Systematic association of common variants identified by 94 different GWAS with open chromatin (DHS) in selected tissues and cells.

<p>The individual GWAS are sorted based on the minimal association p-value with 466 DHS (only selected DHS samples are shown). Size of the dot represents the enrichment over the null distribution and color of the dot represents the significance of the enrichment—with black being the most significant. The bar graphs depict the number of associated SNPs (grey), the fraction of coding SNPs (red) and minor allele frequency (green). Heatmap depicts the distribution of SNPs with respect to transcriptional start sites (intensity of blue depicts the fraction of SNPs within the distance bin). Green/orange/white bar shows the presence of the replication cohort (green—present, white—no replication cohort as specified in the in NHGRI GWAS Catalog) separately for each GWAS. Group bar depicts the annotation of GWAS to one of three “GWAS groups”. Green—GWAS with the best association p-value < = 0.0001, orange < = 0.01 and red—GWAS with the best association p-value < 0.01.</p

Tissues and cell types associated with common variants identified by selected GWASs.

<p>Each point represents the separate replicate of DHS assay in the given tissue.</p

Comparison of selected GWAS parameter between three GWAS groups.

<p>A) The number of associated SNPs B) the fraction of coding SNPs C) minor allele frequency and D) the distribution of SNPs with respect to transcriptional start sites (no line—non significant, * p-value < 0.05, ** p-value < 0.01, using Wilcoxon signed-rank test), green—GWAS with the best association p-value < = 0.0001, orange < = 0.01 and red—GWAS with the best association p-value < 0.01.</p

Schematic description of the association model used to quantify the overlap between regulatory elements (black and red DHS peaks) and disease-associated variants (SNP1, 2 and 3) in various cell types (cell type 1, 2 and 3).

<p>The model estimates the regulatory activity by counting the number of DHS peaks (red) located within the region of a 500kb with the associated tag SNP in the middle.</p

Additional file 1: of Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy

Baseline characteristics of the patients included in the analyses. (DOCX 17 kb

Additional file 2: of Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy

Description of the differentially co-expressed genes in the salmon module (tocilizumab plus methotrexate arm), the purple module (tocilizumab arm), and the black module (methotrexate arm). (DOCX 22 kb

Additional file 5: Table S6. of Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

Upstream regulators. (XLSX 135 kb

Additional file 7: Table S3. of Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

Publicly available datasets. (XLSX 11 kb

DataSheet_1_Conventional dendritic cells type 1 are strongly enriched, quiescent and relatively tolerogenic in local inflammatory arthritis.docx

IntroductionDendritic cells (DC) are crucial for initiating and shaping immune responses. So far, little is known about the functional specialization of human DC subsets in (local) inflammatory conditions. We profiled conventional (c)DC1, cDC2 and monocytes based on phenotype, transcriptome and function from a local inflammatory site, namely synovial fluid (SF) from patients suffering from a chronic inflammatory condition, Juvenile Idiopathic Arthritis (JIA) as well as patients with rheumatoid arthritis (RA).MethodsPaired PB and SF samples from 32 JIA and 4 RA patients were collected for mononuclear cell isolation. Flow cytometry was done for definition of antigen presenting cell (APC) subsets. Cell sorting was done on the FACSAria II or III. RNA sequencing was done on SF APC subsets. Proliferation assays were done on co-cultures after CD3 magnetic activated cell sorting (MACS). APC Toll-like receptor (TLR) stimulation was done using Pam3CSK4, Poly(I:C), LPS, CpG-A and R848. Cytokine production was measured by Luminex.ResultscDC1, a relatively small DC subset in blood, are strongly enriched in SF, and showed a quiescent immune signature without a clear inflammatory profile, low expression of pathogen recognition receptors (PRRs), chemokine and cytokine receptors, and poor induction of T cell proliferation and cytokine production, but selective production of IFNλ upon polyinosinic:polycytidylic acid exposure. In stark contrast, cDC2 and monocytes from the same environment, showed a pro-inflammatory transcriptional profile, high levels of (spontaneous) pro-inflammatory cytokine production, and strong induction of T cell proliferation and cytokine production, including IL-17. Although the cDC2 and monocytes showed an overlapping transcriptional core profile, there were clear differences in the transcriptional landscape and functional features, indicating that these cell types retain their lineage identity in chronic inflammatory conditions.DiscussionOur findings suggest that at the site of inflammation, there is specific functional programming of human DCs, especially cDC2. In contrast, the enriched cDC1 remain relatively quiescent and seemingly unchanged under inflammatory conditions, pointing to a potentially more regulatory role.</p

Select gene expression from RNA sequencing data.

<p>Select gene expression from RNA sequencing data.</p