Eleven Grand Challenges for Inflammatory Bowel Disease Genetics and Genomics.

The past 2 decades have witnessed extraordinary advances in our understanding of the genetic factors influencing inflammatory bowel disease (IBD), providing a foundation for the approaching era of genomic medicine. On behalf of the NIDDK IBD Genetics Consortium, we herein survey 11 grand challenges for the field as it embarks on the next 2 decades of research utilizing integrative genomic and systems biology approaches. These involve elucidation of the genetic architecture of IBD (how it compares across populations, the role of rare variants, and prospects of polygenic risk scores), in-depth cellular and molecular characterization (fine-mapping causal variants, cellular contributions to pathology, molecular pathways, interactions with environmental exposures, and advanced organoid models), and applications in personalized medicine (unmet medical needs, working toward molecular nosology, and precision therapeutics).

Development of a deep learning algorithm for Paneth cell density quantification for inflammatory bowel disease.

Background: Alterations in ileal Paneth cell (PC) density have been described in gut inflammatory diseases such as Crohn's disease (CD) and could be used as a biomarker for disease prognosis. However, quantifying PCs is time-intensive, a barrier for clinical workflow. Deep learning (DL) has transformed the development of robust and accurate tools for complex image evaluation.

Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.

polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD.

Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease.

Background And Aims: The prevalence of inflammatory bowel disease among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-tumor necrosis factor (TNF) immunogenicity (HLA-DQA1∗05) in a cohort of Hispanic patients of diverse ancestral backgrounds.

Ileal Paneth Cell Phenotype is a Cellular Biomarker for Pouch Complications in Ulcerative Colitis.

Background & Aims: Biomarkers that integrate genetic and environmental factors and predict outcome in complex immune diseases such as inflammatory bowel disease (IBD; including Crohn's disease [CD] and ulcerative colitis [UC]) are needed. We showed that morphologic patterns of ileal Paneth cells (Paneth cell phenotype [PCP]; a surrogate for PC function) is one such cellular biomarker for CD. Given the shared features between CD and UC, we hypothesized that PCP is also associated with molecular/genetic features and outcome in UC.

Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients.

Background: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression.

Pre-operative visceral adipose tissue radiodensity is a potentially novel prognostic biomarker for early endoscopic post-operative recurrence in Crohn's disease.

Background: Evidence suggests inflammatory mesenteric fat is involved in post-operative recurrence (POR) of Crohn's disease (CD). However, its prognostic value is uncertain, in part, due to difficulties studying it non-invasively.

Aim: To evaluate the prognostic value of pre-operative radiographic mesenteric parameters for early endoscopic POR (ePOR).

Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease.

Background & Aims: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD.

Methods: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort).

Allogeneic bone marrow transplantation for patients with treatment-refractory Crohn's Disease.

Background & Aims: Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications.

NAD precursors and bile acid sequestration treat preclinical refractory environmental enteric dysfunction.

Environmental enteric dysfunction (EED) is a diffuse small bowel disorder associated with poor growth, inadequate responses to oral vaccines, and nutrient malabsorption in millions of children worldwide. We identify loss of the small intestinal Paneth and goblet cells that are critical for innate immunity, reduced villous height, increased bile acids, and dysregulated nicotinamide adenine dinucleotide (NAD) synthesis signaling as potential mechanisms underlying EED and which also correlated with diminished length-for-age score. Isocaloric low-protein diet (LPD) consumption in mice recapitulated EED histopathology and transcriptomic changes in a microbiota-independent manner, as well as increases in serum and fecal bile acids.

Profiling the inflammatory bowel diseases using genetics, serum biomarkers, and smoking information.

Crohn's disease (CD) and ulcerative colitis (UC) are two etiologically related yet distinctive subtypes of the inflammatory bowel diseases (IBD). Differentiating CD from UC can be challenging using conventional clinical approaches in a subset of patients. We designed and evaluated a novel molecular-based prediction model aggregating genetics, serum biomarkers, and tobacco smoking information to assist the diagnosis of CD and UC in over 30,000 samples.

