Subset Of Inflammatory Bowel Disease Research Articles

P209 Work productivity and unmet needs of treated ulcerative colitis patients: A Japan National Health and Wellness Survey study

Abstract Background Ulcerative colitis (UC), a subset of inflammatory bowel disease (IBD), is a chronic, immune-mediated disease process which causes inflammation and ulceration of the large intestine. In Japan, the annual prevalence of UC in 2014 showed a ten-fold increase in more than 10 years. Despite current treatments, patient-reported disease challenges persist. This study investigated the disease burden and unmet needs of treated UC patients in Japan. Methods This cross-sectional, observational study used existing data from the online, self-administered Japan National Health and Wellness Survey conducted in 2017, 2019, and 2021. Respondents were aged ≥18 years, with self-reported UC and had undergone/were on treatment [5-Aminoslicyclic acid (5-ASA), steroids, immunomodulators (IMs), biologics (Bio)/Janus kinase inhibitors (JAKi), or others]. Data pertaining to demographics and clinical characteristics, medication adherence, health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and indirect cost were collected and analysed. Results Among 293 treated UC patients in Japan, most were conventional treatment users (84%) and 29% were living with UC for ≥15 years. Despite active treatment, 91% of patients reported UC as bothersome to a certain degree, 35% reported having moderate-to-severe disease severity post-treatment, and 55% reported ≥1 persisting UC symptom. Treated patients reported EuroQoL-5-dimension visual analogue scale scores of 68. Depression and anxiety were reported in ≥35% of patients and majority (68%) of employed patients reported work productivity impairment. On average, employed UC patients reported 30-40% WPAI on a weekly basis, resulting in a mean indirect cost of 1.12 million Japanese yen (€8,799) per patient annually. Males, moderate-to-severe disease activity, and low treatment adherence (<80%) were associated with increased WPAI (p<0.05). In comparison to 5-ASA users, Bio/JAKi users had the highest work impairment, while steroid and IM users had higher activity impairment (p<0.05). Conclusion The overall HRQoL scores were lower than the average Japanese healthy population and the indirect cost due to work productivity impairment was high, equating to approximately 1/5 of the average household income. Those with lower treatment adherence consistently reported the highest work and activity impairment. The findings implicate a high disease burden and unmet needs affecting Japanese UC patients despite currently available treatments, suggesting the importance of a new convenient treatment for optimising UC outcomes. Additionally, workplace accommodations and understanding of employers on UC could assist in improving work productivity of UC patients.

Evidence for a Causal Role for Escherichia coli Strains Identified as Adherent-Invasive (AIEC) in Intestinal Inflammation.

Enrichment of adherent-invasive Escherichia coli (AIEC) has been consistently detected in subsets of inflammatory bowel disease (IBD) patients. Although some AIEC strains cause colitis in animal models, these studies did not systematically compare AIEC with non-AIEC strains, and causal links between AIEC and disease are still disputed. Specifically, it remains unclear whether AIEC shows enhanced pathogenicity compared to that of commensal E. coli found in the same ecological microhabitat and if the in vitro phenotypes used to classify strains as AIEC are pathologically relevant. Here, we utilized in vitro phenotyping and a murine model of intestinal inflammation to systematically compare strains identified as AIEC with those identified as non-AIEC and relate AIEC phenotypes to pathogenicity. Strains identified as AIEC caused, on average, more severe intestinal inflammation. Intracellular survival/replication phenotypes routinely used to classify AIEC positively correlated with disease, while adherence to epithelial cells and tumor necrosis factor alpha production by macrophages did not. This knowledge was then applied to design and test a strategy to prevent inflammation by selecting E. coli strains that adhered to epithelial cells but poorly survived/replicated intracellularly. Two E. coli strains that ameliorated AIEC-mediated disease were subsequently identified. In summary, our results show a relationship between intracellular survival/replication in E. coli and pathology in murine colitis, suggesting that strains possessing these phenotypes might not only become enriched in human IBD but also contribute to disease. We provide new evidence that specific AIEC phenotypes are pathologically relevant and proof of principle that such mechanistic information can be therapeutically exploited to alleviate intestinal inflammation. IMPORTANCE Inflammatory bowel disease (IBD) is associated with an altered gut microbiota composition, including expansion of Proteobacteria. Many species in this phylum are thought to contribute to disease under certain conditions, including adherent-invasive Escherichia coli (AIEC) strains, which are enriched in some patients. However, whether this bloom contributes to disease or is just a response to IBD-associated physiological changes is unknown. Although assigning causality is challenging, appropriate animal models can test the hypothesis that AIEC strains have an enhanced ability to cause colitis in comparison to other gut commensal E. coli strains and to identify bacterial traits contributing to virulence. We observed that AIEC strains are generally more pathogenic than commensal E. coli and that bacterial intracellular survival/replication phenotypes contributed to disease. We also found that E. coli strains lacking primary virulence traits can prevent inflammation. Our findings provide critical information on E. coli pathogenicity that may inform development of IBD diagnostic tools and therapies.

