Small and long regulatory RNAs in the immune system and immune diseases

Cellular differentiation is regulated on the level of gene expression and it is known that dysregulation of gene expression can lead to deficiencies in differentiation that contribute to a variety of diseases, particularly of the immune system. Until recently, it was thought that the dysregulation was governed by changes in the binding or activity of a class of proteins called transcription factors. However, the discovery of micro-RNAs and recent descriptions of long noncoding RNAs have given enormous momentum to a whole new field of biology: the regulatory RNAs. In this review, we describe these two classes of regulatory RNAs and summarize what is known about how they regulate aspects of the adaptive and innate immune systems. Finally, we describe what is known about the involvement of micro-RNAs and long noncoding RNAs in three different autoimmune diseases (celiac disease, inflammatory bowel disease, and multiple sclerosis)

Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFN gamma Signaling in Celiac Disease

Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD. We used four different in silico approaches-Mendelian randomization inverse variance weighting, COLOC, LD overlap, and DEPICT-to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signaling and T cell activation pathways. Fifty-one of these genes are targets of known drug compounds or likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAF-type zinc finger domain containing 1 (TRAFD1), and were found to be involved in interferon (IFN)gamma signaling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments in a human monocytic cell line that validated the role of TRAFD1 as an immune regulator acting in trans. Our strategy confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and IFN gamma signaling as well as with MHC I antigen processing, both major players of immune activation and CeD pathogenesis

Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs

Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases

Deconvolution of bulk blood eQTL effects into immune cell subpopulations

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)

Systematic Prioritization of Candidate Genes in Disease Loci Identifies as a Master Regulator of IFNγ Signaling in Celiac Disease.

Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD. We used four different in silico approaches-Mendelian randomization inverse variance weighting, COLOC, LD overlap, and DEPICT-to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signaling and T cell activation pathways. Fifty-one of these genes are targets of known drug compounds or likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAF-type zinc finger domain containing 1 (TRAFD1), and were found to be involved in interferon (IFN)γ signaling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments in a human monocytic cell line that validated the role of TRAFD1 as an immune regulator acting in trans. Our strategy confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and IFNγ signaling as well as with MHC I antigen processing, both major players of immune activation and CeD pathogenesis

A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease

International audienceBackground Approximately 5% of patients with celiac disease (CeD) do not respond to a gluten-free diet and progress to refractory celiac disease (RCD), a severe progression that is characterized by infiltration of intraepithelial T lymphocytes. Patients with RCD type II (RCDII) show clonal expansions of intraepithelial T lymphocytes that result in a poor prognosis and a high mortality rate through development of aggressive enteropathy-associated T-cell lymphoma. It is not known whether genetic variations play a role in severe progression of CeD to RCDII. Patients and methods We performed the first genome-wide association study to identify the causal genes for RCDII and the molecular pathways perturbed in RCDII. The genome-wide association study was performed in 38 Dutch patients with RCDII, and the 15 independent top-associated single nucleotide polymorphism (SNP) variants (P<5x10(-5)) were replicated in 56 independent French and Dutch patients with RCDII. Results After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37x10(-8), odds ratio=2.36) but not with CeD susceptibility. SNP rs2041570 risk allele A was associated with lower levels of FAM188B expression in blood and small intestinal biopsies. Stratification of RCDII biopsies based on rs2041570 genotype showed differential expression of innate immune and antibacterial genes that are expressed in Paneth cells. Conclusion We have identified a novel SNP associated with the severe progression of CeD to RCDII. Our data suggest that genetic susceptibility to CeD might be distinct from the progression to RCDII and suggest a role for Paneth cells in RCDII progression

Additional file 3 of Deconvolution of bulk blood eQTL effects into immune cell subpopulations

Additional file 3 : Supplementary Table 2: Summary statistics from Decon-eQTLs for the 16,362 whole blood eQTLs