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Fee BE, Fee LR, Menechella M, Affeldt B, Sprouse AR, Bounini A, Alwarawrah Y, Molloy CT, Ilkayeva OR, Prinz JA, Lenz DS, MacIver NJ, Rai P, Fessler MB, Coers J, Taylor GA. Type I interferon signaling and peroxisomal dysfunction contribute to enhanced inflammatory cytokine production in IRGM1-deficient macrophages. J Biol Chem 2024; 300:107883. [PMID: 39395806 DOI: 10.1016/j.jbc.2024.107883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 09/30/2024] [Accepted: 10/05/2024] [Indexed: 10/14/2024] Open
Abstract
The human IRGM gene has been linked to inflammatory diseases including sepsis and Crohn's disease. Decreased expression of human IRGM, or the mouse orthologues Irgm1 and Irgm2, leads to increased production of a number of inflammatory chemokines and cytokines in vivo and/or in cultured macrophages. Prior work has indicated that increased cytokine production is instigated by metabolic alterations and changes in mitochondrial homeostasis; however, a comprehensive mechanism has not been elucidated. In the studies presented here, RNA deep sequencing and quantitative PCR were used to show that increases in cytokine production, as well as most changes in the transcriptional profile of Irgm1-/- bone marrow-derived macrophages (BMM), are dependent on increased type I IFN production seen in those cells. Metabolic alterations that drive increased cytokines in Irgm1-/- BMM - specifically increases in glycolysis and increased accumulation of acyl-carnitines - were unaffected by quenching type I IFN signaling. Dysregulation of peroxisomal homeostasis was identified as a novel upstream pathway that governs type I IFN production and inflammatory cytokine production. Collectively, these results enhance our understanding of the complex biochemical changes that are triggered by lack of Irgm1 and contribute to inflammatory disease seen with Irgm1-deficiency.
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Affiliation(s)
- Brian E Fee
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development; Duke University Medical Center, Durham, North Carolina, USA
| | - Lanette R Fee
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development; Duke University Medical Center, Durham, North Carolina, USA
| | - Mark Menechella
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development; Duke University Medical Center, Durham, North Carolina, USA
| | - Bethann Affeldt
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development; Duke University Medical Center, Durham, North Carolina, USA
| | - Aemilia R Sprouse
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development; Duke University Medical Center, Durham, North Carolina, USA
| | - Amina Bounini
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development; Duke University Medical Center, Durham, North Carolina, USA
| | - Yazan Alwarawrah
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, and Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Caitlyn T Molloy
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, and Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Olga R Ilkayeva
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | - Joseph A Prinz
- Duke University School of Medicine, Sequencing and Genomic Technologies, Durham, North Carolina, USA
| | - Devi Swain Lenz
- Duke University School of Medicine, Sequencing and Genomic Technologies, Durham, North Carolina, USA; Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Nancie J MacIver
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, and Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Prashant Rai
- Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Michael B Fessler
- Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Jörn Coers
- Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA; Department of Immunobiology; Duke University Medical Center, Durham, North Carolina, USA
| | - Gregory A Taylor
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development; Duke University Medical Center, Durham, North Carolina, USA; Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA; Department of Immunobiology; Duke University Medical Center, Durham, North Carolina, USA; Geriatric Research, Education, and Clinical Center, Durham VA Health Care System, Durham, North Carolina, USA.
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Mankarious MM, Connelly TM, Harris L, Deiling S, Yochum GS, Koltun WA. Creating a Surgical Biobank: The Hershey Medical Center Experience. Dis Colon Rectum 2023; 66:1174-1184. [PMID: 37378558 DOI: 10.1097/dcr.0000000000002944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
BACKGROUND Tissue harvesting at the time of surgery offers surgeons and scientists a unique opportunity to discover and better understand disease pathophysiology. Tissue biobanking presents challenges in patient consents, specimen collection, preparation, and storage, but the potential for scientific discovery justifies the effort. Although the number of tissue biobanks is increasing worldwide, information regarding necessary infrastructure, process flow, and management of expected obstacles is lacking. OBJECTIVE To provide a framework and motivation for clinician scientists intending to start an intestinal tissue biobank under their direction. DATA SOURCES The Carlino Family Inflammatory Bowel and Colorectal Diseases Biobank is housed at the Milton S. Hershey Medical Center. STUDY SELECTION Review. INTERVENTION Implementation of a surgical tissue biobank at a large tertiary care institution. MAIN OUTCOME MEASURES Assess critical challenges and obstacles over the years as well as keys to the success of the program. RESULTS Over 2 decades, the institutional biobank grew from an IBD biobank to one which now incorporates thousands of surgical specimens representing numerous colorectal diseases. This was done through a process of refinement focusing on patient recruitment and an efficient consenting and specimen management process. The biobank's success is further insured by institutional, external, and philanthropic support; scientific collaborations; and sharing of biological specimens with other groups of dedicated researchers. LIMITATIONS This is a single-center experience in collecting surgically resected colorectal specimens. CONCLUSIONS Surgical specimen biobanks are essential in studying disease cause using genomics, transcriptomics, and proteomic technologies. Therefore, surgeons, clinicians, and scientists should build biobanks at their institutions to promote further scientific discovery and improve specimen diversity.
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Affiliation(s)
- Marc M Mankarious
- Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Tara M Connelly
- Department of Surgery, University Hospital Limerick, Dooradoyle, Limerick, Ireland
| | - Leonard Harris
- Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Sue Deiling
- Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Gregory S Yochum
- Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
- Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Walter A Koltun
- Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
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Connelly TM, Lincango E, Holubar SD. Crohn's of the Pouch: Now What? Clin Colon Rectal Surg 2022; 35:475-486. [PMID: 36591396 PMCID: PMC9797285 DOI: 10.1055/s-0042-1758139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Total proctocolectomy and ileal pouch anal anastomosis (IPAA) is the gold standard surgical treatment for the majority (∼90%) of ulcerative colitis (UC) patients. In cases of carefully selected Crohn's colitis patients without small bowel or perianal involvement an "intentional IPAA" may be a viable option for disease resection and restoration of intestinal continuity. More commonly, Crohn's is incidentally found either in the resection specimen or, more commonly, when inflammatory complications subsequently arise after pouch construction for UC or indeterminate colitis. These incidental Crohn's pouches may be diagnosed early or late period post-IPAA. Crohn's may manifest within the pouch, in the proximal small bowel, and/or distally in the rectal cuff or anus. Like intestinal Crohn's, Crohn's disease of the pouch may be of an inflammatory, fibrostenosing, or fistulizing phenotype. Treatment depends on the phenotype and includes medical treatment, most commonly in the form of tumor necrosis factor inhibitor medications; however, the newer small molecules offer a potential treatment for these patients. Surgery first entails treating the sequelae of Crohn's and is typically staged. In up to 60% of Crohn's pouches, particularly in fistulizing disease and/or recalcitrant perianal disease, the pouch fails and must be defunctioned or excised. In patients with Crohn's pouches in situ long term, outcomes including quality of life are comparable to patients who underwent IPAA for UC.
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Affiliation(s)
- Tara M. Connelly
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Eddy Lincango
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Stefan D. Holubar
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
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Battat R, Sandborn WJ. Advances in the Comprehensive Management of Postoperative Crohn's Disease. Clin Gastroenterol Hepatol 2022; 20:1436-1449. [PMID: 33819666 DOI: 10.1016/j.cgh.2021.03.048] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/21/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023]
Abstract
Patients with postoperative Crohn's disease are difficult to manage because of their risk of experiencing a more severe course, multiple symptom confounders, and poor sensitivity of symptomatic remission to rule out intestinal inflammation. In this group, data are lacking on biologic therapeutic efficacy, and recommendations are lacking for those with multiple medication failures. Novel noninvasive testing can simultaneously exclude alternate causes of symptoms (serum C4, fecal fat, small intestinal bowel overgrowth breath testing) and assess intestinal inflammation (fecal calprotectin, endoscopic healing index). In addition, endoscopy-based disease activity assessment and management are required. Endoscopy should be performed within 6 months of surgery, and aggressive disease activity monitoring can be considered with colonoscopy every 1-2 years subsequently to ensure late recurrence is detected. Patients with multiple resections should be screened for short bowel syndrome. Predictive biomarkers are needed to guide medication selection in this high-risk population. Postoperative prophylactic biologic therapy is prudent for patients with preoperative biologic failure. However, there are no high-quality data to guide which agent should be selected. Selecting biologics with an alternative mechanism of action in those who had failed a biologic with adequate drug concentrations and selection of different agents in those with previous intolerance are reasonable. Significantly more study is required to assess the efficacy of therapies in this setting.