P039 The disappearance of cell death brakes in inflammatory bowel disease: a step towards molecular healing

Abstract Background The core mechanistic driver underpinning the relapsing and progressive nature of inflammatory bowel disease (IBD) remains unknown with current therapies targeting immune or inflammatory pathways. Our in-depth analysis of regulated death pathways remarkably reveals that cell death brakes are removed in intestinal IBD tissue, indicating cells remain “primed” to die regardless of endoscopic and histologic healing. Characterisation of cell death is essential to confirm our hypothesis that disinhibition of programmed cell death is a rudimentary molecular defect in IBD. Restoration of cell death brakes may be intrinsic to molecular healing and novel drug development. Methods Intestinal biopsies are collected from inflamed, marginal and non-inflamed regions during endoscopy for patients with IBD and matched with those without IBD (“controls”). Tissue is processed to quantify cell death signals and changes to the local microbiome using immunoblotting, immunohistochemistry, immunofluorescence, organoid preparation and RNA sequencing (Fig. 1). Laboratory data are correlated with clinical, biochemical, endoscopic and histologic parameters. Results To date, 59 patients have been recruited: 29 controls; 31 IBD (13 Crohn’s disease, 16 ulcerative colitis, 2 pouchitis). Interim analyses of 20 patients show loss of cell death brakes (cIAP1, cIAP2, cFLIP) suggesting disinhibition of cell death even in endoscopically and histologically normal IBD tissue (Fig. 2). Concurrently, there is increased apoptosis (characterised by cleaved caspase-3) in IBD intestinal tissue regardless of inflammatory activity (Fig. 3). Necroptosis, a programmed lytic form of cell death, is active in steady state conditions in controls. Additionally, necroptosis appears markedly elevated in stricturing and penetrating Crohn’s disease compared to other subsets of IBD (Fig. 2). Conclusion This study demonstrates for the first time that cellular death brakes are removed in intestinal tissue in IBD, despite deep remission with seemingly effective biologic therapy. Disinhibition of programmed cell death is likely intrinsic to the inflammatory sequence underlying disease recurrence and progression. Restoration of cell death brakes may hence be key to achieving long-term, relapse-free remission and should be considered an aspirational goal for both drug development and achievement of molecular healing. Our results challenge current dogma based on murine data that necroptosis occurs in the absence of apoptosis and that necroptosis is universally increased in all forms of IBD. Instead, we propose that a balance of apoptosis and necroptosis is essential in intestinal homeostasis with endotyping of disease based on cell death profile a feasible goal towards precision medicine in IBD.

The deubiquitinase USP25 supports colonic inflammation and bacterial infection and promotes colorectal cancer.

Bacterial infection or abnormal colonization in the gastrointestinal system is associated with subsets of inflammatory bowel disease and colorectal cancer. Here we demonstrated essential roles of ubiquitin-specific protease 25 (USP25) in experimental colitis, bacterial infections and colon cancer. Knockout or pharmacologic inhibition of USP25 potentiated immune responses after induction of experimental colitis or bacterial infections that promoted clearance of infected bacteria and resolution of inflammation and attenuated Wnt and SOCS3-pSTAT3 signaling, which inhibited colonic tumorigenesis. USP25 levels were positively or negatively correlated with Fusobacterium nucleatum colonization and β-catenin levels or SOCS3 levels in human colorectal tumor biopsies, respectively, and predicted poor prognosis of patients with cancers in the gastrointestinal system. Our findings suggest USP25 as a promoter and druggable target for gastrointestinal infections and cancers.

