Publications by authors named "Subra Kugathasan"

207 Publications

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

Am J Hum Genet 2021 09 26;108(9):1765-1779. Epub 2021 Aug 26.

Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn 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 a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the 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 TWASs for stratification of risk of disease complications.
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http://dx.doi.org/10.1016/j.ajhg.2021.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456180PMC
September 2021

Early Change in Fecal Calprotectin Predicts One-Year Outcome in Children Newly Diagnosed with Ulcerative Colitis.

J Pediatr Gastroenterol Nutr 2021 Aug 24. Epub 2021 Aug 24.

Division of Pediatric Gastroenterology, Dept of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA Division of Gastroenterology, Brendan Gastroenterology & Hepatology & Nutrition, Nationwide Children's Hospital, Columbus, OH, USA Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, ON, Canada Division of Pediatric Gastroenterology, Nutrition & Liver Diseases, Hasbro Children's Hospital, and the Alpert School of Medicine at Brown University. Providence, RI, USA Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of East Ontario, Ottawa, ON, Canada Division of Pediatric Gastroenterology, Cohen Children's Medical Center of New York, New Hyde Park, NY, USA Pediatric Gastroenterology and Nutrition, Goryeb Children's Hospital-Atlantic Health, Morristown, NJ, USA Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA.

Introduction: While fecal calprotectin (FC) is used to assess disease activity in ulcerative colitis (UC) there are little data concerning the role of serial FC levels at diagnosis in predicting clinical course. We sought to determine whether FC at diagnosis or early change following therapy predicts clinical outcome in pediatric UC.Methods: Children with newly diagnosed UC were treated with standardized regimens of mesalamine or corticosteroids (CS). CS tapering and escalation to additional therapy or colectomy were by protocol. Patients with baseline or week 4 or week 12 FC levels were included in the analysis. Our primary outcome was CS-free remission on mesalamine at Week 52. We compared the prognostic value of a baseline FC as well as a change in FC by week 4 or week 12 in predicting clinical outcomes.

Results: The study included 352 children (113 initial mesalamine, 239 initial CS, mean age 12.6 years) with UC. At Week 52, 135 (38.3%), 84 (23.8%), and 19 (5.4%) children achieved CS-free remission, needed anti-TNF therapy or had colectomy respectively. Baseline FC was not associated with CS-free remission at week 52. However, both week 4 (OR 0.95, 95% CI 0.90 - 1.00) and week 12 FC levels (OR 0.91, 95% CI 0.87 - 0.96) were associated with outcomes, with the latter having a stronger association with CS-free remission. Patients with a > 75% decrease by 12 weeks, had a three-fold increased likelihood of CS-free remission at 1 year.

Discussion: Longitudinal changes in FC may predict 1 year outcomes better than values at diagnosis in children with new diagnosis of UC.
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http://dx.doi.org/10.1097/MPG.0000000000003291DOI Listing
August 2021

Profiling non-coding RNA levels with clinical classifiers in pediatric Crohn's disease.

BMC Med Genomics 2021 07 29;14(1):194. Epub 2021 Jul 29.

Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 1760 Haygood Drive, W-427, Atlanta, GA, 30322, USA.

Background: Crohn's disease (CD) is a heritable chronic inflammatory disorder. Non-coding RNAs (ncRNAs) play an important role in epigenetic regulation by affecting gene expression, but can also directly affect protein function, thus having a substantial impact on biological processes. We investigated whether non-coding RNAs (ncRNA) at diagnosis are dysregulated during CD at different CD locations and future disease behaviors to determine if ncRNA signatures can serve as an index to outcomes.

Methods: Using subjects belonging to the RISK cohort, we analyzed ncRNA from the ileal biopsies of 345 CD and 71 non-IBD controls, and ncRNA from rectal biopsies of 329 CD and 61 non-IBD controls. Sequence alignment was done (STAR package) using Human Genome version 38 (hg38) as reference panel. The differential expression (DE) analysis was performed with EdgeR package and DE ncRNAs were identified with a threshold of fold change (FC) > 2 and FDR < 0.05 after multiple test corrections.