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Affiliation(s)
- Robert Battat
- Jill Roberts Center for IBD, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York.
| | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California
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5
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Immunity-related GTPase IRGM at the intersection of autophagy, inflammation, and tumorigenesis. Inflamm Res 2022; 71:785-795. [PMID: 35699756 PMCID: PMC9192921 DOI: 10.1007/s00011-022-01595-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/25/2022] [Indexed: 12/26/2022] Open
Abstract
The human immunity-related GTPase M (IRGM) is a GTP-binding protein that regulates selective autophagy including xenophagy and mitophagy. IRGM impacts autophagy by (1) affecting mitochondrial fusion and fission, (2) promoting the co-assembly of ULK1 and Beclin 1, (3) enhancing Beclin 1 interacting partners (AMBRA1, ATG14L1, and UVRAG), (4) interacting with other key proteins (ATG16L1, p62, NOD2, cGAS, TLR3, and RIG-I), and (5) regulating lysosomal biogenesis. IRGM also negatively regulates NLRP3 inflammasome formation and therefore, maturation of the important pro-inflammatory cytokine IL-1β, impacting inflammation and pyroptosis. Ultimately, this affords protection against chronic inflammatory diseases. Importantly, ten IRGM polymorphisms (rs4859843, rs4859846, rs4958842, rs4958847, rs1000113, rs10051924, rs10065172, rs11747270, rs13361189, and rs72553867) have been associated with human inflammatory disorders including cancer, which suggests that these genetic variants are functionally relevant to the autophagic and inflammatory responses. The current review contextualizes IRGM, its modulation of autophagy, and inflammation, and emphasizes the role of IRGM as a cross point of immunity and tumorigenesis.
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Alwarawrah Y, Danzaki K, Nichols AG, Fee BE, Bock C, Kucera G, Hale LP, Taylor GA, MacIver NJ. Irgm1 regulates metabolism and function in T cell subsets. Sci Rep 2022; 12:850. [PMID: 35039539 PMCID: PMC8763923 DOI: 10.1038/s41598-021-04442-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 12/17/2021] [Indexed: 12/24/2022] Open
Abstract
Immunity Related GTPases (IRG) are a family of proteins produced during infection that regulate membrane remodeling events in cells, particularly autophagy and mitophagy. The human IRGM gene has been strongly associated with Crohn's disease and other inflammatory diseases through Genome-Wide Association studies. Absence of Irgm1 in mice prompts intestinal inflammation, autoimmunity, and impaired immune control of pathogenic bacteria and protozoa. Although prior work has focused on a prominent role for IRGM/Irgm1 in regulating macrophage function, the work described here addresses a potential role of Irgm1 in regulating the function of mature T cells. Irgm1 was found to be highly expressed in T cells in a manner that varied with the particular T cell subset and increased with activation. Mice with a complete lack of Irgm1, or a conditional lack of Irgm1 specifically in T cells, displayed numerous changes in T cell numbers and function in all subsets examined, including CD4+ (Th1 and Treg) and CD8+ T cells. Related to changes in T cell number, apoptosis was found to be increased in Irgm1-deficient CD4+ and CD8+ T cells. Altered T cell metabolism appeared to be a key driver of the phenotypes: Glucose metabolism and glycolysis were increased in Irgm1-deficient CD4+ and CD8+ T cells, and muting these effects with glycolytic inhibitors partially restored T cell function and viability.
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Affiliation(s)
- Yazan Alwarawrah
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, University of North Carolina, Chapel Hill, NC, USA
| | - Keiko Danzaki
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC, USA
| | - Amanda G Nichols
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, University of North Carolina, Chapel Hill, NC, USA
| | - Brian E Fee
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA
- Geriatric Research, Education, and Clinical Center, Durham VA Health Care System, Durham, NC, USA
| | - Cheryl Bock
- Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Gary Kucera
- Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Laura P Hale
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
| | - Gregory A Taylor
- Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA.
- Geriatric Research, Education, and Clinical Center, Durham VA Health Care System, Durham, NC, USA.
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
- Department of Immunology, Duke University Medical Center, Durham, NC, USA.
| | - Nancie J MacIver
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, University of North Carolina, Chapel Hill, NC, USA.
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
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Wang MH, Friton JJ, Raffals LE, Leighton JA, Pasha SF, Picco MF, Monroe K, Nix BD, Newberry RD, Faubion WA. Novel Genetic Variant Predicts Surgical Recurrence Risk in Crohn's Disease Patients. Inflamm Bowel Dis 2021; 27:1968-1974. [PMID: 33724339 DOI: 10.1093/ibd/izaa362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND We aimed to identify a model of clinical and genetic risk factors through hypothesis-free search across genome that can predict the surgical recurrence risk after the first abdominal surgery in CD patients. MATERIALS AND METHODS Two independent inflammatory bowel disease (IBD) cohort studies were used to derive and validate the genetic risk profile. The study subjects were genotyped using Illumina Immunochip custom genotyping array. Surgical recurrence was defined as having the second or more abdominal bowel resections after the first abdominal surgery at the time of study enrollment; nonsurgical recurrence was defined as having no further abdominal resection after the first abdominal surgery. RESULTS Among 372 CD patients who had at least 1 abdominal surgery at the study enrollment, 132 (35.5%) had subsequent surgical recurrence after their first abdominal surgery, and 240 (64.5%) required no subsequent abdominal surgery at the end of follow up. Among clinical factors, multivariable analysis showed that history of immunomodulatory use (odds ratio [OR], 3.96; P = 0.002) and early era of CD first surgery (OR, 1.12; P = 1.01E-04) remained significant. Genotypic association tests identified a genome-wide significant locus rs2060886 in TCF4 at chr18q21.2 associated with surgical recurrence risk (OR, dom, 4.10 [2.37-7.11]; P = 4.58E-08). CONCLUSIONS Novel genetic locus rs2060886 in TCF4 was associated with surgical recurrence risk at genome-wide significance level among CD patients after their first abdominal surgery. Early era of CD first intestinal surgery predicts higher surgical recurrence risk. These results suggest that genetic variants may help guide the CD management strategy in patients at the highest risk of repeated abdominal surgeries.
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Affiliation(s)
- Ming-Hsi Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.,Gastroenterology, Mayo Clinic Health System in Mankato, Mankato, Minnesota, USA
| | - Jessica J Friton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Laura E Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jonathan A Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Shabana F Pasha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Michael F Picco
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Kelly Monroe
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Billy D Nix
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Rodney D Newberry
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - William A Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Kline BP, Weaver T, Brinton DL, Harris L, Yochum GS, Berg AS, Koltun WA. Clinical and Genetic Factors Impact Time to Surgical Recurrence After Ileocolectomy for Crohn's Disease. Ann Surg 2021; 274:346-351. [PMID: 31714311 DOI: 10.1097/sla.0000000000003660] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate factors associated with time to surgical recurrence after Crohn's ileocolectomy. SUMMARY BACKGROUND DATA The most common surgery performed for Crohn's disease is ileocolectomy. Identifying patients at high risk for surgical recurrence may assist with medical and surgical decision-making. METHODS Data were obtained from 409 patients with Crohn's disease (CD) who had undergone ≥1 ileocolectomies at Penn State Hershey Medical Center. Six single-nucleotide polymorphisms (SNPs) associated with CD were evaluated in these patients: rs2076756, rs2066844, and rs2066845 in NOD2, rs4958847 and rs13361189 in IRGM, and rs2241880 in ATG16L1. Genotype and clinical factors were analyzed to determine associations with time to recurrent ileocolectomy. A subgroup analysis was performed on 241 patients naïve to biologics before initial ileocolectomy to assess the effect of biologic therapy on time to recurrent surgery. RESULTS There were 286 patients who underwent a single ileocolectomy, whereas 123 required multiple ileocolectomies. Ileocolonic involvement [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.21-3.00, P = 0.006] and rs2066844 in NOD2 (HR 1.8, 95% CI 1.17-2.77, P = 0.007) were associated with decreased time to surgical recurrence by multivariate analysis. In patients naïve to preoperative biologics, the initiation of postoperative biologics was associated with a 40% decreased incidence of surgical recurrence (HR 0.60, CI 0.39-0.93, P = 0.02) over time. CONCLUSIONS Ileocolonic distribution of disease and the rs2066844 SNP in NOD2 are associated with shorter time to recurrent ileocolectomy. The initiation of postoperative biologics in naïve patients was associated with a reduced incidence of recurrence over time.