Dynamic immunoglobulin responses to gut bacteria during inflammatory bowel disease

ABSTRACT Aberrant immune responses against gut microbiota are thought to be key drivers of inflammatory bowel disease (IBD) pathogenesis. However, the extent and targets of immunoglobulin (Ig) A versus IgG responses to gut bacteria in IBD and its association with IBD severity is not well understood. Here, we address this by analyzing fecal samples from Crohn’s disease (CD), ulcerative colitis (UC), and Non-IBD patients by flow cytometry for the frequency of bacteria that were endogenously bound with IgA and/or IgG. Assessment of IBD patients from two geographically distinct cohorts revealed increased percentages of IgA- and IgG-bound fecal bacteria compared to non-IBD controls. Notably, the two major subsets of IBD showed distinct patterns of Ig-bound bacteria, with CD activity associated with increases in both IgA and IgG-bound bacteria, whereas UC activity correlated only with increases in IgG-bound bacteria. Analysis of the flow sorted Ig-bound bacterial repertoire by 16S rDNA sequencing revealed taxa that were Ig-bound specifically in IBD. Notably, this included bacteria that are also thought to reside in the oral pharynx, including Gemella, Peptostreptococcus, and Streptococcus species. These data show that the pattern of IgA and IgG binding to fecal bacteria is distinct in UC and CD. In addition, the frequency of Ig-bound fecal bacteria may have potential as a non-invasive biomarker for disease activity. Finally, our results support the hypothesis that immune responses to oral pharyngeal bacteria may play an important role in the pathogenesis of IBD.

Differences in colonic crypt morphology of spontaneous and colitis-associated murine models via second harmonic generation imaging to quantify colon cancer development

BackgroundColorectal cancer remains the second leading cause of cancer death in the United States, and increased risk in patients with ulcerative colitis (a subset of inflammatory bowel disease) has motivated studies into early markers of dysplasia. The development of clinically translatable multiphoton imaging systems has allowed for the potential of in vivo label-free imaging of epithelial crypt structures via autofluorescence and/or second harmonic generation (SHG). SHG has been used to investigate collagen structures in various types of cancer, though the changes that colorectal epithelial collagen structures undergo during tumor development, specifically colitis-associated tumors, have not been fully investigated.MethodsThis study used two murine models, using A/J mice, one for spontaneous carcinoma and one for colitis-associated carcinoma, to investigate and quantify SHG image features that could potentially inform future study designs of endoscopic multiphoton imaging systems. The spontaneous tumor model comprised a series of six weekly injections of azoxymethane (AOM model). The colitis-associated tumor model comprised a single injection of AOM, followed by cycles of drinking water with dissolved dextran sodium sulfate salt (AOM-DSS model). SHG images of freshly resected murine colon were acquired with a multiphoton imaging system, and image features, such as crypt size, shape and distribution, were quantified using an automated algorithm.ResultsThe comparison of quantified features of crypt morphology demonstrated the ability of our quantitative image feature algorithms to detect differences between spontaneous (AOM model) and colitis-associated (AOM-DSS model) murine colorectal tissue specimens. There were statistically significant differences in the mean and standard deviation of nearest neighbor (distance between crypts) and circularity between the Control cohort, AOM and AOM-DSS cohorts. We also saw significance between AOM and AOM-DSS cohorts when calculating nearest neighbor in images acquired at fixed depths.ConclusionThe results provide insight into the ability of SHG imaging to yield relevant data about the crypt microstructure in colorectal epithelium, specifically the potential to distinguish between spontaneous and colitis-associated murine models using quantification of crypt shape and distribution, informing future design of translational multiphoton imaging systems and protocols.

IgG and Fcγ Receptors in Intestinal Immunity and Inflammation.