Genetic variation in environmental enteropathy and stunting in Zambian children: A pilot genome wide association study using the H3Africa chip.

Purpose: Stunting is known to be heavily influenced by environmental factors, so the genetic contribution has received little attention. Here we report an exploration of genetic influences in stunted Zambian children with environmental enteropathy.

Method: Children with stunting (LAZ < -2) were enrolled and given nutritional therapy.

Sex-Dimorphic Analyses Identify Novel and Sex-Specific Genetic Associations in Inflammatory Bowel Disease.

Background: Sex is an integral variable often overlooked in complex disease genetics. Differences between sexes have been reported in natural history, disease complications, and age of onset in inflammatory bowel disease (IBD). While association studies have identified >230 IBD loci, there have been a limited number of studies investigating sex differences underlying these genetic associations.

Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients.

Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719).

Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.

Objective: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in ().

Design: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed.

Potential determinants of low circulating glucagon-like peptide 2 concentrations in Zambian children with non-responsive stunting.

New Findings: What is the central question of this study? Non-responsive stunting is characterised by a progressive decline of circulating glucagon-like peptide 2: what are the possible causes of this decline? What is the main finding and its importance? In contrast with the established loss of Paneth and goblet cells in environmental enteropathy, there was no evidence of a parallel loss of enteroendocrine cells as seen by positive tissue staining for chromogranin A. Transcriptomic and genomic analyses showed evidence of genetic transcripts that could account for some of the variability seen in circulating glucagon-like peptide 2 values.

Abstract: Nutrient sensing determines digestive and hormonal responses following nutrient ingestion.

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls.

Crohn's disease in endoscopic remission, obesity, and cases of high genetic risk demonstrates overlapping shifts in the colonic mucosal-luminal interface microbiome.

Background: Crohn's disease (CD) patients demonstrate distinct intestinal microbial compositions and metabolic characteristics compared to unaffected controls. However, the impact of inflammation and underlying genetic risk on these microbial profiles and their relationship to disease phenotype are unclear. We used lavage sampling to characterize the colonic mucosal-luminal interface (MLI) microbiome of CD patients in endoscopic remission and unaffected controls relative to obesity, disease genetics, and phenotype.

Histo-Blood Group Antigens, Enteropathogen Carriage and Environmental Enteropathy in Stunted Zambian Children.

Objectives: Stunting, the most common form of childhood undernutrition, is associated with environmental enteropathy (EE). Enteric infections are believed to play a role in the pathophysiology of EE and stunting though the exact mechanism remains undetermined. The FUT2 (secretor) and FUT3 (Lewis) genes have been shown to be associated with some symptomatic enteric infections in both children and adults.

Stratification of risk of progression to colectomy in ulcerative colitis via 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 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).

Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation.

Intestinal Paneth cells modulate innate immunity and infection. In Crohn's disease, genetic mutations together with environmental triggers can disable Paneth cell function. Here, we find that a western diet (WD) similarly leads to Paneth cell dysfunction through mechanisms dependent on the microbiome and farnesoid X receptor (FXR) and type I interferon (IFN) signaling.

Crohn's disease-associated ATG16L1 T300A genotype is associated with improved survival in gastric cancer.

Background: A non-synonymous single nucleotide polymorphism of the ATG16L1 gene, T300A, is a major Crohn's disease (CD) susceptibility allele, and is known to be associated with increased apoptosis induction in the small intestinal crypt base in CD subjects and mouse models. We hypothesized that ATG16L1 T300A genotype also correlates with increased tumor apoptosis and therefore could lead to superior clinical outcome in cancer subjects.

Methods: T300A genotyping by Taqman assay was performed for gastric carcinoma subjects who underwent resection from two academic medical centers.

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC).

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

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.