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Affiliation(s)
- Bryan P Kline
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA
| | - Taelor Weaver
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA
| | - David L Brinton
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA
| | - Leonard Harris
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA
| | - Gregory S Yochum
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, College of Medicine, Hershey, PA
| | - Arthur S Berg
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA
- Department of Public Health Sciences, Division of Biostatistics and Bioinformatics, The Pennsylvania State University, College of Medicine, Hershey, PA USA
| | - Walter A Koltun
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA
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Dang JT, Dang TT, Wine E, Dicken B, Madsen K, Laffin M. The Genetics of Postoperative Recurrence in Crohn Disease: A Systematic Review, Meta-analysis, and Framework for Future Work. CROHN'S & COLITIS 360 2021; 3:otaa094. [PMID: 36778938 PMCID: PMC9802308 DOI: 10.1093/crocol/otaa094] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Indexed: 12/12/2022] Open
Abstract
Background Recurrence following abdominal surgery in Crohn disease is over 50%. The impact of genetics on postoperative recurrence is not well defined. Methods A literature search was conducted where inclusion required an assessment, by genotype, of postoperative recurrence. The primary endpoint was odds of surgical recurrence. Results Twenty-eight studies identified a total of 6715 patients. Thirteen loci were identified as modifying the risk of recurrence. NOD2 was identified as a risk factor for recurrence by multiple works (cumulative odds ratio: 1.64, P = 0.003). Conclusions A NOD2 risk allele is associated with recurrence following surgery in Crohn disease. Progress in this area will require standardized reporting in future works.
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Affiliation(s)
- Jerry T Dang
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - ThucNhi T Dang
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Eytan Wine
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Bryan Dicken
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Karen Madsen
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Michael Laffin
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada,Address correspondence to: Michael Laffin, MD, PhD, Department of Surgery, University of Alberta, University of Alberta Hospital, 8440 112 Street NW, Edmonton, AB T6G 2B7, Canada ()
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10
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Taylor GA, Huang HI, Fee BE, Youssef N, Jewell ML, Cantillana V, Schoenborn AA, Rogala AR, Buckley AF, Feng CG, Vallance BA, Gulati AS, Hammer GE. Irgm1-deficiency leads to myeloid dysfunction in colon lamina propria and susceptibility to the intestinal pathogen Citrobacter rodentium. PLoS Pathog 2020; 16:e1008553. [PMID: 32453761 PMCID: PMC7274479 DOI: 10.1371/journal.ppat.1008553] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/05/2020] [Accepted: 04/15/2020] [Indexed: 01/09/2023] Open
Abstract
IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity. IRGM dysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.
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Affiliation(s)
- Gregory A. Taylor
- Geriatric Research, Education, and Clinical Center, VA Health Care Center, Durham, North Carolina, United States of America
- Departments of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina, United States of America
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
- Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America
- * E-mail: (GAT); (GEH)
| | - Hsin-I Huang
- Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Brian E. Fee
- Geriatric Research, Education, and Clinical Center, VA Health Care Center, Durham, North Carolina, United States of America
| | - Nourhan Youssef
- Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Mark L. Jewell
- Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Viviana Cantillana
- Departments of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Alexi A. Schoenborn
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Allison R. Rogala
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Pediatrics, Division of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Anne F. Buckley
- Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Carl G. Feng
- Department of Infectious Diseases and Immunology, University of Sydney, Sydney, NSW, Australia
| | - Bruce A. Vallance
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Ajay S. Gulati
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Pediatrics, Division of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Gianna E. Hammer
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
- Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America
- * E-mail: (GAT); (GEH)
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Abstract
BACKGROUND Ileocolectomy is the most common surgery performed for Crohn's disease, and postoperative complications occur frequently. There has been minimal evaluation of complications after ileocolectomy as a function of both clinical and genetic factors. OBJECTIVE The purpose of this study was to evaluate both genetic and clinical factors associated with complications after Crohn's ileocolectomy. DESIGN This was a retrospective clinical and genetic cohort study. SETTINGS This study was conducted at a high-volume tertiary care center. PATIENTS We identified 269 patients with Crohn's disease who had undergone 287 ileocolectomies at our institution between July 2008 and October 2018. MAIN OUTCOME MEASURES We measured the association of complications with a combination of clinical factors and 6 Crohn's-associated single nucleotide polymorphisms in NOD2 (rs2076756, rs2066844, and rs2066845), IRGM (rs4958847 and rs13361189), and ATG16L1 (rs2241880). RESULTS There were 86 ileocolectomies of 287 (30%) with complications requiring intervention. The single nucleotide polymorphism rs13361189 in the gene IRGM was significantly associated with complications on univariate and multivariate analysis. There were 61 patients with a variant at the rs13361189 single nucleotide polymorphism and 26 of them had complications, although only 55 of the 208 wild-type patients had complications (43% vs 26%; OR = 2.1; p = 0.02). Other significant factors associated with complication after ileocolectomy were open surgery, placement of a proximal ileostomy, and a greater perioperative decrease in hematocrit. LIMITATIONS This study was limited by its retrospective design and inherent selection bias. CONCLUSIONS In addition to clinical risk factors, the rs13361189 single nucleotide polymorphism in the IRGM gene was independently associated with complications after ileocolectomy for Crohn's disease. The use of such genetic determinants may identify patients at increased risk for surgical complications after ileocolectomy. See Video Abstract at http://links.lww.com/DCR/B124. FACTORES CLÍNICOS Y GENÉTICOS ASOCIADOS CON COMPLICACIONES DESPUÉS DE LA ILEOCOLECTOMÍA DE CROHN: La ileocolectomía es la cirugía más común realizada para la enfermedad de Crohn y con frecuencia ocurren complicaciones postoperatorias. Ha habido una evaluación mínima de complicaciones después de la ileocolectomía, en función de factores clínicos y genéticos.Evaluar factores genéticos y clínicos asociados con complicaciones, después de la ileocolectomía por Crohn.Estudio retrospectivo de cohorte clínico y genético.Este estudio se realizó en un centro de atención terciaria de alto volumen.Identificamos a 269 pacientes con enfermedad de Crohn, sometidos a 287 ileocolectomías en nuestra institución, entre julio de 2008 y octubre de 2018.La asociación de complicaciones con una combinación de factores clínicos y seis polimorfismos de un solo nucleótido asociados a Crohn en NOD2 (rs2076756, rs2066844 y rs2066845), IRGM (rs4958847 y rs13361189) y ATG16L1 (rs2241880).Hubieron 86 ileocolectomías en 287 (30%) pacientes con complicaciones que requirieron intervención. El polimorfismo de un solo nucleótido rs13361189 en el gen IRGM se asoció significativamente con complicaciones en el análisis univariado y multivariado. Hubieron 61 pacientes con una variante en el polimorfismo de un solo nucleótido rs13361189 y 26 de ellos tuvieron complicaciones, mientras que solo 55 de los 208 pacientes de tipo salvaje (WT) tuvieron complicaciones (43% vs 26%, OR 2.1, p = 0.02). Otros factores significativos asociados con las complicaciones después de la ileocolectomía fueron, la cirugía abierta, la colocación de una ileostomía proximal y una mayor disminución perioperatoria del hematocrito.Este estudio estuvo limitado por su diseño retrospectivo y sesgo de selección inherente.Además de los factores de riesgo clínicos, el polimorfismo de un solo nucleótido rs13361189 en el gen IRGM se asoció independientemente con complicaciones después de la ileocolectomía, para la enfermedad de Crohn. El uso de tales determinantes genéticos puede identificar a los pacientes con mayor riesgo de complicaciones quirúrgicas, después de la ileocolectomía. Consulte Video Resumen en http://links.lww.com/DCR/B124.
