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

Bakker, Olivier B.; Aguirre-Gamboa, Raúl; Sanna, Serena; Oosting, Marije; Smeekens, Sanne P.; Jaeger, Martin; Zorro, Maria M.; Võsa, Urmo; Withoff, Sebo; Netea‐Maier, Romana T.; Koenen, Hans J. P. M.; Joosten, Irma; Xavier, Ramnik J.; Franke, Lude; Kumar, Vinod; Wijmenga, Cisca; Netea, Mihai G.; Li, Yang

doi:10.1038/s41590-018-0121-3

Cited by 112 publications

(137 citation statements)

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“…Interestingly, we identified an association between S. aureus stimulated IL-1ß cytokine production and rare variants in IL18BP, recurrent in the top-responders. The encoded protein (IL-18BP) inhibits IL-18 signaling [39], and previous studies have shown that IL-18BP levels are negatively correlated with cytokine production by lymphocytes [12]. The identified burden in top-responders here, suggests that these rare variants in IL18BP negatively affect IL-18BP levels, allowing for high S. aureus induced cytokine production.…”

Section: Discussionmentioning

confidence: 61%

“…Over the past decades, various studies have identified a role for common genetic variation on cytokine level and response, however a significant proportion of inter-individual variability remains to be determined [12][13][14][15]. Considering the increasing evidence that specific combinations of variants with variable frequencies can influence phenotypic variability [16][17][18], in particular for a combination of phenotypic characteristics that do not fit one specific clinical diagnosis [30], we hypothesized that the inter-individual variability in cytokine responses might be subjectable to same concept.…”

Section: Discussionmentioning

confidence: 99%

“…Raw IL-1β and IL-6 cytokine production by Peripheral Blood Mononuclear Cells (PBMCs) in response to stimulation with either 100ng/mL Lipopolysaccharide (LPS), 10µg/mL Phytohemagglutinin (PHA), heat-killed Candida albicans 10 6 CFU/mL (C. albicans) and 1x10 6 /mL Staphylococcus aureus (S. aureus), were likewise evenly distributed between females and males (Supplementary Figure S1B), and were log-transformed prior to analysis. Based on the above-mentioned distributions in combination with the fact that previous research has shown that both age and gender can influence cytokine responses [12][13][14][15], both variables were included as covariates in our analyses.…”

Section: Study Cohortmentioning

confidence: 99%

“…Characteristic of an inflammatory disease is abnormal inflammation in terms of an aberrant immune response, and understanding how the immune response becomes apparent in general is therefore key in understanding the basis of an inflammatory disease. For this reason, in the past few decades various studies have focused on determining the genetic variation that contributes to the interindividual variability in immune responses [12][13][14][15]. In summary, these studies show the separate and shared contribution of host and environmental factors to an immunological response after a specific stimulus.…”

Section: Introductionmentioning

confidence: 99%

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Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses

Deuren

Arts

Cavalli

et al. 2020

Preprint

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Interleukin(IL)-1 signaling is of major importance in human innate cytokine responses. Common variants in underlying genes have been linked to various inflammation-mediated diseases and stimulation induced cytokine responses, but the role of rare variants remains to be elucidated.In this study, we characterize the role of rare and common genetic variation, as identified by molecular inversion probe-based sequencing, in 48 genes related to the IL-1 pathway. We examined the inter-individual variability in in vitro stimulation-specific human cytokine responses from 463 healthy individuals of the Human Functional Genomics Project and assessed the role of rare and common genetic variants, separately and combined, by means of the Sequence Kernel Association Test with various variant grouping strategies.We identified strong NCF4 and CASP1 rare genetic variant associations with IL-6 cytokine production in response to PHA (P=7.2E -05 ) and LPS (P=3.0E -05 ) stimulation. In addition, common variants in IL36A and IL38 were associated to both C. albicans induced IL-1β and IL-6 (IL36A P=0.0442 and 0.0037; IL38 P=0.0092 and 0.0082), an effect that was magnified on the respective IL-30 subpathway level (IL-1β P=0.0017; IL-6 P=1.8E -04 ). The inflammatory-phenotype level analysis confirmed the common variant signature for the immunological response to C. albicans by an association with the anti-inflammatory group (IL-1β P=1.87E -03 ; IL-6 P=5.75E -04 ), and we validated this finding for non-coding common variants. Lastly, we identified a rare variant signature for LPS-induced IL-6 production with the pro-inflammatory group (P=2.42E -04 ), and we detected a new role for anti-inflammatory rare variants on S. aureus stimulated IL-6 cytokine (P=6.71E -03 ).In conclusion, we show that both common and rare genetic variation in genes of the IL-1 pathway, separately and combined, differentially influence in vitro cytokine responses to various stimuli in healthy individuals. This study therefore provides insight into potential mechanisms that are translatable into new hypothesis-driven characterization of common and rare genetic variant involvement in a wide variety of inflammatory and immunological mechanisms and diseases.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Study Cohortmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses

