Case-case genome-wide association analysis identifying genetic loci with divergent effects on Crohn's disease and ulcerative colitis.

Crohn's disease (CD) and ulcerative colitis (UC), two major subtypes of inflammatory bowel disease, show substantial differences in their clinical course and treatment response. To identify the genetic factors underlying the distinct characteristics of these two diseases, we performed a genome-wide association study (GWAS) between CD (n = 2359) and UC (n = 2175) in a Korean population, followed by replication in an independent sample of 772 CD and 619 UC cases. Two novel loci were identified with divergent effects on CD and UC: rs9842650 in CD200 and rs885026 in NCOR2. In addition, the seven established susceptibility loci [major histocompatibility complex (MHC), TNFSF15, OTUD3, USP12, IL23R, FCHSD2 and RIPK2] reached genome-wide significance. Of the nine loci, six (MHC, TNFSF15, OTUD3, USP12, IL23R and CD200) were replicated in the case-case GWAS of European populations. The proportion of variance explained in CD-UC status by polygenic risk score analysis was up to 22.6%. The area under the receiver-operating characteristic curve value was 0.74, suggesting acceptable discrimination between CD and UC. This CD-UC GWAS provides new insights into genetic differences between the two diseases with similar symptoms and might be useful in improving their diagnosis and treatment.

Identification of shared loci associated with both Crohn's disease and leprosy in East Asians.

Genome-wide association studies (GWAS) of Crohn's disease (CD) in European and leprosy in Chinese population have shown that CD and leprosy share genetic risk loci. As these shared loci were identified through cross-comparisons across different ethnic populations, we hypothesized that meta-analysis of GWAS on CD and leprosy in East Asian populations would increase power to identify additional shared loci. We performed a cross-disease meta-analysis of GWAS data from CD (1621 cases and 4419 controls) and leprosy (2901 cases 3801 controls) followed by replication in additional datasets comprising 738 CD cases and 488 controls and 842 leprosy cases and 925 controls. We identified one novel locus at 7p22.3, rs77992257 in intron 2 of ADAP1, shared between CD and leprosy with genome-wide significance (P = 3.80 × 10-11) and confirmed 10 previously established loci in both diseases: IL23R, IL18RAP, IL12B, RIPK2, TNFSF15, ZNF365-EGR2, CCDC88B, LACC1, IL27, NOD2. Phenotype variance explained by the polygenic risk scores derived from Chinese leprosy data explained up to 5.28% of variance of Korean CD, supporting similar genetic structures between the two diseases. Although CD and leprosy shared a substantial number of genetic susceptibility loci in East Asians, the majority of shared susceptibility loci showed allelic effects in the opposite direction. Investigation of the genetic correlation using cross-trait linkage disequilibrium score regression also showed a negative genetic correlation between CD and leprosy (rg [SE] = -0.40[0.13], P = 2.6 × 10-3). These observations implicate the possibility that CD might be caused by hyper-sensitive reactions toward pathogenic stimuli.

Characterization of Th17 tissue-resident memory cells in non-inflamed intestinal tissue of Crohn's disease patients.

Crohn's disease (CD) is a chronic inflammatory disorder affecting the bowel wall. Tissue-resident memory T (Trm) cells are implicated in CD, yet their characteristics remain unclear. We aimed to investigate the transcriptional profiles and functional characteristics of Trm cells in the small bowel of CD and their interactions with immune cells. Seven patients with CD and four with ulcerative colitis as controls were included. Single-cell RNA sequencing and paired T cell receptor sequencing assessed T cell subsets and transcriptional signatures in lamina propria (LP) and submucosa/muscularis propria-enriched fractions (SM/MP) from small bowel tissue samples. We detected 58,123 T cells grouped into 16 populations, including the CD4+ Trm cells with a Th17 signature and CD8+ Trm clusters. In CD, CD4+ Trm cells with a Th17 signature, termed Th17 Trm, showed significantly increased proportions within both the LP and SM/MP areas. The Th17 Trm cluster demonstrated heightened expression of tissue-residency marker genes (ITGAE, ITGA1, and CXCR6) along with elevated levels of IL17A, IL22, CCR6, and CCL20. The clonal expansion of Th17 Trm cells in CD was accompanied by enhanced transmural dynamic potential, as indicated by significantly higher migration scores. CD-prominent Th17 Trm cells displayed an increased interferon gamma (IFNγ)-related signature possibly linked with STAT1 activation, inducing chemokines (i.e., CXCL10, CXCL8, and CXCL9) in myeloid cells. Our findings underscored the elevated Th17 Trm cells throughout the small bowel in CD, contributing to disease pathogenesis through IFNγ induction and subsequent chemokine production in myeloid cells.

Impact of Sarcopenia on Clinical Course of Inflammatory Bowel Disease in Korea.