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12
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Zhao M, Burisch J. Impact of Genes and the Environment on the Pathogenesis and Disease Course of Inflammatory Bowel Disease. Dig Dis Sci 2019; 64:1759-1769. [PMID: 31073736 DOI: 10.1007/s10620-019-05648-w] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Crohn's disease and ulcerative colitis constitute two major subgroups of inflammatory bowel diseases (IBD), a group of complex polygenic diseases characterized by chronic and progressive inflammation in the gastrointestinal tract. In recent years, methodological advances in genetic analysis have greatly expanded our understanding of the genetic background of IBD. So far, more than 240 genetic risk loci have been identified for IBD. However, these risk alleles explain less than 30% of the susceptibility to disease development, suggesting that environmental factors contribute considerably. The increasing occurrence of IBD in Eastern countries following their 'westernization', as well as the increased risk of disease among those who migrate to high-incidence regions, also suggest that the environment is key in the pathogenesis of IBD. In this review, we summarize the current evidence on the role of genetic and environmental factors in the susceptibility to, and disease course of, IBD, and we suggest how these findings might be applied to clinical practice.
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Affiliation(s)
- Mirabella Zhao
- Gastro Unit, Hvidovre University Hospital, Kettegaard Alle 30, 2650, Hvidovre, Denmark
| | - Johan Burisch
- Gastro Unit, Hvidovre University Hospital, Kettegaard Alle 30, 2650, Hvidovre, Denmark.
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13
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Matthews SM, Eshelman MA, Berg AS, Koltun WA, Yochum GS. The Crohn's disease associated SNP rs6651252 impacts MYC gene expression in human colonic epithelial cells. PLoS One 2019; 14:e0212850. [PMID: 30794691 PMCID: PMC6386311 DOI: 10.1371/journal.pone.0212850] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 02/11/2019] [Indexed: 12/11/2022] Open
Abstract
Crohn’s disease (CD) is a debilitating inflammatory bowel disease (IBD) that arises from chronic inflammation in the gastrointestinal tract. Genome-wide association studies (GWAS) have identified over 200 single nucleotide polymorphisms (SNPs) that are associated with a predisposition for developing IBD. For the majority, the causal variant and target genes affected are unknown. Here, we investigated the CD-associated SNP rs6651252 that maps to a gene desert region on chromosome 8. We demonstrate that rs6651252 resides within a Wnt responsive DNA enhancer element (WRE) and that the disease associated allele augments binding of the TCF7L2 transcription factor to this region. Using CRISPR/Cas9 directed gene editing and epigenetic modulation, we find that the rs6651252 enhancer regulates expression of the c-MYC proto-oncogene (MYC). Furthermore, we found MYC transcript levels are elevated in patient-derived colonic segments harboring the disease-associated allele in comparison to those containing the ancestral allele. These results suggest that Wnt/MYC signaling contributes to CD pathogenesis and that patients harboring the disease-associated allele may benefit from therapies that target MYC or MYC-regulated genes.
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Affiliation(s)
- Stephen M. Matthews
- Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
- Department of Surgery, Division of Colon and Rectal Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Melanie A. Eshelman
- Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
- Department of Surgery, Division of Colon and Rectal Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Arthur S. Berg
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Walter A. Koltun
- Department of Surgery, Division of Colon and Rectal Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Gregory S. Yochum
- Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
- Department of Surgery, Division of Colon and Rectal Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
- * E-mail:
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14
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Teimoori-Toolabi L, Samadpoor S, Mehrtash A, Ghadir M, Vahedi H. Among autophagy genes, ATG16L1 but not IRGM is associated with Crohn's disease in Iranians. Gene 2018; 675:176-184. [PMID: 29960072 DOI: 10.1016/j.gene.2018.06.074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 06/19/2018] [Accepted: 06/22/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND The prevalence of inflammatory bowel diseases is uprising in countries like Iran. Genetic predisposing elements play prominent role in the pathogenesis of Crohn's disease. In this study we studied the role of autophagy genes like IRGM (Immunity related GTPase M) and ATG16L1 (Autophagy related 16 like 1) in the pathogenesis of Crohn's Disease in Iranian patients. METHODS One hundred thirty-eight patients and 99 normal controls were recruited in this study. Polymorphisms in -1644 and -308 upstream of IRGM gene were studied by PCR-sequencing and 20 kb CNVdel/insertion was studied by specific PCR. Rs10065171, rs4958847 in IRGM gene and rs2241880 in ATG16L1 were studied by Taqman genotyping assays. RESULTS None of the so-called predisposing alleles of IRGM gene predispose Iranians to Crohn's disease while the prevalence of some of them like CNV deletion was higher in normal controls. Surprisingly all the so-called predisposing alleles in IRGM were linked to each other (especially rs4958847 with rs10065172 and polymorphisms in -308 region with rs4958847). Patients harboring A allele in rs4958847 site showed higher ratio of fibrostenotic type of disease while in patients with C/T genotype in rs4958847, colonic involvement was seen more frequently. G allele in ATG16L1 was associated with Crohn's disease though it was not associated with any phenotypic manifestation. CONCLUSION In our study the association of ATG16L1 to Crohn's disease in Iranian patients was confirmed while it was shown that the studied polymorphisms in IRGM was not associated with Crohn's disease. Therefore in order to have a better picture about the genetics of Crohn's disease in Iranian patients, it is recommended to study other clinically effective polymorphisms in IRGM and ATG16L1 in addition to other genes which are responsible for the process of autophagy.
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Affiliation(s)
- Ladan Teimoori-Toolabi
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran; Molecular Medicine Department, Pasteur Institute of Iran, Tehran, Iran.
| | - Sanaz Samadpoor
- Molecular Medicine Department, Pasteur Institute of Iran, Tehran, Iran
| | | | - Mahdis Ghadir
- Molecular Medicine Department, Pasteur Institute of Iran, Tehran, Iran
| | - Homayoon Vahedi
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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15
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Gklavas A, Dellaportas D, Papaconstantinou I. Risk factors for postoperative recurrence of Crohn's disease with emphasis on surgical predictors. Ann Gastroenterol 2017; 30:598-612. [PMID: 29118554 PMCID: PMC5670279 DOI: 10.20524/aog.2017.0195] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 07/10/2017] [Indexed: 12/12/2022] Open
Abstract
Intestinal resection for Crohn’s disease is not curative and postoperative recurrence rates remain high. Early detection of indices associated with recurrence and risk stratification are fundamental for the postoperative management of patients. Early endoscopy at 6-12 months is the “gold standard” procedure, whereas other modalities such as fecal calprotectin and imaging techniques can contribute to the diagnosis of recurrence. The purpose of this review is to summarize current data regarding risk factors correlated with postoperative relapse. Smoking is a well-established, modifiable risk factor. There are sufficient data that correlate penetrating disease, perianal involvement, extensive resections, prior surgery, histological features (plexitis and granulomas), and improper management after resection with high rates for recurrence. The literature provides conflicting data for other possible predictors, such as age, sex, family history of inflammatory bowel disease, location of disease, strictureplasties, blood transfusions, and postoperative complications, necessitating further evidence. On the other hand, surgical factors such as anastomotic configuration, open or laparoscopic approach, and microscopic disease at specimen margins when macroscopic disease is resected, seem not to be related with an increased risk of recurrence. Further recognition of histological features as well as gene-related factors are promising fields for research.