Results: In total, we identified 130 CD specific DE ncRNAs (89 in ileum and 41 in rectum) when compared to non-IBD controls. Similarly, 35 DE ncRNAs were identified between B1 and B2 in ileum, whereas no differences among CD disease behaviors were noticed in rectum. We also found inflammation specific ncRNAs between inflamed and non-inflamed groups in ileal biopsies. Overall, we observed that expression of mir1244-2, mir1244-3, mir1244-4, and RN7SL2 were increased during CD, regardless of disease behavior, location, or inflammatory status. Lastly, we tested ncRNA expression at baseline as potential tool to predict the disease status, disease behaviors and disease inflammation at 3-year follow up.

Conclusions: We have identified ncRNAs that are specific to disease location, disease behavior, and disease inflammation in CD. Both ileal and rectal specific ncRNA are changing over the course of CD, specifically during the disease progression in the intestinal mucosa. Collectively, our findings show changes in ncRNA during CD and may have a clinical utility in early identification and characterization of disease progression.
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http://dx.doi.org/10.1186/s12920-021-01041-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323253PMC
July 2021

Altered splicing associated with the pathology of inflammatory bowel disease.

Hum Genomics 2021 07 23;15(1):47. Epub 2021 Jul 23.

School of Biological Sciences and Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA, 30332, USA.

Background: Aberrant splicing of individual genes is a well-known mechanism promoting pathology for a wide range of conditions, but disease is less commonly attributed to global disruption of exon usage. To explore the possible association of aberrant splicing with inflammatory bowel disease, we developed a pipeline for quantifying transcript abundance and exon inclusion transcriptome-wide and applied it to a dataset of ileal and rectal biopsies, both obtained in duplicate from 34 pediatric or young adult cases of ulcerative colitis and Crohn's disease.

Results: Expression and splicing covary to some extent, and eight individuals exhibited aberrant profiles that can be explained by altered ratios of epithelial to stromal and immune cells. Ancestry-related biases in alternative splicing accounting for 5% of the variance were also observed, in part also related to cell-type proportions. In addition, two individuals were identified who had 284 exons with significantly divergent percent spliced in exons, including in the established IBD risk gene CEACAM1, which caused their ileal samples to resemble the rectum.

Conclusions: These results imply that quantitative differences in splice usage contribute to the pathology of inflammatory bowel disease in a previously unrecognized manner.
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http://dx.doi.org/10.1186/s40246-021-00347-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305504PMC
July 2021

Ileal Derived Organoids From Crohn's Disease Patients Show Unique Transcriptomic and Secretomic Signatures.

Cell Mol Gastroenterol Hepatol 2021 14;12(4):1267-1280. Epub 2021 Jul 14.

Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, Georgia. Electronic address:

Background & Aims: We used patient-derived organoids (PDOs) to study the epithelial-specific transcriptional and secretome signatures of the ileum during Crohn's disease (CD) with varying phenotypes to screen for disease profiles and potential druggable targets.

Methods: RNA sequencing was performed on isolated intestinal crypts and 3-week-old PDOs derived from ileal biopsies of CD patients (n = 8 B1, inflammatory; n = 8 B2, stricturing disease) and non-inflammatory bowel disease (IBD) controls (n = 13). Differentially expressed (DE) genes were identified by comparing CD vs control, B1 vs B2, and inflamed vs non-inflamed. DE genes were used for computational screening to find candidate small molecules that could potentially reverse B1and B2 gene signatures. The secretome of a second cohort (n = 6 non-IBD controls, n = 7 CD, 5 non-inflamed, 2 inflamed) was tested by Luminex using cultured organoid conditioned medium.

Results: We found 90% similarity in both the identity and abundance of protein coding genes between PDOs and intestinal crypts (15,554 transcripts of 19,900 genes). DE analysis identified 814 genes among disease group (CD vs non-IBD control), 470 genes different between the CD phenotypes, and 5 false discovery rate correction significant genes between inflamed and non-inflamed CD. The PDOs showed both similarity and diversity in the levels and types of soluble cytokines and growth factors they released. Perturbagen analysis revealed potential candidate compounds to reverse B2 disease phenotype to B1 in PDOs.

