Genetic Variants Associated with Inflammatory Bowel Disease and Gut Graft-versus-host Disease.
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ABSTRACT:
SUBMITTER: Martin PJ
PROVIDER: S-EPMC8579259 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION:The family history of inflammatory bowel disease (IBD) has been strongly associated with risk of developing IBD. This study aimed to identify the host genetic and gut microbial signatures in familial IBD. METHODS:Genetic analyses using genome-wide single nucleotide polymorphism genotyping and whole exome sequencing were performed to calculate weighted genetic risk scores from known IBD-associated common variants and to identify rare deleterious protein-altering variants specific to patients with familial IBD in 8 Korean families that each included more than 2 affected first-degree relatives (FDRs) and their unaffected FDR(s). In parallel, gut microbial community was analyzed by 16S rRNA sequencing of stools from the sample individuals. RESULTS:The risk of familial IBD was not well explained by the genetic burden from common IBD-risk variants, suggesting the presence of family-shared genetic and environmental disease-risk factors. We identified 17 genes (AC113554.1, ACE, AKAP17A, AKAP9, ANK2, ASB16, ASIC3, DNPH1, DUS3L, FAM200A, FZD10, LAMA5, NUTM2F, PKN1, PRR26, WDR66, and ZC3H4) that each contained rare, potentially deleterious variants transmitted to the affected FDRs in multiple families. In addition, metagenomic analyses revealed significantly different diversity of gut microbiota and identified a number of differentially abundant taxa in affected FDRs, highlighting 22 novel familial disease-associated taxa with large abundance changes and the previously reported gut dysbiosis including low alpha diversity in IBD and 16 known IBD-specific taxa. DISCUSSION:This study identified familial IBD-associated rare deleterious variants and gut microbial dysbiosis in familial IBD.
| S-EPMC7386341 | biostudies-literature
Project description:Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.
| S-EPMC6240460 | biostudies-other
Project description:Host NOD-like receptor family pyrin domain-containing 6 (NLRP6) regulates innate immune responses and gastrointestinal homeostasis. Its protective role in intestinal colitis and tumorigenesis is dependent on the host microbiome. Host innate immunity and microbial diversity also play a role in the severity of allogeneic immune-mediated gastrointestinal graft-versus-host disease (GVHD), the principal toxicity after allogeneic haematopoietic cell transplantation. Here, we examined the role of host NLRP6 in multiple murine models of allogeneic bone marrow transplantation. In contrast to its role in intestinal colitis, host NLRP6 aggravated gastrointestinal GVHD. The impact of host NLRP6 deficiency in mitigating GVHD was observed regardless of co-housing, antibiotic treatment or colonizing littermate germ-free wild-type and NLRP6-deficient hosts with faecal microbial transplantation from specific pathogen-free wild-type and Nlrp6-/- animals. Chimaera studies were performed to assess the role of NLRP6 expression on host haematopoietic and non-haematopoietic cells. The allogeneic [B6Ly5.2 → Nlrp6-/-] animals demonstrated significantly improved survival compared to the allogeneic [B6Ly5.2 → B6] animals, but did not alter the therapeutic graft-versus-tumour effects after haematopoietic cell transplantation. Our results unveil an unexpected, pathogenic role for host NLRP6 in gastrointestinal GVHD that is independent of variations in the intestinal microbiome and in contrast to its well-appreciated microbiome-dependent protective role in intestinal colitis and tumorigenesis.
| S-EPMC6689241 | biostudies-literature
Project description:Sclerotic graft-versus-host disease (GVHD) is a distinctive phenotype of chronic GVHD after allogeneic hematopoietic cell transplantation, characterized by fibrosis of skin or fascia. Sclerotic GVHD has clinical and histopathological similarities with systemic sclerosis, an autoimmune disease whose risk is influenced by genetic polymorphisms. We examined 13 candidate single-nucleotide polymorphisms (SNPs) that have a well-documented association with systemic sclerosis to determine whether these SNPs are also associated with the risk of sclerotic GVHD. The study cohort included 847 consecutive patients who were diagnosed with chronic GVHD. Genotyping was performed using microarrays, followed by imputation of unobserved SNPs. The donor rs10516487 (BANK1: B-cell scaffold protein with ankyrin repeats 1) TT genotype was associated with lower risk of sclerotic GVHD (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.21-0.87; P = .02). Donor and recipient rs2056626 (CD247: T-cell receptor ζ subunit) GG or GT genotypes were associated with higher risk of sclerotic GVHD (HR, 1.57; 95% CI, 1.13-2.18; P = .007 and HR, 1.66; 95% CI, 1.19-2.32; P = .003, respectively). Donor and recipient rs987870 (5'-flanking region of HLA-DPA1) CC genotypes were associated with higher risk of sclerotic GVHD (HR, 2.50; 95% CI, 1.22-5.11; P = .01 and HR, 2.13; 95% CI, 1.00-4.54; P = .05, respectively). In further analyses, the recipient DPA1*01:03∼DPB1*04:01 haplotype and certain amino acid substitutions in the recipient P1 peptide-binding pocket of the HLA-DP heterodimer were associated with risk of sclerotic GVHD. Genetic components associated with systemic sclerosis are also associated with sclerotic GVHD. HLA-DP-mediated antigen presentation, T-cell response, and B-cell activation have important roles in the pathogenic mechanisms of both diseases.
| S-EPMC5025901 | biostudies-literature
Project description:Dermatologists are ideally suited to manage the various cutaneous sequelae of graft-versus-host disease (GVHD) outlined in part I of this review. However, the complexity of the patient with GVHD, including comorbidities, potential drug interactions related to polypharmacy, and the lack of evidence-based treatment guidelines, are significant challenges to optimizing patient care. In this section, we will provide an outline for the role of the dermatologist in a multispecialty approach to caring for patients with GVHD.