Deuren

Arts

Cavalli

et al. 2020

Preprint

Self Cite

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“…We regressed out the PCs included in the analysis of each layer previous to model calculation. As described in de Bakker et al 84 , we performed an initial variable selection step by identifying the genetic variants or chromatin features in a +-150kb window that significantly correlated with gene expression (Spearman p-value < 0.05). In order to keep only independent variables in the set of predictors, in the instances where pairs of genetic variants or chromatin features were correlated (Spearman correlation > 0.4), we removed the variable with a lower correlation with gene expression.…”

Section: Gene Expression Variance Deconvolutionmentioning

confidence: 99%

Immune disease variants modulate gene expression in regulatory CD4+ T cells and inform drug targets

Bossini‐Castillo

Glinos

Kunowska

et al. 2019

Preprint

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Identifying cellular functions dysregulated by disease associated variants could implicate novel pathways for drug targeting or modulation in cell therapies. Variants associated with immune diseases point towards the role of CD4+ regulatory T cells (Tregs), cell type critical for immune homeostasis. To translate the effects of immune disease alleles on Treg function we mapped genetic regulation (QTL) of gene expression and chromatin activity in Tregs. We identified 123 loci where Treg QTLs colocalized with immune disease variants. These colocalizations indicated that dysregulation of key Treg pathways, including cell activation via CD28 and IL-2 signalling mediated by STAT5A contribute to the shared pathobiology of immune diseases. Finally, using disease GWAS signals colocalizing with Treg QTLs, we identified 34 known drug targets and 270 targets with drug tractability evidence. Our study is 1 the first in-depth characterization of immune disease variant effects on Treg gene expression modulation and dysregulation of Treg function.

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Whole transcriptome analysis of high and low IFN‐α producers reveals differential response patterns following rhinovirus stimulation

et al. 2021

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Objectives Viral respiratory infections cause considerable morbidity and economic loss. While rhinoviruses (RV) typically cause little more than the common cold, they can produce severe infections and disease exacerbations in susceptible individuals, such as those with asthma. Variations in the regulation of key antiviral cytokines, particularly type I interferon (IFN‐α and IFN‐β), may contribute to RV susceptibility. To understand this variability, we compared the transcriptomes of high and low type I IFN producers. Methods Blood mononuclear cells from 238 individuals with or without asthma were cultured in the presence or absence of RV. Those samples demonstrating high or low RV‐stimulated IFN‐α production (N = 75) underwent RNA‐sequencing. Results Gene expression patterns were similar in samples from healthy participants and those with asthma. At baseline, the high IFN‐α producer group showed higher expression of genes associated with plasmacytoid dendritic cells, the innate immune response and vitamin D activation, but lower expression of oxidative stress pathways than the low IFN‐α producer group. After RV stimulation, the high IFN‐α producer group showed higher expression of genes found in immune response biological pathways and lower expression of genes linked to developmental and catabolic processes when compared to the low IFN‐α producer group. Conclusions These differences suggest that the high IFN‐α group has a higher level of immune system readiness, resulting in a more intense and perhaps more focussed pathogen‐specific immune response. These results contribute to a better understanding of the variability in type I IFN production between individuals.

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

Cited by 112 publications

References 58 publications

Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses

Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses

Immune disease variants modulate gene expression in regulatory CD4+ T cells and inform drug targets

Whole transcriptome analysis of high and low IFN‐α producers reveals differential response patterns following rhinovirus stimulation

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