Conclusions: PDOs are similar at the transcriptome level with the in vivo epithelium and retain disease-specific gene expression for which we have identified secretome products, druggable targets, and corresponding pharmacologic agents. Targeting the epithelium could reverse a stricturing phenotype and improve outcomes.
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http://dx.doi.org/10.1016/j.jcmgh.2021.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455365PMC
July 2021

Predicting disease course in ulcerative colitis using stool proteins identified through an aptamer-based screen.

Nat Commun 2021 06 28;12(1):3989. Epub 2021 Jun 28.

Department Biomedical Engineering, University of Houston, Houston, TX, USA.

In the search for improved stool biomarkers for inflammatory bowel disease (IBD), an aptamer-based screen of 1129 stool proteins was conducted using stool samples from an IBD cohort. Here we report that of the 20 proteins subsequently validated by ELISA, stool Ferritin, Fibrinogen, Haptoglobin, Hemoglobin, Lipocalin-2, MMP-12, MMP-9, Myeloperoxidase, PGRP-S, Properdin, Resistin, Serpin A4, and TIMP-1 are significantly elevated in both ulcerative colitis (UC) and Crohn's disease (CD) compared to controls. When tested in a longitudinal cohort of 50 UC patients at 4 time-points, fecal Fibrinogen, MMP-8, PGRP-S, and TIMP-2 show the strongest positive correlation with concurrent PUCAI and PGA scores and are superior to fecal calprotectin. Unlike fecal calprotectin, baseline stool Fibrinogen, MMP-12, PGRP-S, TIMP-1, and TIMP-2 can predict clinical remission at Week-4. Here we show that stool proteins identified using the comprehensive aptamer-based screen are superior to fecal calprotectin alone in disease monitoring and prediction in IBD.
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http://dx.doi.org/10.1038/s41467-021-24235-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239008PMC
June 2021

Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study.

Lancet Gastroenterol Hepatol 2021 08 19;6(8):616-627. Epub 2021 Jun 19.

Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.

Background: Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis.

Methods: The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557.

Findings: 93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p<0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period.

Interpretation: Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis.

Funding: AbbVie.
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http://dx.doi.org/10.1016/S2468-1253(21)00142-4DOI Listing
August 2021

Site- and Taxa-Specific Disease-Associated Oral Microbial Structures Distinguish Inflammatory Bowel Diseases.

Inflamm Bowel Dis 2021 11;27(12):1889-1900

Division of Pediatric Gastroenterology, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

Background: The gut and oral microbiome have independently been shown to be associated with inflammatory bowel disease (IBD). However, it is not known to what extent gut and oral microbial disease markers converge in terms of their composition in IBD. Further, the spatial and temporal variation within the oral microenvironments of IBD remain to be elucidated.

Patients And Methods: We used a prospectively recruited cohort of patients with IBD (n = 47) and unrelated healthy control patients (n = 18) to examine the spatial and temporal distribution of microbiota within the various oral microenvironments, represented by saliva, tongue, buccal mucosa, and plaque, and compared them with stool. Microbiome characterization was performed using 16S rRNA gene sequencing.

Results: The oral microbiome displayed IBD-associated dysbiosis, in a site- and taxa-specific manner. Plaque samples depicted a relatively severe degree of dysbiosis, and the disease-associated dysbiotic bacterial groups were predominantly the members of the phylum Firmicutes. Our 16S rRNA gene analyses show that oral microbiota can distinguish patients with IBD from healthy control patients, with salivary microbiota performing the best, closely matched by stool and other oral sites. Longitudinal profiles of microbial composition suggest that some taxa are more consistently perturbed than others, preferentially in a site-dependent fashion.

Conclusions: Collectively, these data indicate the potential of using oral microbial profiles in screening and monitoring patients with IBD. Furthermore, these results support the importance of spatial and longitudinal microbiome sampling to interpret disease-associated dysbiotic states and eventually to gain insights into disease pathogenesis.
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http://dx.doi.org/10.1093/ibd/izab082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599042PMC
November 2021

Clinical and Host Biological Factors Predict Colectomy Risk in Children Newly Diagnosed With Ulcerative Colitis.

Inflamm Bowel Dis 2021 Apr 27. Epub 2021 Apr 27.

Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Background: Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC).