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Affiliation(s)
- Antonios Gklavas
- 2 Department of Surgery, Aretaieion University Hospital, University of Athens, School of Medicine, Athens, Greece
| | - Dionysios Dellaportas
- 2 Department of Surgery, Aretaieion University Hospital, University of Athens, School of Medicine, Athens, Greece
| | - Ioannis Papaconstantinou
- 2 Department of Surgery, Aretaieion University Hospital, University of Athens, School of Medicine, Athens, Greece
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16
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Lightner AL, Pemberton JH, Dozois EJ, Larson DW, Cima RR, Mathis KL, Pardi DS, Andrew RE, Koltun WA, Sagar P, Hahnloser D. The surgical management of inflammatory bowel disease. Curr Probl Surg 2017; 54:172-250. [PMID: 28576304 DOI: 10.1067/j.cpsurg.2017.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Amy L Lightner
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN.
| | - John H Pemberton
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Eric J Dozois
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - David W Larson
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Robert R Cima
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Kellie L Mathis
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Rachel E Andrew
- Division of Colorectal Surgery, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA
| | - Walter A Koltun
- Division of Colorectal Surgery, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA
| | - Peter Sagar
- Division of Colorecal surgery, St. James University Hospital, Leeds, England
| | - Dieter Hahnloser
- Division of Colorecal surgery, Lausanne University Hospital, Lausanne, Switzerland
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Pilla-Moffett D, Barber MF, Taylor GA, Coers J. Interferon-Inducible GTPases in Host Resistance, Inflammation and Disease. J Mol Biol 2016; 428:3495-513. [PMID: 27181197 PMCID: PMC5010443 DOI: 10.1016/j.jmb.2016.04.032] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 04/23/2016] [Accepted: 04/30/2016] [Indexed: 01/18/2023]
Abstract
Cell-autonomous immunity is essential for host organisms to defend themselves against invasive microbes. In vertebrates, both the adaptive and the innate branches of the immune system operate cell-autonomous defenses as key effector mechanisms that are induced by pro-inflammatory interferons (IFNs). IFNs can activate cell-intrinsic host defenses in virtually any cell type ranging from professional phagocytes to mucosal epithelial cells. Much of this IFN-induced host resistance program is dependent on four families of IFN-inducible GTPases: the myxovirus resistance proteins, the immunity-related GTPases, the guanylate-binding proteins (GBPs), and the very large IFN-inducible GTPases. These GTPase families provide host resistance to a variety of viral, bacterial, and protozoan pathogens through the sequestration of microbial proteins, manipulation of vesicle trafficking, regulation of antimicrobial autophagy (xenophagy), execution of intracellular membranolytic pathways, and the activation of inflammasomes. This review discusses our current knowledge of the molecular function of IFN-inducible GTPases in providing host resistance, as well as their role in the pathogenesis of autoinflammatory Crohn's disease. While substantial advances were made in the recent past, few of the known functions of IFN-inducible GTPases have been explored in any depth, and new functions await discovery. This review will therefore highlight key areas of future exploration that promise to advance our understanding of the role of IFN-inducible GTPases in human diseases.
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Affiliation(s)
- Danielle Pilla-Moffett
- Department of Molecular Genetics and Microbiology, and Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Matthew F Barber
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Gregory A Taylor
- Department of Medicine, Duke University, Durham, NC 27708, USA; Department of Molecular Genetics and Microbiology, and Immunology, Duke University, Durham, NC 27708, USA; Center for the Study of Aging, Duke University, Durham, NC 27708, USA; Geriatric Research and Education and Clinical Center, Veteran Affairs Medical Center, Durham, NC 27710, USA.
| | - Jörn Coers
- Department of Molecular Genetics and Microbiology, and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
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Germain A, Guéant RM, Chamaillard M, Bresler L, Guéant JL, Peyrin-Biroulet L. CARD8 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease. Dig Liver Dis 2015; 47:938-42. [PMID: 26283210 DOI: 10.1016/j.dld.2015.07.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 07/11/2015] [Accepted: 07/20/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Post-operative recurrence is frequent in Crohn's disease. Genetic factors associated with post-operative recurrence remain poorly understood. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. METHODS Crohn's disease patients who had at least one bowel resection were retrospectively identified from the "Nancy IBD cohort". Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for 200 genetic variants and analyzed with the log-rank test. RESULTS 137 patients had at least 1 resection in our cohort: 38 had a surgical recurrence (28%). In multivariate analysis, current smoker status (OR 6.97, 95% CI 1.85-26.22, p=0.004), post-operative complications after prior surgery (OR 2.72, 95% CI 1.02-7.22, p=0.044), and Caspase recruitment domain-containing protein 8 (CARD8) homozygosity for the risk allele (OR 7.56, 95% CI 1.13-50.37, p=0.036) remained significantly and independently associated with surgical recurrence. CONCLUSION Current smoker status was associated with increased risk of surgical recurrence. A novel association between CARD8 and increased risk of surgical recurrence in Crohn's disease was observed. CARD8 could be a new marker for risk stratification and prevention of recurrent surgery.
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Affiliation(s)
- Adeline Germain
- Department of Digestive Surgery, University Hospital of Nancy-Brabois, Vandoeuvre-les-Nancy, France; INSERM U954, Nutrition-Génétique et Exposition aux risques environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France.
| | - Rosa-Maria Guéant
- INSERM U954, Nutrition-Génétique et Exposition aux risques environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Mathias Chamaillard
- Institut Pasteur de Lille, Center for infection and immunity of Lille, Lille, France; INSERM U1019, Team 7, Equipe FRM, Lille, France
| | - Laurent Bresler
- Department of Digestive Surgery, University Hospital of Nancy-Brabois, Vandoeuvre-les-Nancy, France
| | - Jean-Louis Guéant
- INSERM U954, Nutrition-Génétique et Exposition aux risques environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Laurent Peyrin-Biroulet
- INSERM U954, Nutrition-Génétique et Exposition aux risques environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France; Department of Gastroenterology, University Hospital of Nancy-Brabois, Vandoeuvre-les-Nancy, France
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19
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Castaño-Rodríguez N, Kaakoush NO, Goh KL, Fock KM, Mitchell HM. Autophagy in Helicobacter pylori Infection and Related Gastric Cancer. Helicobacter 2015; 20:353-69. [PMID: 25664588 DOI: 10.1111/hel.12211] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Autophagy, a degradation pathway in which cytoplasmic content is engulfed and degraded by lysosomal hydrolases, plays a pivotal role in infection and inflammation. Given that defects in autophagy lead to increased susceptibility to infection, we investigated the role of autophagy in Helicobacter pylori-related gastric cancer (GC). MATERIALS AND METHODS Gene expression of 84 molecules was examined through quantitative real-time PCR in gastric epithelial cells (AGS) and macrophages (THP-1) upon exposure to H. pylori GC026 (GC) and 26695 (gastritis). Further, ATG16L1 rs2241880, IRGM rs13361189, and IRGM rs4958847, polymorphisms that have been investigated in relation to H. pylori infection or GC in Caucasians, were detected by MALDI-TOF mass spectrometry in 304 ethnic Chinese (86 noncardia GC cases/218 functional dyspepsia controls). RESULTS Gene expression analyses showed twenty-eight molecules involved in vesicle nucleation, elongation, and maturation to be significantly down-regulated in H. pylori GC026-challenged AGS cells. Further, core autophagy proteins and autophagy regulators were differentially expressed in H. pylori-challenged THP-1-derived macrophages. Analyses of the selected polymorphisms showed that ATG16L1 rs2241880 increased the risk of GC (OR: 2.38, 95% CI: 1.34-4.24) and H. pylori infection (OR: 1.49, 95% CI: 1.02-2.16) while IRGM rs4958847 decreased GC risk (OR: 0.26, 95% CI: 0.09-0.74) in ethnic Chinese, these effect sizes being especially strong in H. pylori-infected individuals (ATG16L1 rs2241880 and IRGM rs13361189). CONCLUSIONS Our findings indicate that highly virulent H. pylori strains markedly modulate autophagy in the host cell. Further, for the first time, autophagy polymorphisms were associated with GC in Chinese, a high GC-risk population.
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Affiliation(s)
- Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Nadeem O Kaakoush
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Khean-Lee Goh
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kwong Ming Fock
- Division of Gastroenterology, Department of Medicine, Changi General Hospital, Singapore City, Singapore
| | - Hazel M Mitchell
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia
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20
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Liu Z, Shen B. Overcoming difficulty in diagnosis and differential diagnosis of Crohn's disease: the potential role of serological and genetic tests. Expert Rev Mol Diagn 2015; 15:1133-41. [PMID: 26295589 DOI: 10.1586/14737159.2015.1068121] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Crohn's disease (CD) represents a heterogeneous group of chronic inflammatory disorders with various phenotypes. Establishing a definite diagnosis of CD should be based upon a combined assessment of clinical, endoscopic, radiological and pathological features. Although segmental disease distribution, transmural inflammation and non-caseating epithelioid granulomas have been considered as a 'hallmarks' for CD, clear diagnosis of CD in some patients has been challenging, due to overlapping endoscopic, radiographic and histologic features with other inflammatory bowel disease-like conditions. Laboratory markers (serological and genetic tests) may provide additional clues for the diagnosis and differential diagnosis of CD. This review focuses on the application of the currently available serological and genomic markers and in diagnosis and differential diagnosis of CD.
