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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 2+ -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., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abnormalities of the intestinal microbiota are implicated in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), two spectra of inflammatory bowel disease (IBD). However, the high complexity and low inter-individual overlap of intestinal microbial composition are formidable barriers to identifying microbial taxa representing this dysbiosis. These difficulties might be overcome by an ecologic analytic strategy to identify modules of interacting bacteria (rather than individual bacteria) as quantitative reproducible features of microbial composition in normal and IBD mucosa. We sequenced 16S ribosomal RNA genes from 179 endoscopic lavage samples from different intestinal regions in 64 subjects (32 controls, 16 CD and 16 UC patients in clinical remission). CD and UC patients showed a reduction in phylogenetic diversity and shifts in microbial composition, comparable to previous studies using conventional mucosal biopsies. Analysis of weighted co-occurrence network revealed 5 microbial modules. These modules were unprecedented, as they were detectable in all individuals, and their composition and abundance was recapitulated in an independent, biopsy-based mucosal dataset 2 modules were associated with healthy, CD, or UC disease states. Imputed metagenome analysis indicated that these modules displayed distinct metabolic functionality, specifically the enrichment of oxidative response and glycan metabolism pathways relevant to host-pathogen interaction in the disease-associated modules. The highly preserved microbial modules accurately classified IBD status of individual patients during disease quiescence, suggesting that microbial dysbiosis in IBD may be an underlying disorder independent of disease activity. Microbial modules thus provide an integrative view of microbial ecology relevant to IBD.

We tested the hypothesis that Crohn's disease (CD)-related genetic polymorphisms involved in host innate immunity are associated with shifts in human ileum-associated microbial composition in a cross-sectional analysis of human ileal samples. Sanger sequencing of the bacterial 16S ribosomal RNA (rRNA) gene and 454 sequencing of 16S rRNA gene hypervariable regions (V1-V3 and V3-V5), were conducted on macroscopically disease-unaffected ileal biopsies collected from 52 ileal CD, 58 ulcerative colitis and 60 control patients without inflammatory bowel diseases (IBD) undergoing initial surgical resection. These subjects also were genotyped for the three major NOD2 risk alleles (Leu1007fs, R708W, G908R) and the ATG16L1 risk allele (T300A). The samples were linked to clinical metadata, including body mass index, smoking status and Clostridia difficile infection. The sequences were classified into seven phyla/subphyla categories using the Naïve Bayesian Classifier of the Ribosome Database Project. Centered log ratio transformation of six predominant categories was included as the dependent variable in the permutation based MANCOVA for the overall composition with stepwise variable selection. Polymerase chain reaction (PCR) assays were conducted to measure the relative frequencies of the Clostridium coccoides - Eubacterium rectales group and the Faecalibacterium prausnitzii spp. Empiric logit transformations of the relative frequencies of these two microbial groups were included in permutation-based ANCOVA. Regardless of sequencing method, IBD phenotype, Clostridia difficile and NOD2 genotype were selected as associated (FDR ≤ 0.05) with shifts in overall microbial composition. IBD phenotype and NOD2 genotype were also selected as associated with shifts in the relative frequency of the C. coccoides--E. rectales group. IBD phenotype, smoking and IBD medications were selected as associated with shifts in the relative frequency of F. prausnitzii spp. These results indicate that the effects of genetic and environmental factors on IBD are mediated at least in part by the enteric microbiota.

Previous European studies suggest NOD2/CARD15 and interleukin-23 receptor (IL-23R) donor or recipient variants are associated with adverse clinical outcomes in allogeneic hematopoietic stem cell transplantation. We reexamined these findings as well as the role of another inflammatory bowel disease (IBD) susceptibility gene (immunity-related GTPase family, M [IRGM]) on transplantation outcomes in 390 US patients and their matched unrelated donors, accrued between 1995 and 2004. Patients received T-replete grafts with mostly myeloablative conditioning regimens. Multivariate analyses were performed for overall survival, disease-free survival, transplantation-related mortality, relapse, and acute and chronic graft-versus-host disease. Of 390 pairs, NOD2/CARD15 variant single nucleotide polymorphisms (SNPs) were found in 14% of donors and 17% of recipients. In 3% both donor and recipient had a mutant SNP. Thirteen percent of donors and 16% of recipients had variant IL23R SNPs, with 3% having both donor and recipient variants. Twenty-three percent of both donors and recipients had variant IRGM SNPs. None of the 3 IBD-associated alleles showed a statistically significant association with any adverse clinical outcomes. Our results do not support an association between the 3 IBD-associated SNPs and adverse outcomes after matched unrelated donor hematopoietic cell transplantations in US patients.

Susceptibility to Crohn’s disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn’s disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn’s disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn’s disease patients carrying the Crohn’s disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn’s disease patients homozygous for the ATG16L1 Crohn’s disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn’s disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells. [ABSTRACT FROM AUTHOR]

We evaluated the effect of potential clinical factors on surgical recurrence of ileal Crohn’s disease after initial ileocolic resection. One hundred seventy-six patients with ileal Crohn’s disease who underwent an ileocolic resection with anastomosis were identified from our database. The outcome of interest was time from first to second ileocolic resection. Survival analysis was used to assess the significance of the Montreal phenotype classification, smoking habit, a family history of inflammatory bowel disease and other clinical variables. In our final Cox model, a family history of inflammatory bowel disease (hazard ratio 2.24, 95 percent confidence interval 1.16–4.30, P = 0.016), smoking at time of initial ileocolic resection (hazard ratio 2.08, 95 percent confidence interval 1.11–3.91, P = 0.023) was associated with an increased risk of a second ileocolic resection while postoperative prescription of immunomodulators (hazard ratio 0.40, 95 percent confidence interval 0.18–0.88, P = 0.022) was associated with a decreased risk of a second ileocolic resection. Both a family history of inflammatory bowel disease and smoking at the time of the initial ileocolic resection are associated with an increased risk of a second ileocolic resection. Postoperative prescription of immunomodulators is associated with a reduced risk of surgical recurrence. This study supports the concept that both genetic and environmental factors influence the risk of surgical recurrence of ileal Crohn’s disease. [ABSTRACT FROM AUTHOR]

Examines the effect of protozoan parasite Entamoeba histolytica in the inflammation and ulceration of the intestines. Activation of the transcription factor NF-[sub k]B in human intestinal epithelial cells; Contributions of interleukin1-beta converting enzyme in the intestinal inflammation; Role of amoebic cysteine proteinase in gut inflammation.