Methods: This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used.

Results: Four hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]).

Conclusions: A small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.
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http://dx.doi.org/10.1093/ibd/izab061DOI Listing
April 2021

A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease.

Nature 2021 05 31;593(7858):275-281. Epub 2021 Mar 31.

The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD2, which increase the risk of stricturing. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14 peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid-stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn's disease, and suggest that gp130 blockade may benefit some patients with Crohn's disease-potentially as a complement to anti-TNF therapy.
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http://dx.doi.org/10.1038/s41586-021-03484-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284870PMC
May 2021

DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk.

J Clin Invest 2021 05;131(9)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multiomic analyses using 2872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance. We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C, which is induced also in mucosal biopsies of patients with IBD. DUOX2-deficient mice replicated increased IL-17C induction in the intestine, with outlier high Il17c expression linked to the mucosal expansion of specific Proteobacteria pathobionts. Integrated microbiota/host gene expression analyses in patients with IBD corroborated IL-17C as a marker for epithelial activation by gram-negative bacteria. Finally, the impact of DUOX2 variants on IL-17C induction provided a rationale for variant stratification in case control studies that substantiated DUOX2 as an IBD risk gene. Thus, our study identifies an association of deleterious DUOX2 variants with a preclinical hallmark of disturbed microbiota-immune homeostasis that appears to precede the manifestation of IBD.
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http://dx.doi.org/10.1172/JCI141676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087203PMC
May 2021

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Am J Hum Genet 2021 03 17;108(3):431-445. Epub 2021 Feb 17.

Division of Gastroenterology, Hepatology and Nutrition, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, VA 23284, USA.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008495PMC
March 2021

Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.

Hum Mol Genet 2021 04;30(5):356-369

Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Victoria 3010, Australia.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.
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http://dx.doi.org/10.1093/hmg/ddab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098114PMC
April 2021

Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease.

Inflamm Bowel Dis 2021 10;27(11):1707-1718

Cincinnati Children's Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Background: Transmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures.

Materials And Methods: Baseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH.

Results: After controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression.

Conclusions: Pediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.
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http://dx.doi.org/10.1093/ibd/izaa339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528150PMC
October 2021

Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort.

Gastroenterology 2021 04 24;160(5):1546-1557. Epub 2020 Dec 24.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background And Aims: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology.

Methods: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population.

Results: Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation.

Conclusions: Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.
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http://dx.doi.org/10.1053/j.gastro.2020.12.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237248PMC
April 2021

Stressful life events, depression, and the moderating role of psychophysiological reactivity in patients with pediatric inflammatory bowel disease.

J Psychosom Res 2021 02 30;141:110323. Epub 2020 Nov 30.

Emory/Children's Pediatric Institute, United States of America. Electronic address:

Objective: The development of depressive symptoms in youth with IBD is a concerning disease complication, as higher levels of depressive symptoms have been associated with poorer quality of life and lower medication adherence. Previous research has examined the association between disease activity and depression, but few studies have examined individual differences in experience of stressful life events in relation to depressive symptoms. The purpose of the current study is to examine the relation between stressful life events and depression within pediatric IBD and to determine whether individual differences in stress response moderates this association.

Methods: 56 youth ages 8-17 years old diagnosed with IBD completed questionnaires about their depressive symptoms and history of stressful life events. We assessed skin conductance reactivity (SCR) to a stressful task as an index of psychophysiological reactivity.

Results: Stressful life events (r = 0.36, p = .007) were positively related to depressive symptoms. Youth who demonstrated a greater maximum SC level during the IBD-specific stress trial compared to baseline (n = 32) reported greater depressive symptoms. For these same participants, the relationship between stressful life events and depressive symptoms depended on SCR F(3, 28) = 4.23, p = .01, such that at moderate and high levels of SCR, a positive relationship between stressful life events and depressive symptoms was observed.

Conclusions: The relationship between stressful life events and depressive symptoms in youth with IBD may depend on individual differences in processing stress, such that risk may increase with greater psychophysiological reactivity.
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http://dx.doi.org/10.1016/j.jpsychores.2020.110323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855667PMC
February 2021

It Takes Two to Make It Right: Dual Biologic and Small Molecule Therapy for Treatment-Refractory Pediatric Inflammatory Bowel Disease.