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Affiliation(s)
- Zhaoxiu Liu
- a 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
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Connelly TM, Messaris E. Predictors of recurrence of Crohn’s disease after ileocolectomy: A review. World J Gastroenterol 2014; 20:14393-14406. [PMID: 25339826 PMCID: PMC4202368 DOI: 10.3748/wjg.v20.i39.14393] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 05/08/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Recurrence after ileocolectomy for Crohn’s disease (CD) is common and occurs in up to 80% of patients. Such recurrence can result in repeated surgical interventions, an increased need for medical treatment and, frequently, an impaired quality of life. The aim of this overview is to provide a summary of the factors associated with disease recurrence after ileocolectomy for CD. Recurrence can be measured clinically or endoscopically using established scoring systems. Radiology and serologic tests can also be used, oftentimes in conjunction with endoscopy and/or clinical findings. Many patient and operative factors as well as pharmacologic treatments have been studied as potential predictors of recurrence. Of these, only smoking and immunomodulatory or biologic medical treatment have repeatedly been shown to effect recurrence. Genetic predictors have been studied and suggested but further evaluation in larger cohorts is necessary. This paper highlights validated, reproducible scoring systems for recurrence and the key findings of studies including patient demographics, operative techniques, various pharmacological treatments and histological findings as predictors of recurrence post ileocolectomy in CD.
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Zhang J, Chen J, Gu J, Guo H, Chen W. Association of IL23R and ATG16L1 with susceptibility of Crohn's disease in Chinese population. Scand J Gastroenterol 2014; 49:1201-6. [PMID: 25048429 DOI: 10.3109/00365521.2014.936031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES To investigate whether gene polymorphisms of ATG16L1 and IL23R are associated with the susceptibility of Crohn's disease (CD) in Chinese population. METHODS A total of 420 patients with CD and 450 age- and sex-matched healthy volunteers from Chinese Han population were included in this study. Single nucleotide polymorphisms (SNPs) rs2241880 of ATG16L1 and rs11209026, rs1004819, and rs1495965 of IL23R were genotyped. The differences of genotype and allele distributions between CD patients and healthy controls were assessed using the Chi-squared test. Besides, subgroup analysis of disease groups was performed using the Chi-squared test. RESULTS For ATG16L1, patients were found to have significantly higher proportion of genotype GG (18.3%), when compared with the normal controls (12.4%). Allele G was found to be the risk allele for the disease (34.3% vs. 29.0%, p = 0.016) with an odds ratio of 1.18. For IL23R, all three SNPs were found not to be associated with the development of CD. None of these four SNPs was found to be associated with the clinical features of the patients, including age at diagnosis, disease location, and behavior. CONCLUSION The original genome-wide association studies finding on ATG16L1 gene should be robust and this gene does play a role in the pathogenesis of CD in the Chinese population. However, the role of IL23R gene in the occurrence of CD remains obscure.
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Affiliation(s)
- Jie Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Soochow University , Suzhou , China
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Baskaran K, Pugazhendhi S, Ramakrishna BS. Association of IRGM gene mutations with inflammatory bowel disease in the Indian population. PLoS One 2014; 9:e106863. [PMID: 25191865 PMCID: PMC4156415 DOI: 10.1371/journal.pone.0106863] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 08/01/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Mutations in the IRGM gene have been associated with Crohn's disease in several populations but have not been explored in Indian patients with this disease. This study examined the association of IRGM mutations with ulcerative colitis and Crohn's disease in Indian patients with inflammatory bowel disease. METHODS The IRGM gene was amplified in four segments and Sanger-sequenced in 101 participants (42 Crohn's disease, 39 ulcerative colitis, and 20 healthy controls). Ten single nucleotide polymorphisms (SNP) were genotyped in 1200 participants (352 Crohn's disease, 400 ulcerative colitis, and 448 healthy controls) using Sequenom MassARRAY iPLEX. Disease associations were evaluated for each of the ten SNPs. RESULTS Thirty one mutations were identified in the IRGM gene, of which two had not hitherto been reported (150226250- ss947429272 & 150227858- ss947429273). Ten SNPs (6 from the above and 4 from the literature) were evaluated. Significant associations with Crohn's disease were noted with the T allele of rs1000113 (OR 1.46, 95% CI 1.12-1.90), T allele of rs9637876 (OR 1.25, 95% CI 1.005-1.561) and C allele of rs 13361189 (OR 1.33, 95% CI 1.07-1.669). Two SNPs--rs11747270 and rs180802994--did not exhibit Hardy-Weinberg equilibrium but were associated with both Crohn's disease and ulcerative colitis in this population. The remaining SNPs did not show significant associations with either Crohn's disease or ulcerative colitis. CONCLUSIONS Association of IRGM gene SNPs with Crohn's disease is reported for the first time in Indian patients. We also report, for the first time, an association of rs 9637876 in the IRGM gene with Crohn's disease.
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Affiliation(s)
- Kirankumar Baskaran
- Wellcome Trust Research Laboratory, Christian Medical College, Vellore, India
| | | | - Balakrishnan S Ramakrishna
- Wellcome Trust Research Laboratory, Christian Medical College, Vellore, India; SRM Institutes for Medical Science, Vadapalani, Chennai, India
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Fowler SA, Ananthakrishnan AN, Gardet A, Stevens CR, Korzenik JR, Sands BE, Daly MJ, Xavier RJ, Yajnik V. SMAD3 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease. J Crohns Colitis 2014; 8:845-51. [PMID: 24461721 PMCID: PMC4237062 DOI: 10.1016/j.crohns.2014.01.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 12/12/2013] [Accepted: 01/03/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS More than 80% of Crohn's disease (CD) patients will require surgery. Surgery is not curative and rates of re-operation are high. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. METHODS CD patients who had at least one CD-related bowel resection were identified from the Prospective Registry in IBD Study at Massachusetts General Hospital (PRISM). The primary outcome was surgical recurrence. Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for each genetic variant and analyzed with the log-rank test. RESULTS 194 patients were identified who had at least 1 resection. Of these, 69 had two or more resections. Clinical predictors for repeat surgery were stricturing (HR 4.18, p=0.022) and penetrating behavior (HR 3.97, p=0.024). Smoking cessation was protective for repeat surgery (HR 0.45, p=0.018). SMAD3 homozygosity for the risk allele was also independently associated with increased risk of repeat surgery (HR 4.04, p=0.001). NOD2 was not associated with increased risk of surgical recurrence. CONCLUSION Stricturing and penetrating behavior were associated with increased risk of surgical recurrence, while smoking cessation was associated with a decreased risk. A novel association between SMAD3 and increased risk of repeat operation and shorter time to repeat surgery was observed. This finding is of particular interest as SMAD3 may represent a new therapeutic target specifically for prevention of post-surgical disease recurrence.
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Affiliation(s)
- Sharyle A Fowler
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | - Agnes Gardet
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA
| | | | - Joshua R Korzenik
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Bruce E Sands
- Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY
| | - Mark J Daly
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA
| | - Ramnik J Xavier
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA
| | - Vijay Yajnik
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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Nunes T, Bernardazzi C, de Souza HS. Cell death and inflammatory bowel diseases: apoptosis, necrosis, and autophagy in the intestinal epithelium. BIOMED RESEARCH INTERNATIONAL 2014; 2014:218493. [PMID: 25126549 PMCID: PMC4121991 DOI: 10.1155/2014/218493] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 06/13/2014] [Indexed: 02/07/2023]
Abstract
Cell death mechanisms have been associated with the development of inflammatory bowel diseases in humans and mice. Recent studies suggested that a complex crosstalk between autophagy/apoptosis, microbe sensing, and enhanced endoplasmic reticulum stress in the epithelium could play a critical role in these diseases. In addition, necroptosis, a relatively novel programmed necrosis-like pathway associated with TNF receptor activation, seems to be also present in the pathogenesis of Crohn's disease and in specific animal models for intestinal inflammation. This review attempts to cover new data related to cell death mechanisms and inflammatory bowel diseases.
