Biology subjects

Kugathasan, S.

Publications and source records attributed to Kugathasan, S..

6 recordsLinked to original sources

bioRxiv2025

snATAC-Express infers Gene Expression from Prioritized Chromatin Accessibility Peaks using Machine Learning

BackgroundSingle cell multi-omic investigation opens-up new opportunities to understand mechanisms of gene regulation. Existing methods for inferring transcript abundance from chromatin accessibility fail to prioritize the most relevant peaks and tend to assume positive associations between ATAC peaks and RNA counts. We hypothesize that gene regulation can be modeled as a function of combined positive and negative interactions among peaks and that causal regulatory variants are enriched in the vicinity of the most critical peaks. ResultsA machine learning pipeline leveraging single nuclear multiomic transcriptome and chromatin accessibility data is developed to model gene expression as a function of ATAC peak intensity. Multiome data was available for 18 immune cell types from 29 donors, 19 with Crohns disease. The pipeline aggregates results from three machine learning approaches (random forest regression, XGBoost, and Light GBM) as well as linear regression to identify which ATAC peaks contribute to explaining variation among donors and cell types in pseudobulk gene expression. The coefficient of determination with cross-validation was used to identify robust models which typically explain between 5% and 40% of transcript abundance, utilizing on average 47% of the ATAC peaks, representing a significant gain in predictive accuracy. The most important peaks are enriched in GWAS variants for inflammatory bowel disease and the autoimmune disease systemic lupus erythematosus, but not for rheumatoid arthritis. ConclusionAtlanta Plots visualize the proportion of ATAC peaks contributing to a predictive model of gene expression as well as the proportion of variance explained by the model. Software implementing our pipeline, "snATAC-Express", is freely available on GitHub.

bioinformatics↗

bioRxiv2023

Crohn's patients and healthy infants share immunodominant B cell response to commensal flagellin peptide epitopes

About half of patients with Crohns disease (CD) develop selective serum IgG response to flagellin proteins of the Lachnospiraceae family. Here, we identified a dominant B cell peptide epitope in CD, locating in the highly conserved "hinge region" between the D0 and D1 domains at the amino-terminus of Lachnospiraceae flagellins. Serum IgG reactive to this epitope is present at an elevated level in adult CD patients and in pediatric CD patients at diagnosis. Most importantly, high levels of serum IgG to the hinge epitope were found in most infants from 3 different geographic regions (Uganda, Sweden, and the USA) at one year of age. This vigorous homeostatic response decrements with age as it is not present in healthy adults. These data identify a distinct subset of CD patients, united by a shared reactivity to this dominant flagellin epitope that may represent failure of a homeostatic response beginning in infancy.

immunology↗

bioRxiv2021

Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status. By contrast, in Crohns disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS). Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications.

genetics↗

bioRxiv2020

Methylation Quantitative Trait Loci are Largely Consistent across Disease States in Crohns disease

BackgroundIn a recent study, we identified 1189 CpG sites whose DNA methylation (DNAm) level in blood distinguished Crohns disease (CD) cases from controls. We also demonstrated that the vast majority of these differences were a consequence of disease, rather than a cause of CD. Since methylation can be influenced by both genetic and environmental factors, here we focus on CpGs under demonstrable genetic control (methylation quantitative trait loci, or mQTLs). By comparing mQTL patterns across disease states and tissue (blood vs. ileum), we may distinguish patterns unique to CD. Such DNAm patterns may be relevant for the developmental origins of CD. MethodsWe investigated three datasets: (i) 402 blood samples from 164 newly diagnosed pediatric CD patients taken at two time points, and 74 non-IBD controls (ii) 780 blood samples from a non-CD adult population and (iii) 40 ileal biopsies (17 CD cases and 23 non-IBD controls) from group (i). Genome-wide DNAm profiling and genotyping were performed using the Illumina MethylationEPIC and Illumina Multi-Ethnic arrays. SNP-CpG associations were tested via linear models adjusted for age, gender, disease status, disease subtype, estimated cell type and three genotype-based principal components. We used a Bonferroni-adjusted significance threshold to identify significantly associated SNP-CpG pairs, but also considered larger sets identified by a false discovery rate criterion ResultsIn total, we observed 535,448 SNP-CpG associations between 287,881 SNPs and 12,843 CpG sites (P<8.21x10-14). These associations and their effects are highly consistent across different ages, races, disease states, and tissue types, suggesting that the vast majority of these mQTLs participate in common gene regulation. However, genes near CpGs associated with IBD SNPs were enriched for 18 KEGG pathways relevant to IBD-linked immune function and inflammatory responses. We observed suggestive evidence for a small number of tissue-specific associations and disease-specific ileal associations in ileum, though larger studies will be needed to confirm these results. ConclusionThe vast majority of blood derived mQTLs are commonly shared across individuals. However, we have identified a subset of such, which may be involved in processes related to CD. Independent cohort studies will be required to validate these findings.

genomics↗

bioRxiv2019

Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23

BACKGROUND & AIMSDysregulated immune responses are the cause of inflammatory bowel diseases. Studies in both mice and humans suggest a central role of IL-23 producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for select IL-23 targeting therapies as part of personalized medicine. METHODSWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA-sequencing to derive a transcriptomic signature of hyper-inflammatory monocytes. Using gene network correlation analysis, we deconvolve this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTSWe characterized monocyte subsets of healthy individuals and patients with inflammatory bowel disease that express IL-23. We identified auto- and paracrine sensing of IL-1/IL-1{beta} and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion, uptake of whole bacteria induced IL-23 production via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to anti-TNF therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSIONOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyper-inflammation-associated IL-23 production in patients with severe ulcerating active Crohns disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with inflammatory bowel disease that might benefit from IL-23p19 and/or IL-1/IL-1{beta}-targeting therapies upstream of IL-23. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/719492v2_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@16598faorg.highwire.dtl.DTLVardef@11e5116org.highwire.dtl.DTLVardef@15d831borg.highwire.dtl.DTLVardef@4a697e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2018

Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

Clinical benefits to cytokine blockade in ileal Crohns disease (iCD) have been limited to a subset of patients. Whether cellular and molecular heterogeneity contributes to variability in treatment responses has been unclear. Using single cell technologies combining scRNAseq, CyTOF and multiplex tissue imaging, we mapped the cellular landscape of inflamed ileum lesions, adjacent non-inflamed ileum and matched circulating blood cells of iCD patients. In inflamed tissues, we identified a pathogenic module characterized by an inflammatory mononuclear phagocyte (Inf.MNP)-associated cellular response organized around inflammatory macrophages and mature dendritic cells in a subset of iCD patients. We confirmed the Inf.MNP-associated cellular response in 4 independent iCD cohorts (n=441) and showed that presence of this pathogenic module at diagnosis correlated with primary resistance to anti-TNF therapy. Single cell mapping of iCD tissues identifies a complex cellular signature of anti-TNF resistance thereby revealing novel biomarkers of treatment response and tailored therapeutic opportunities.

immunology↗