Inflamm Bowel Dis 2021 07;27(8):1361-1362

Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

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http://dx.doi.org/10.1093/ibd/izaa279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427718PMC
July 2021

Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease.

Gastroenterology 2021 02 5;160(3):809-822.e7. Epub 2020 Nov 5.

F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background And Aims: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls.

Methods: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted.

Results: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders.

Conclusions: Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.
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http://dx.doi.org/10.1053/j.gastro.2020.10.041DOI Listing
February 2021

PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.

Brain Behav Immun 2021 01 3;91:429-436. Epub 2020 Nov 3.

Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA; Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA. Electronic address:

Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.
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http://dx.doi.org/10.1016/j.bbi.2020.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749859PMC
January 2021

Machine learning identifies novel blood protein predictors of penetrating and stricturing complications in newly diagnosed paediatric Crohn's disease.

Aliment Pharmacol Ther 2021 01 1;53(2):281-290. Epub 2020 Nov 1.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: There is a need for improved risk stratification in Crohn's disease.

Aim: To identify novel blood protein biomarkers associated with future Crohn's disease complications METHODS: We performed a case-cohort study utilising a paediatric inception cohort, the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's disease (RISK) study. All patients had inflammatory disease (B1) at baseline. Outcomes were development of stricturing (B2) or penetrating (B3) complications. We assayed 92 inflammation-related proteins in baseline plasma using a proximity extension assay (Olink Proteomics). An ensemble machine learning technique, random survival forests (RSF), selected variables predicting B2 and B3 complications. Selected analytes were compared to clinical variables and serology only models. We examined selected proteins in a single-cell sequencing cohort to analyse differential cell expression in blood and ileum.

Results: We included 265 patients with mean age 11.6 years (standard deviation [SD] 3.2). Seventy-three and 34 patients, respectively, had B2 and B3 complications within mean 1123 (SD 477) days for B2 and 1251 (442) for B3. A model with 5 protein markers predicted B3 complications with an area under the curve (AUC) of 0.79 (95% confidence interval [CI] 0.76-0.82) compared to 0.69 (95% CI 0.66-0.72) for serologies and 0.74 (95% CI 0.71-0.77) for clinical variables. A model with 4 protein markers predicted B2 complications with an AUC of 0.68 (95% CI 0.65-0.71) compared to 0.62 (95% CI 0.59-0.65) for serologies and 0.52 (95% CI 0.50-0.55) for clinical variables. B2 analytes were highly expressed in ileal stromal cells while B3 analytes were prominent in peripheral blood and ileal T cells.

Conclusions: We identified novel blood proteomic markers, distinct for B2 and B3, associated with progression of paediatric Crohn's disease.
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http://dx.doi.org/10.1111/apt.16136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770008PMC
January 2021

Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.

Gut 2021 Jun 9;70(6):1023-1036. Epub 2020 Oct 9.

Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK

Objective: Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine.

Design: We 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 hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples.

Results: We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β 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 after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.

Conclusion: Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.
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http://dx.doi.org/10.1136/gutjnl-2020-321731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108288PMC
June 2021

Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease.

J Crohns Colitis 2020 Aug 8. Epub 2020 Aug 8.

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background And Aims: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures.

Methods: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied.

Results: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)).

Conclusion: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904088PMC
August 2020

Analysis of Using the Total White Blood Cell Count to Define Severe New-onset Ulcerative Colitis in Children.

J Pediatr Gastroenterol Nutr 2020 09;71(3):354-360

Connecticut Children's Medical Center, Hartford, CT.

Objectives: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis.

Methods: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (<65) and total Mayo score, severe (10-12) versus not severe (<10); mucosal disease by Mayo endoscopic subscore, severe (3) versus not severe (<3); and extensive disease versus not extensive (left-sided and proctosigmoiditis).