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Affiliation(s)
- Tiago Nunes
- Nutrition and Immunology Chair, ZIEL-Research Center for Nutrition and Food Sciences, Technical University of Munich, Weihenstephan, 85354 Freising, Germany
| | - Claudio Bernardazzi
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitario, Universidade Federal do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255, Ilha do Fundão, 21941-913 Rio de Janeiro, RJ, Brazil
| | - Heitor S. de Souza
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitario, Universidade Federal do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255, Ilha do Fundão, 21941-913 Rio de Janeiro, RJ, Brazil
- D'Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, 22281-100 Rio de Janeiro, RJ, Brazil
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Jakobsen C, Cleynen I, Andersen PS, Vermeire S, Munkholm P, Paerregaard A, Wewer V. Genetic susceptibility and genotype-phenotype association in 588 Danish children with inflammatory bowel disease. J Crohns Colitis 2014; 8:678-85. [PMID: 24394805 DOI: 10.1016/j.crohns.2013.12.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 11/28/2013] [Accepted: 12/15/2013] [Indexed: 02/06/2023]
Abstract
AIM To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. MATERIAL AND METHODS In this case-control study we included IBD patients <18 years of age at diagnosis from the Danish National Patient Registry and healthy children <18 years of age were randomly selected from the Danish Central Office of Civil Registration. The latter had filled out a questionnaire regarding health status, and DNA was obtained from blood samples and the buccal mucosa. Patient files were retrieved and clinical information was extracted. DNA was obtained from Guthrie cards from the Danish National Neonatal Screening Biobank (PKU-biobanken) at Statens Serum Institut and from blood samples. RESULTS A total of 588 IBD patients (244 Crohn's disease (CD), 318 ulcerative colitis (UC) and 26 IBD-unclassified (IBDU)) and 543 healthy controls were included. We found an association between CD and rs22411880 (ATG16L1, odds ratio (OR)=1.7 [1.1-1.7], p=0.003), rs5743289 (NOD2, OR=1.4 [1.1-1.9], p=0.009) and the paediatric specific rs1250550 (ZMIZ1, OR=0.7 [0.5-0.9], p=0.01). None of the investigated 41 SNPs were associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. CONCLUSION We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant genotype-phenotype associations were found. For future studies aimed at finding predictors for disease course in (paediatric) IBD, it will be worthwhile to include a combination of genetic, clinical and serological markers.
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Affiliation(s)
- C Jakobsen
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark.
| | - I Cleynen
- Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - P S Andersen
- Department of Microbiology and Infection Control, State Serum Institute, Copenhagen, Denmark
| | - S Vermeire
- Department of Gastroenterology, University Hospitals Leuven, Belgium
| | - P Munkholm
- Department of Gastroenterology, Medical Section, Herlev University Hospital, Copenhagen, Denmark
| | - A Paerregaard
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark
| | - V Wewer
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark
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Deuring JJ, Fuhler GM, Konstantinov SR, Peppelenbosch MP, Kuipers EJ, de Haar C, van der Woude CJ. Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease. Gut 2014; 63:1081-91. [PMID: 23964099 DOI: 10.1136/gutjnl-2012-303527] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Although genome wide association studies have partly uncovered the genetic basis of Crohn's disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intestinal crypt-base. Here, we investigate whether genomic variations in ATG16L1 affect Paneth cell function. DESIGN Genomic variation of ATG16L1 (T300A, rs2241880) was determined in DNA from 78 patients with CD and 12 healthy controls. Paraffin-embedded ileal biopsies from patients with genotype AA (n=17), GA (n=38) and patients with the GG allele (n=23) were stained for GRP78, phospho-EIF2α, lysozyme, cleaved-caspase 3, phosphohistone H3, phospho-IκB, p65, phospho-p38MAPK and PHLDA1. Microbial composition of biopsies was assessed by PCR. Disease phenotype was scored. RESULTS In patients with quiescent disease but with an ATG16L1 risk allele, the endoplasmic reticulum (ER) stress markers GRP78 and pEIF2α were highly expressed in Paneth cells. Other CD risk gene variations did not correlate with Paneth cell ER stress. Functionally, patients with ER-stressed Paneth cells showed no changes in intestinal epithelial cells proliferation or apoptosis, Paneth cell or stem cell numbers, p65, phospho-IκB and phospho-p38 staining. However, a significantly increased presence of adherent-invasive Escherichia coli was observed in biopsies from patients with ER-stressed Paneth cells. Phenotypically, patients with GRP78 positive Paneth cells have relatively less colonic disease over ileal disease (-21%, p=0.04), more fistulas (+21%, p=0.05) and an increased need for intestinal surgery (+38%, p=0.002). CONCLUSIONS The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD.
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Affiliation(s)
- J Jasper Deuring
- Department Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Gwenny M Fuhler
- Department Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Sergey R Konstantinov
- Department Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Ernst J Kuipers
- Department Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Colin de Haar
- Department Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - C Janneke van der Woude
- Department Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
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The influence of CTGF single-nucleotide polymorphisms on outcomes in Crohn's disease. Ann Surg 2013; 258:767-73; discussion 773-4. [PMID: 24121259 DOI: 10.1097/sla.0000000000000247] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To examine the association between single-nucleotide polymorphisms (SNPs) in CTGF (connective tissue growth factor) and patient outcomes after terminal ileal resection for Crohn's disease. BACKGROUND The primary indication for intestinal resection in Crohn's disease is fibrostenotic terminal ileal disease. CTGF is a cytokine overexpressed in the intestine of patients with Crohn's disease that influences outcomes in other disease processes. METHODS DNA was extracted from formalin-fixed, paraffin-embedded tissue from 147 patients with Crohn's disease who had undergone terminal ileal resection between 1981 and 2009. Genotyping was performed for 4 CTGF SNPs (rs9402373, rs12526196, rs6918698, and rs9399005), which modulate nuclear factor binding and CTGF production, and a smad3 SNP (rs17293632) involved in the CTGF pathway. Patients were phenotyped using the Montreal Disease Classification. RESULTS Sixty-seven of 147 patients (45.6%) were male; the mean age at diagnosis was 30.3 ± 12.6 years and the mean follow-up duration was 8.3 ± 7.1 years. Genotype-phenotype analysis demonstrated that the rs6918698GG genotype was associated with an older age of disease onset [>40 years; 30.6% vs 13.2%; odds ratio (OR): 2.891; 95% confidence interval (CI): 1.170-7.147). The rs9402373CC genotype was positively associated with type B1 disease (50.7% vs 26.3%; OR: 2.876; 95% CI: 1.226-6.743) and negatively associated with B2 disease (37.0% vs 65.0%; OR: 0.317; 95% CI: 0.144-0.699). None of the 5 SNPs assessed influenced clinical or surgical recurrence of Crohn's disease after intestinal resection. On multivariate analysis, male sex odds ratio (OR): 0.235; 95% CI: 0.073-0.755; P = 0.015] and never having smoked tobacco (OR: 0.249; 95% CI: 0.070-0.894; P = 0.033) reduced the risk, whereas having a prior appendectomy increased the risk (OR: 5.048; 95% CI: 1.632-15.617; P = 0.005) of surgical recurrence. CONCLUSIONS These data implicate the rs6918698GG genotype with an age of disease onset of greater than 40 years in Crohn's disease whereas the rs9402373CC genotype is associated with a nonstricturing, nonpenetrating disease phenotype. CTGF SNPs do not influence the rate of recurrence after terminal ileal resection for Crohn's disease.
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Abstract
Inflammatory bowel diseases (IBDs; e.g., Crohn's disease [CD] and ulcerative colitis [UC]) are chronic immunologically mediated diseases characterized by frequent relapses, often requiring hospitalization and surgery. There is substantial heterogeneity in the progressive natural history of disease with cumulative accrual of bowel damage and impairment of functioning. Recent advances in therapeutics have significantly improved our ability to achieve disease remission; yet therapies remain expensive and are associated with significant side effects precluding widespread use in all patients with IBD. Consequently, algorithms for the management of patients with IBD require a personalized approach incorporating an individual's projected likely natural history, the probability of response to a specific therapeutic agent and an informed approach to management of loss of response to current therapies.
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Affiliation(s)
- Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, 165 Cambridge Street, 9th Floor, Boston, MA 02114, USA.
