans to further our understanding of the anti-Candida host response. We show that differential expression analysis upon Candida stimulation in single-cell expression data can reveal the important cell types involved in the host response against Candida. This confirmed the known major role of monocytes, but more interestingly, also uncovered an important role for NK cells. Moreover, combining the power of bulk RNA-seq with the high resolution of single-cell RNA-seq data led to the identification of 27 Candida-response QTLs and revealed the cell types potentially involved herein. Integration of these response QTLs with a GWAS on candidemia susceptibility uncovered a potential new role for LY86 in candidemia susceptibility. Finally, experimental follow-up confirmed that LY86 knockdown results in reduced monocyte migration towards the chemokine MCP-1, thereby implying that this reduced migration may underlie the increased susceptibility to candidemia. Altogether, our integrative systems genetics approach identifies previously unknown mechanisms underlying the immune response to Candida infection.
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http://dx.doi.org/10.1371/journal.ppat.1008408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173933PMC
April 2020

Integration of multi-omics data and deep phenotyping enables prediction of cytokine responses.

Nat Immunol 2018 07 21;19(7):776-786. Epub 2018 May 21.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

The immune response to pathogens varies substantially among people. Whereas both genetic and nongenetic factors contribute to interperson variation, their relative contributions and potential predictive power have remained largely unknown. By systematically correlating host factors in 534 healthy volunteers, including baseline immunological parameters and molecular profiles (genome, metabolome and gut microbiome), with cytokine production after stimulation with 20 pathogens, we identified distinct patterns of co-regulation. Among the 91 different cytokine-stimulus pairs, 11 categories of host factors together explained up to 67% of interindividual variation in cytokine production induced by stimulation. A computational model based on genetic data predicted the genetic component of stimulus-induced cytokine production (correlation 0.28-0.89), and nongenetic factors influenced cytokine production as well.
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http://dx.doi.org/10.1038/s41590-018-0121-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022810PMC
July 2018
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