Fcγ receptors (FcγR) are cell surface glycoproteins that mediate cellular effector functions of immunoglobulin G (IgG) antibodies. Genetic variation in FcγR genes can influence susceptibility to a variety of antibody-mediated autoimmune and inflammatory disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). More recently, however, genetic studies have implicated altered FcγR signaling in the pathogenesis of inflammatory bowel disease (IBD), a condition classically associated with dysregulated innate and T cell immunity. Specifically, a variant of the activating receptor, FcγRIIA, with low affinity for IgG, confers protection against the development of ulcerative colitis, a subset of IBD, leading to a re-evaluation of the role of IgG and FcγRs in gastrointestinal tract immunity, an organ system traditionally associated with IgA. In this review, we summarize our current understanding of IgG and FcγR function at this unique host-environment interface, from the pathogenesis of colitis and defense against enteropathogens, its contribution to maternal-fetal cross-talk and susceptibility to cancer. Finally, we discuss the therapeutic implications of this information, both in terms of how FcγR signaling pathways may be targeted for the treatment of IBD and how FcγR engagement may influence the efficacy of therapeutic monoclonal antibodies in IBD.

Proinflammatory Properties of Peroxidized Fat May Contribute to the Etiology of Crohn's Disease.

Crohn's disease (CD) is a well-known subset of inflammatory bowel disease (IBD) that results in patchy inflammation through the entire thickness of the bowel wall, with the ability to target virtually any part of the gastrointestinal tract, but most commonly affecting the area between the ileum and the cecum. While a bacterial origin of Crohn's is well speculated, it is difficult to pinpoint what drives inflammation in these subjects, particularly the flare-ups or the sudden symptomatic intensification or recurrence. This review aims at tracing the etiology of CD back to diet, particularly fried foods, a known aggravator of symptoms. Based on the reactions that frying entails, the chemical composition of the food is altered in ways that can lead to maldigestion and inflammation. Current evidence suggests a direct dietary role in the inflammation underlying CD or the flare-ups. The presented review focuses on an underresearched, yet, very applicable topic. We suggest that emphasis should be put on dietary alteration as a means of treatment for patients with CD to supplement current therapy for optimal results. With the widespread popularity of fried foods, it is important to raise awareness about the potential negative outcomes that are prevalent worldwide.

High level of IgG4 as a biomarker for a new subset of inflammatory bowel disease

The roles of B and plasma cells in the pathogenesis of inflammatory bowel disease (IBD) are largely unrevealed. Data on the characteristics of IgG4 in patients with IBD are scarce. In this case-control study, serum IgG4 levels were comparable between patients with IBD and healthy individuals, whereas patients with IBD had dramatically higher mucosal IgG4 counts than healthy individuals. In patients with UC, mucosal IgG4 counts were positively correlated with serum IgG4 levels, serum IgG4/IgG ratios, and the Mayo Index; serum IgG4 levels and IgG4/IgG ratios were associated with a history of intestinal surgery and medications. A significant mucosal IgG4 count was found in 33.3% of patients with IBD, whereas, elevated serum IgG4 levels were found in only 9.9% of patients with IBD. Lesions were more severe and extensive in IBD patients with high levels of serum and mucosal IgG4. High levels of serum and mucosal IgG4 decreased after treatment with glucocorticoids or other immunosuppressants. High IgG4 level may be a biomarker for a new subset of IBD. More studies are warranted to explore this new subset of IBD for personalized therapy in the future.

A Pseudotumor? No! Itʼs a Granulomatous Diverticulitis in Disguise!