Results: Mean age was 12.7 years; 49.6% (n = 212) were girls, and 83% (n = 351) were Caucasian. Severe total Mayo score was present in 28% (n = 120), mean PUCAI score was 49.8 ± 20.1, and 33% (n = 142) had severe mucosal disease with extensive involvement in 82% (n = 353). Classification and regression trees identified white blood cell count, erythrocyte sedimentation rate, and platelet count (PLT) as the set of 3 best blood laboratory tests to predict disease extent and severity. For mucosal severity, albumin (Alb) replaced PLT. Classification models for PUCAI and total Mayo provided sensitivity of at least 0.65 using standard clinical cut-points with misclassification rates of approximately 30%.

Conclusions: A combination of the white blood cell count, erythrocyte sedimentation rate, and either PLT or albumin is the best predictive subset of standard laboratory tests to identify severe from nonsevere clinical or mucosal disease at diagnosis in relation to objective clinical scores.
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http://dx.doi.org/10.1097/MPG.0000000000002797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482284PMC
September 2020

Reduced expression of COVID-19 host receptor, is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn's disease.

medRxiv 2020 Apr 23. Epub 2020 Apr 23.

Angiotensin-Converting Enzyme 2 ( ) has been identified as the host receptor for SARS-coronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn's disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. was downregulated in CD compared to controls in independent cohorts. Within CD, expression was reduced in inflamed ileal tissue and also remarkably, from uninvolved tissue in patients with a worse prognosis in both adult and pediatric cohorts. In active CD, small bowel expression was restored by anti-TNF therapy particularly in anti-TNF responders. Collectively our data suggest that downregulation is associated with inflammation and worse outcomes in CD.
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http://dx.doi.org/10.1101/2020.04.19.20070995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276052PMC
April 2020

Performance of Interferon-gamma Release Assays for Tuberculosis Screening in Pediatric Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2019 12;69(6):e162

Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine.

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http://dx.doi.org/10.1097/MPG.0000000000002501DOI Listing
December 2019

Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.

Cell 2019 09 29;178(6):1493-1508.e20. Epub 2019 Aug 29.

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.
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http://dx.doi.org/10.1016/j.cell.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060942PMC
September 2019

Serologic, but Not Genetic, Markers Are Associated With Impaired Anthropometrics at Diagnosis of Pediatric Crohn's Disease.

J Pediatr Gastroenterol Nutr 2019 11;69(5):e129-e134

Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition.

Objectives: Children with Crohn's disease may present with malnutrition and linear growth impairment, which can be secondary to insufficient caloric intake, chronic inflammation, malabsorption, and suppression of growth-promoting hormones. We evaluated clinical, serologic, and genetic data to determine risk factors for impaired anthropometrics in Crohn's disease at diagnosis.

Methods: Our study evaluated 772 children newly diagnosed with Crohn's disease, inflammatory phenotype, enrolled in the RISK Stratification Project to determine the factors associated with anthropometric impairment. Data were collected on demographics, growth parameters, disease location, serologic and immunologic markers, and disease severity. We performed a genome-wide association study of genetic polymorphisms associated with inflammatory bowel disease. Regression analysis determined associations between anthropometrics and clinical, serologic, and genetic variables.

Results: There were 59 (7%) children with height z score <-2, 126 (14%) with a weight z score <-2, and 156 (17%) with a body mass index z score <-2. Linear growth impairment was associated with hypoalbuminemia (P = 0.0052), elevated granulocyte-macrophage colony stimulating factor autoantibodies (P = 0.0110), and elevated CBir antibodies against flagellin (P = 0.0117). Poor weight gain was associated with female sex (P = 0.0401), hypoalbuminemia (P = 0.0162), and thrombocytosis (P = 0.0081). Malnutrition was associated with hypoalbuminemia (P = 0.0061) and thrombocytosis (P = 0.0011). Children with moderate or severe disease had lower weight (P = 0.02 and P = 1.16×10, respectively) and body mass index z scores (P = 2.7 × 10 and P = 1.01 × 10, respectively) than children with quiescent and mild disease. There was no association between age of diagnosis, Tanner stage, or disease location and having impaired anthropometrics. There was no genome-wide association between the genetic polymorphisms and the serologic variables and anthropometric measurements.