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30
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Abstract
Inflammatory bowel diseases (Crohn's disease and ulcerative colitis) are chronic immunologically mediated diseases of the gut. Advances in genetics have revolutionized our understanding of the pathogenesis of these conditions with 163 risk loci identified, encompassing a variety of immunologic functions. There is substantial heterogeneity in the natural history of these diseases with respect to disease onset, course, and progression to complications. There are also significant variations in response to therapies and susceptibility to therapy-related and disease-related complications. An important need in the field is to identify predictors of disease course, complications, and likelihood of response and adverse events to allow for targeted therapeutic decision making. The genotype of an individual in constant and non-modifiable, and thus could potentially fulfill the role of important predictors of these outcomes. In this review, we discuss the existing literature on the prediction of various disease phenotypes in Crohn's disease and ulcerative colitis using underlying genotype. We also identify gaps in the literature and suggest future directions for research. There is need for large, multi-institutional, and international collaborative consortia with efficient and detailed cohort accrual, phenotypic definition, genotyping, and dynamic assessments of external (e.g., diet) and internal (microbiome) environment to allow us to progress toward personalized and precision medicine in the management of these complex diseases.
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Michail S, Bultron G, Depaolo RW. Genetic variants associated with Crohn's disease. APPLICATION OF CLINICAL GENETICS 2013; 6:25-32. [PMID: 23935379 PMCID: PMC3735034 DOI: 10.2147/tacg.s33966] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Crohn’s disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks the intestine as it cross reacts against gut microbial antigens. The study of genetic variants associated with Crohn’s disease has shed light on our understanding of disease pathophysiology. A large number of genetic variants identified in Crohn’s disease are related to genes targeting microbial recognition and bacterial wall sensing, the most common being NOD2/CARD15 gene. This review will discuss the recent advance in our knowledge of genetic variants of this disease and how they influence the disease course and prognosis.
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Affiliation(s)
- Sonia Michail
- The University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA
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Abstract
This chapter addresses the longstanding question of whether inflammatory bowel disease (IBD) is really one or two diseases. The straightforward answer is that ulcerative colitis (UC) and Crohn's disease (CD) embody separate diseases more than a single syndrome. In reality, however, the question is more complex. This chapter makes the case that there are actually many more than just two diseases under the rubric of IBD.
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Miheller P, Kiss LS, Juhasz M, Mandel M, Lakatos PL. Recommendations for identifying Crohn's disease patients with poor prognosis. Expert Rev Clin Immunol 2013; 9:65-76. [PMID: 23256765 DOI: 10.1586/eci.12.86] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Clinical presentation at diagnosis and the disease course of Crohn's disease is heterogeneous and variable over time. The majority of patients with Crohn's disease will develop at least one stricturing or perforating complication requiring surgery during follow-up. New data support a change in the natural history of the disease associated with the advent of biologicals and tailored treatment strategy. Therefore, it is important to identify patients at risk for disease progression as soon as possible. In recent years, much emphasis has been placed on determining important predictive factors. Complex evaluation of factors such as clinical and endoscopic presentation, fecal, serological and routine laboratory tests, and genetic factors is needed. This review summarizes the available evidence and will hopefully assist clinicians when choosing a treatment strategy in everyday practice.
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Affiliation(s)
- Pal Miheller
- Second Department of Medicine, Semmelweis University, H-1083 Budapest, Hungary
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Abstract
PURPOSE OF REVIEW The field of colorectal surgery continues to move forward as technical innovations emerge and as surgeons ask critical questions. The results of subsequent investigations often lead to changes in practice. This review examines recent publications that describe these practice changes. RECENT FINDINGS We identified and reviewed recent publications in the areas of rectal cancer controversies, genetic risk profiling, practice improvements, diverticulitis, enhanced recovery protocols, fecal incontinence, and single incision laparoscopic surgery. SUMMARY New technologies and practice innovations will continue to enhance patient outcomes. Multiinstitutional studies, randomized when able, are necessary to further define the safety and efficacy of new surgical techniques and to further define best practices in colorectal surgery.
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Common alleles that influence autophagy and the risk for inflammatory bowel disease. Curr Opin Immunol 2012; 24:522-9. [PMID: 23041451 DOI: 10.1016/j.coi.2012.08.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 08/07/2012] [Accepted: 08/09/2012] [Indexed: 12/15/2022]
Abstract
Genetic studies of inflammatory bowel disease (IBD) have identified multiple risk loci that contain genes involved in autophagy. Although autophagy was traditionally considered to be a homeostatic response to ensure the recycling of cellular materials, it has now been additionally established to have roles in immunity and inflammation. In this review, we highlight how genetics have begun to identify a broader role for autophagy as a key pathway in Crohn's disease (CD). We review recent studies that have implicated autophagy in the regulation of mucosal homeostasis, including roles in intracellular defense, vesicular trafficking, and inflammatory signaling. Finally, we discuss studies that have begun to demonstrate how CD risk polymorphisms cause defects in autophagy and promote a breakdown of intestinal homeostasis.
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Songane M, Kleinnijenhuis J, Alisjahbana B, Sahiratmadja E, Parwati I, Oosting M, Plantinga TS, Joosten LAB, Netea MG, Ottenhoff THM, van de Vosse E, van Crevel R. Polymorphisms in autophagy genes and susceptibility to tuberculosis. PLoS One 2012; 7:e41618. [PMID: 22879892 PMCID: PMC3412843 DOI: 10.1371/journal.pone.0041618] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 06/22/2012] [Indexed: 12/11/2022] Open
Abstract
Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB) among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana. We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls, and between patients infected with different M. tuberculosis genotypes, as determined by spoligotyping. The same autophagy polymorphisms were studied in correlation with ex-vivo production of TNF, IL-1β, IL-6, IL-8, IFN-γ and IL-17 in healthy volunteers. No association was found between TB and polymorphisms in the genes ATG10, ATG16L2, ATG2B, ATG5, ATG9B, IRGM, LAMP1, LAMP3, P2RX7, WIPI1, MTOR and ATG4C. Associations were found between polymorphisms in LAMP1 (p = 0.02) and MTOR (p = 0.02) and infection with the successful M. tuberculosis Beijing genotype. The polymorphisms examined were not associated with M. tuberculosis induced cytokines, except for a polymorphism in ATG10, which was linked with IL-8 production (p = 0.04). All associations found lost statistical significance after correction for multiple testing. This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB, with M. tuberculosis Beijing genotype infection or with ex-vivo pro-inflammatory cytokine production.
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Affiliation(s)
- Mario Songane
- Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Johanneke Kleinnijenhuis
- Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Bachti Alisjahbana
- Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
- Health Research Unit, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Edhyana Sahiratmadja
- Health Research Unit, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
- Department of Biochemistry, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Ida Parwati
- Department of Clinical Pathology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Marije Oosting
- Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Theo S. Plantinga
- Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Leo A. B. Joosten
- Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Mihai G. Netea
- Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Tom H. M. Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Esther van de Vosse
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Reinout van Crevel
- Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- * E-mail:
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Henderson P, Stevens C. The role of autophagy in Crohn's disease. Cells 2012; 1:492-519. [PMID: 24710487 PMCID: PMC3901108 DOI: 10.3390/cells1030492] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Revised: 07/20/2012] [Accepted: 07/23/2012] [Indexed: 02/05/2023] Open
Abstract
(Macro)-autophagy is a homeostatic process by which eukaryotic cells dispose of protein aggregates and damaged organelles. Autophagy is also used to degrade micro-organisms that invade intracellularly in a process termed xenophagy. Genome-wide association scans have recently identified autophagy genes as conferring susceptibility to Crohn's disease (CD), one of the chronic inflammatory bowel diseases, with evidence suggesting that CD arises from a defective innate immune response to enteric bacteria. Here we review the emerging role of autophagy in CD, with particular focus on xenophagy and enteric E. coli strains with an adherent and invasive phenotype that have been consistently isolated from CD patients with ileal disease.
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Affiliation(s)
- Paul Henderson
- Department of Child Life and Health, 20 Sylvan Place, University of Edinburgh, Edinburgh EH9 1UW, UK.
| | - Craig Stevens
- Gastrointestinal Unit, Institute for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
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Connelly TM, Koltun WA. The Role of Genetics in the Surgical Management of Inflammatory Bowel Disease. SEMINARS IN COLON AND RECTAL SURGERY 2012. [DOI: 10.1053/j.scrs.2012.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
|
39
|
Surgical genomics: using new technology to answer age-old questions. Dis Colon Rectum 2012; 55:113-4. [PMID: 22228151 DOI: 10.1097/dcr.0b013e31823d3aa8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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