Diverticular Disease (DD) encompasses a broad scope of manifestations including chronic inflammatory segmental colitis which is a distinct entity that can occasionally exhibit granulomatous reaction. This unique variant of diverticulosis associated colitis (DAC) usually affects the left colon sparing rectum, cecum and ascending colon. Caution should be exercised to distinguish DAC from Crohn's or ulcerative colitis. Granulomatous colitis associated with left sided diverticulosis has been rarely described, we herein report the 1st case in the English literature of granulomatous colitis affecting the right colon and presenting atypically as a hypermetabolic tumor externally abutting the bowel, that was further identified as organized granulomatous reaction. 77 yr old man with DM and HTN presents with right lower abdominal pain of few weeks. Physical exam revealed a palpable RLQ mass. Abdominal CT scan showed a 5.5cm irregular soft tissue mass abutting on ascending colon medially (Fig 1). Colonoscopy disclosed diverticulosis in sigmoid and ascending colon with no evidence of tumors. On PET scan the mass exhibited increased metabolic activity suspicious for biological tumor activity (Fig 2). CT guided biopsy revealed inflammatory cells. Patient underwent diagnostic laparoscopy and fresh frozen section was inconclusive. Robotic assisted right hemicolectomy enbloc with the mass was then performed. Pathology showed diverticulitis with localized suppurative granulomatous inflammation in pericolic fat. The non-caseating granuloma consisted of epithelioid histiocytes with eosinophic cytoplasms and eccentric nuclei (Fig 3). Immunostains were positive for CD68 and Vimentin, negative for Pancytokeratin (Fig 3), eliminating the possibility of a carcinoma or a sarcoma. DD is a leading cause of hospitalizations in developed countries, affecting 30-50% of individuals older than 60 years. DAC is chronic mucosal inflammation occuring in colon segments affected by DD, typically sparing rectum and proximal colon. Its prevalence varies between 1.15 and 11.4% of those suffering from DD. Pathogenesis is heterogenous and includes mechanisms that play part in inflammatory bowel disease (IBD), especially in patients with granulomatous colitis like our case. Whether DAC exists as a separate entity or whether it is a subset of IBD is still unclear. Better understanding of this multifaceted disease and its optimal management will only be possible with increased awareness amongst clinicians.Figure: Abdominal computed tomography scan revealing a 5.5cm irregular soft tissue mass abutting the ascending colon medially and verging on the anterior abdominal wall.Figure: PET scan showing increased metabolic activity of the respective mass suspicious for biological tumor activity.Figure: Pathology image of the non-caseating granulomas consisting of epithelioid histiocytes with abundant eosinophic cytoplasm and eccentric nuclei. Immunostains were positive for CD68 (Fig 3-B) and Vimentin (Fig 3-C), negative for Pancytokeratin (Fig 3-D), eliminating the possibility of a carcinoma or a sarcoma.

Identification of Variants in Genes Associated with Single-gene Inflammatory Bowel Disease by Whole-exome Sequencing.

Most cases of inflammatory bowel disease (IBD) are caused by complex host-environment interaction. There are a number of conditions associated with a single-gene mutation, most cases are very early onset (aged < 6 yr), present with a unique form of disease and often have atypical features. Whole-exome data for 147 pediatric patients with IBD were interrogated for a panel of 51 genes associated with monogenic IBD. Observed variation was categorized according to the American College of Medical Genetics (ACMG) guidelines to identify rare, novel, and known variants that might contribute to IBD. Five hundred seventy-four variants were identified across 51 genes. These were categorized in line with ACMG guidance to remove benign variants and to identify "pathogenic" and "likely pathogenic" variants. In 6 patients, we observed 6 pathogenic variants of which CYBA(c.287+2T>C), COL7A1(c.6501+1G>C), LIG4(p.R814X), and XIAP(p.T470S) were known causative mutations, and FERMT1(p.R271Q) and SKIV2L(c.354+5G>A) were novel. In the 3 patients with XIAP, SKIV2L, and FERMT1 variants, individuals' disease features resembled the monogenic phenotype. This was despite apparent heterozygous carriage of pathogenic variation for the latter 2 genes. The XIAP variant was observed in a hemizygous male. Whole-exome sequencing allows for identification of known and de novo potentially causative mutations in genes associated with monogenic IBD. Although these are rare conditions, it is vital to identify causative mutations early to improve prognosis. We postulate that in a subset of IBD, heterozygous mutations (in genes believed to manifest IBD through autosomal recessive inheritance) may contribute to clinical presentation.

Combined Foxp3 and IgG4 staining reveal distinct subsets of inflammatory bowel disease

The two disease model in idiopathic inflammatory bowel disease (IBD), i.e. ulcerative colitis (UC) vs. Crohn's disease (CD), insufficiently captures the diseases' genetic and phenotypic diversity. We have utilized immunohistochemical staining for two markers of “regulatory” immune cells, IgG4 and FoxP3, to better characterize IBD, hoping to improve diagnosis, prognostication, and therapy. These stains were examined in cases of CD (n=11), UC (n=11), and demographically equivalent disease‐free patients (n=22). Biopsies taken from sites throughout the colon at all levels of disease activity were evaluated. The maximal number of cells staining per high power field (hpf) was scored. Neither IgG4 nor FoxP3 counts correlated with diagnosis (p&gt;;0.05). Both correlated with disease activity (both p≈0.01). Neither showed correlation with age, gender, or anatomic site. Generalized linear models did not determine IgG4 or FoxP3 counts to be good predictors of diagnosis, even when corrected for disease activity. However, supervised hierarchical clustering revealed that the combination of the two stains identified clinically meaningful subsets of disease (Figure 1).These data provide insight into IBD that will help guide future understanding and therapies, going beyond the currently prevailing two disease paradigm.Research was supported entirely by internal (i.e. departmental) funds.