| S-EPMC7357210 | biostudies-literature
Project description:ObjectivesInflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by a complex pathophysiology that is thought to result from an aberrant immune response to a dysbiotic luminal microbiota in genetically susceptible individuals. New technologies support the joint assessment of host-microbiome interaction.MethodsUsing whole genome sequencing and shotgun metagenomics, we studied the clinical features, host genome, and stool microbial metagenome of 85 IBD patients, and compared the results to 146 control individuals. Genetic risk scores, computed on 159 single nucleotide variants, and human leukocyte antigen (HLA) types differentiated IBD patients from healthy controls.ResultsGenetic risk was associated with the need for use of biologics in IBD and, modestly, with the composition of the gut microbiome. As compared with healthy controls, IBD patients had hallmarks of stool microbiome dysbiosis, with loss of a diversified core microbiome, enrichment and depletion of specific bacteria, and enrichment of bacterial virulence factors.ConclusionsWe show that genetic risk may have a role in early risk stratification in the care of IBD patients and propose that expression of virulence factors in a dysbiotic microbiome may contribute to pathogenesis in IBD.
| S-EPMC5795019 | biostudies-literature
Project description:Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III-IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1?, IFN?, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.
| S-EPMC5688060 | biostudies-literature
Project description:The intestine can be the target of several immunologically mediated diseases, including graft-versus-host disease (GVHD) and inflammatory bowel disease (IBD). GVHD is a life-threatening complication that occurs after allogeneic hematopoietic stem cell transplantation. Involvement of the gastrointestinal tract is associated with a particularly high mortality. GVHD development starts with the recognition of allo-antigens in the recipient by the donor immune system, which elicits immune-mediated damage of otherwise healthy tissues. IBD describes a group of immunologically mediated chronic inflammatory diseases of the intestine. Several aspects, including genetic predisposition and immune dysregulation, are responsible for the development of IBD, with Crohn's disease and ulcerative colitis being the two most common variants. GVHD and IBD share multiple key features of their onset and development, including intestinal tissue damage and loss of intestinal barrier function. A further common feature in the pathophysiology of both diseases is the involvement of cytokines such as type I and II interferons (IFNs), amongst others. IFNs are a family of protein mediators produced as a part of the inflammatory response, typically to pathogens or malignant cells. Diverse, and partially paradoxical, effects have been described for IFNs in GVHD and IBD. This review summarizes current knowledge on the role of type I, II and III IFNs, including basic concepts and controversies about their functions in the context of GVHD and IBD. In addition, therapeutic options, research developments and remaining open questions are addressed.
| S-EPMC8264264 | biostudies-literature
Project description:BackgroundGastrointestinal acute graft-versus-host disease (GI aGVHD) is a lethal complication following allogeneic hematopoietic stem cell transplantation (HSCT). However, it is still very difficult to make a diagnosis of GI aGVHD in practice. To date, no consensus plasma biomarker of GI aGVHD can be used to help make a diagnosis. Here, we attempted to identify GI aGVHD associated plasma proteins in murine model, which can help make a diagnosis of GI aGVHD.MethodsWe used 8-plex isobaric tags for relative and absolute quantitation (8-plex iTRAQ) to screen out proteins in plasma samples taken from murine models before and after allogeneic HSCT. Next mRNA expressions were validated by quantitative real-time polymerase chain reaction in mouse intestinal epithelial samples.ResultsWe found that five proteins were increased at least 2-fold in the allogeneic group at day 7 compared with days 0, 3 and 15 (after Cyclosporin A treatment) and the syngeneic group at day 7. These 5 proteins were VNN3, ZNF746, C4BP, KNG1 and FETUB, and they were consistent with results from negative labeling with 8-plex iTRAQ. Furthermore, increase in mRNA level of VNN3 was confirmed in murine intestinal epithelial samples with aGVHD.ConclusionsOur results demonstrate that plasma VNN3 protein is associated with GI aGVHD in murine model.
| S-EPMC5755465 | biostudies-literature
Project description:BackgroundInflammatory bowel disease is the result of both genes and environment. Canadian First Nations people, despite living in a region with a high prevalence of inflammatory bowel disease, are relatively protected from this disease. We aimed to compare the carriage of genetic variants associated with inflammatory bowel disease in healthy First Nations and white people.MethodsDNA was extracted from the venous blood of healthy First Nations (n = 340) and white (n = 285) participants from Manitoba. Genotyping was performed for 69 single nucleotide polymorphisms (SNPs) with known or suspected associations with inflammatory bowel disease. We compared the genotypes between groups by logistic regression, adjusting for multiple testing. We calculated a risk score for the NOD2 gene by adding the number of risk alleles at three important NOD2 SNPs (G908R, R702W and 3020insC).ResultsWe found genetic variation between white and First Nations participants at 45 of 69 SNPs. Notably, carriage of the ATG16L1 T300A mutation was lower in First Nations participants (p = 4.1 × 10(-30)). Cumulative carriage of important NOD2 variants was significantly lower among First Nations participants (3.9% v. 15.2%; p < 0.0001 for risk score) than among white participants. Risk variants in IL23R (p = 0.014) and IL12B (p = 1.2 × 10(-16)), among others, were more prevalent among First Nations participants than among white participants.InterpretationThe low prevalence of variants associated with bacterial processing and handling in First Nations people may explain their relative protection from inflammatory bowel disease. Increased carriage of a number of risk variants, for example in the interleukin-23/Th17 pathway, is especially intriguing given their importance in other inflammatory diseases of high incidence in First Nations populations.
| S-EPMC3348221 | biostudies-literature