Conclusions: This is the largest study evaluating growth in treatment-naïve children with Crohn's disease, inflammatory phenotype. It is the first study to use genome-wide sequencing to assess for genetic determinants of growth impairment. Granulocyte-macrophage colony stimulating factor autoantibodies and CBir antibodies are more likely to be elevated in children with growth impairment. Future investigations should evaluate the relationship between genetic polymorphisms, pathologic immune responses, and the biological pathways regulating growth.
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http://dx.doi.org/10.1097/MPG.0000000000002462DOI Listing
November 2019

Management of Anti-drug Antibodies to Biologic Medications in Children With Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2019 11;69(5):551-556

Division of Pediatric Gastroenterology, Emory University School of Medicine Atlanta, Children's Healthcare of Atlanta, Atlanta, GA.

Background: Treatment of pediatric inflammatory bowel disease (IBD) with monoclonal anti- tumor necrosis factor-alpha (TNFα) can result in immunogenicity and formation of anti-drug antibodies (ADAs). ADAs are associated with loss of clinical response and worsening disease progression. Data examining treatment interventions to overcome ADA in pediatric patients with IBD are lacking.

Results: Medical records were reviewed from 234 children and adolescents with IBD treated with infliximab or adalimumab who underwent therapeutic drug monitoring (626 tests). All patients who had detectable antibodies were further analyzed. A total 58 patients (24.8%) developed ADA while being treated with infliximab or adalimumab. The incidence of antibody development was 12.9 per 100 person-years of anti-TNF treatment. Twenty-eight patients underwent dose optimization and 54% had undetectable ADA on follow-up monitoring. The mean duration of antibody suppression was 16.8 ± 10.9 months in those who were successfully suppressed with optimization. Patients who switched to a second anti-TNF medication were not more likely to develop antibodies to the second agent.

Conclusions: With limited therapies for IBD and the chronicity of the disease, we advocate salvage of the current anti-TNF through dose optimization in pediatric patients with antibody level <10 U/mL.
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http://dx.doi.org/10.1097/MPG.0000000000002440DOI Listing
November 2019

Anti-TNF Therapy Is Emerging as the Primary Treatment Modality in Pediatric Inflammatory Bowel Disease.

Inflamm Bowel Dis 2020 01;26(1):139-140

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.

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http://dx.doi.org/10.1093/ibd/izz158DOI Listing
January 2020

Performance of Interferon-Gamma Release Assays for Tuberculosis Screening in Pediatric Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2019 10;69(4):e111-e116

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine.

Objectives: The aim of the study was to analyze the diagnostic accuracy and utility of QuantiFERON-TB Gold In-Tube, an interferon-gamma release assay (IGRA), as a screening tool for latent tuberculosis infection (LTBI) in pediatric patients with inflammatory bowel disease (IBD) undergoing treatment with anti-tumor necrosis factor (anti-TNF) medications. To describe cases of tuberculosis in the pediatric IBD population, TB treatment courses, outcomes, and their effect on IBD management.

Methods: A single-center, retrospective cohort study of pediatric IBD patients who underwent tuberculosis screening. IGRA testing from 2011 to 2017 were analyzed to determine result rates, characteristics, and outcomes.

Results: One thousand seven hundred fifty-four (1,754) tests were performed on 859 patients. One thousand six hundred thirty-four (1,634) tests were negative, 9 were positive, and 111 were indeterminate. Eight of 9 positive tests resulted during repeat annual screening while receiving IBD treatment. Five patients were treated for latent tuberculosis infection (LTBI), and 4 were false-positives. IBD therapy was interrupted in 3 patients, with no negative long-term outcomes. We report 1 known false-negative, in a patient who developed disseminated TB on anti-TNF therapy. Indeterminate testing rates were higher at IBD diagnosis than during treatment (10.3% vs 5.3%, P < 0.001). Follow-up testing of indeterminate results was negative in all patients retested, with 14 patients lost to follow-up. No patient with indeterminate testing developed TB.

Conclusions: IGRAs are a useful tool to screen for LTBI, both before anti-TNF therapy and during treatment. Results should be used in concert with detailed history and examination. Positive and indeterminate results should be promptly repeated for timely TB diagnosis and to minimize interruptions in IBD therapy.
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http://dx.doi.org/10.1097/MPG.0000000000002428DOI Listing
October 2019
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