Ulcerative Proctitis, Rectal Prolapse, and Intestinal Pseudo-Obstruction in Transgenic Mice Overexpressing Hepatocyte Growth Factor/Scatter Factor

Hepatocyte growth factor/scatter factor (HGF/SF) can stimulate growth of gastrointestinal epithelial cells in vitro; however, the physiological role of HGF/SF in the digestive tract is poorly understood. To elucidate this in vivo function, mice were analyzed in which an HGF/SF transgene was overexpressed throughout the digestive tract. Nearly a third of all HGF/SF transgenic mice in this study (28 of 87) died by 6 months of age as a result of sporadic intestinal obstruction of unknown etiology. Enteric ganglia were not overtly affected, indicating that the pathogenesis of this intestinal lesion was different from that operating in Hirschsprung's disease. Transgenic mice also exhibited a rectal inflammatory bowel disease (IBD) with a high incidence of anorectal prolapse. Expression of interleukin-2 was decreased in the transgenic colon, indicating that HGF/SF may influence regulation of the local intestinal immune system within the colon. These results suggest that HGF/SF plays an important role in the development of gastrointestinal paresis and chronic intestinal inflammation. HGF/SF transgenic mice may represent a useful model for the study of molecular mechanisms associated with a subset of IBD and intestinal pseudo-obstruction. Moreover, our data identify previously unappreciated side effects that may be encountered when using HGF/SF as a therapeutic agent.

CONVENTIONAL DRUG THERAPY IN INFLAMMATORY BOWEL DISEASE

The conventional treatment of inflammatory bowel disease should center around the liberal use of one of the many available forms of 5-ASA. Sulfasalazine should be used initially with the newer mesalamine-only containing drugs being reserved for sulfasalazine-intolerant patients or for those patients who require larger doses of medication. The choice of the delivery method should be made with the knowledge of the extent of disease and the potential coverage areas of the individual delivery methods. Systemic and topical glucocorticoids are an invaluable adjunct to 5-ASA therapy, but their use must be directed with the goal of remission induction. The tapering of glucocorticoids should be as prompt as the maintenance of remission allows, with a useful general guideline of decreasing the dose by 1 mg per day. Immunosuppressive therapy, including azathioprine and 6-mercaptopurine, holds promise for refractory cases of inflammatory bowel disease and for their potential steroid sparing properties; antibiotic therapy with metronidazole and ciprofloxacin in the absence of documented infectious disease offers additional routes to control disease. The majority of patients require a combination of drugs to attain remission. Only further study will reveal the ideal regimen for each of the different subsets of inflammatory bowel disease.

Intercellular adhesion molecule 1 gene associations with immunologic subsets of inflammatory bowel disease

Background & Aims: Inflammatory bowel disease is characterized by a failure to down-regulate the usual self-limited gut inflammatory response, suggesting that one or more of the predisposing genes could be those that determine the level of the immune response along the inflammatory pathway. The aim of this study was to examine potential associations of intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms with inflammatory bowel disease or subsets of inflammatory bowel disease. Methods: One hundred eighteen patients with ulcerative colitis (UC) and 130 patients with Crohn's disease (CD) as well as 77 ethnically matched controls were tested for antineutrophil cytoplasmic antibodies (ANCAs) and genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for ICAM-1 polymorphisms at codon 241 (exon 4) and codon 469 (exon 6). Results: There was no significant difference between all patients with UC, patients with CD, and controls in either polymorphism. However, when stratified by ANCA status, ANCA-negative UC showed a significantly increased frequency of allele R241 compared with ANCA-positive UC (16.0% vs. 6.6%; P = 0.047, Fisher's Exact Test). In contrast, it was ANCA-positive CD that had an increased allele frequency compared with ANCA-negative CD (19.6% vs. 8.4%; P = 0.027, Fisher's Exact Test). Conclusions: Because the codon 241 polymorphism is in a functionally important domain III of ICAM-1, we may have identified an actual responsible genetic variation for genetically heterogeneous subsets of both UC and CD.