BACKGROUND AND AIMS: Reduced body muscle mass is a poor prognostic factor for inflammatory bowel disease (IBD). In this study, we investigated the prevalence of sarcopenia at diagnosis and its clinical significance in Korean patients with IBD. METHODS: The prevalence of sarcopenia in IBD patients between June 1989 and December 2016 was investigated using a well-characterized referral center-based cohort. Abdominopelvic computed tomography within six months from IBD diagnosis was used for the evaluation. Sarcopenia was defined as an L3 skeletal muscle index of < 49 cm2/m2 for male and < 31 cm2/m2 for female. The clinical characteristics and outcomes were evaluated with respect to sarcopenia. RESULTS: A total of 1,027 patients (854 Crohn's disease [CD]; 173 ulcerative colitis [UC]) were evaluated. Sarcopenia was found in 56.8% of the population (CD, 57.5%; UC, 53.2%), and male were more likely to be sarcopenic (CD, 94.3%; UC, 91.6%). There were no significant differences in the cumulative risk of using steroids, immunomodulators, biologics, and bowel resections (or colectomy) with or without sarcopenia during follow-up (median: CD, 5.8 years; UC, 3.7 years). In sarcopenic patients with CD, there was a significantly higher cumulative risk of perianal surgeries than in non-sarcopenic patients with CD (Log-rank test; P = 0.001). However, the risk of perianal surgeries was not significant in multivariate analysis (Odds ratio 1.368; 95% confidence interval 0.782-2.391; P = 0.272). CONCLUSION: Sarcopenia at diagnosis may have no significant prognostic value for medical treatment and bowel resection, but it may be associated with perianal CD.

High Risk of Fractures Within 7 Years of Diagnosis in Asian Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: In this nationwide population-based study, we investigated the risk of vertebral and hip fractures in patients with inflammatory bowel disease (IBD). METHODS: Using data from the Korean National Health Insurance claims database gathered between 2007 and 2016, we calculated the incidence rate ratios (IRRs) of vertebral and hip fractures in patients with newly diagnosed IBD (n = 18,228; 64.1% male, 65.9% ulcerative colitis) compared with an age- and sex-matched control population (matching ratio, 1:10; n = 186,871). RESULTS: During a median follow-up period of 4.5 years, the incidence rate and IRR of vertebral and hip fractures in patients with IBD were 2.88 per 1000 person-years and 1.24 (95% CI, 1.08-1.42), respectively. The cumulative risk of vertebral and hip fractures in IBD patients was 0.6%, 1.4%, and 1.9% at 2, 5, and 7 years after diagnosis, respectively, and this risk of fracture in IBD patients was higher than that in matched controls (P = .002). The use of corticosteroids further increased the risk of fractures in IBD patients (IRR, 1.37; 95% CI, 1.13-1.65) compared with matched controls. The risk of fractures was significantly higher in patients with Crohn's disease (CD) (IRR, 1.56; 95% CI, 1.19-2.04) than in matched controls, and this risk remained higher in patients with CD without corticosteroid exposure (IRR, 1.62; 95% CI, 1.12-2.34). The risk of fracture increased with age and was particularly high in females and in those with comorbidities. CONCLUSIONS: The risk of fractures was significantly high in newly diagnosed IBD patients, especially in those with CD regardless of corticosteroid exposure.

Inflammatory bowel disease and Parkinson's disease: common pathophysiological links.

Inflammatory bowel disease and Parkinson's disease are chronic progressive disorders that mainly affect different organs: the gut and brain, respectively. Accumulating evidence has suggested a bidirectional link between gastrointestinal inflammation and neurodegeneration, in accordance with the concept of the 'gut-brain axis'. Moreover, recent population-based studies have shown that inflammatory bowel disease might increase the risk of Parkinson's disease. Although the precise mechanisms underlying gut-brain interactions remain elusive, some of the latest findings have begun to explain the link. Several genetic loci are shared between both disorders with a similar direction of effect on the risk of both diseases. The most interesting example is LRRK2 (leucine-rich repeat kinase 2), initially identified as a causal gene in Parkinson's disease, and recently also implicated in Crohn's disease. In this review, we highlight recent findings on the link between these seemingly unrelated diseases with shared genetic susceptibility. We discuss supporting and conflicting data obtained from epidemiological and genetic studies along with remaining questions and concerns. In addition, we discuss possible biological links including the gut-brain axis, microbiota, autoimmunity, mitochondrial function and autophagy.

Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation.

OBJECTIVE: Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive. DESIGN: We investigated the role of the prostaglandin E2 (PGE2) receptor PTGER4 on the differentiation of intestinal macrophages in patients with IBD and mouse models of intestinal inflammation. We studied mucosal healing and intestinal epithelial barrier regeneration in Csf1r-iCre Ptger4fl/fl mice during dextran sulfate sodium (DSS)-induced colitis. The effect of PTGER4+ macrophage secreted molecules was investigated on epithelial organoid differentiation. RESULTS: Here, we describe a subset of PTGER4-expressing intestinal macrophages with mucosal healing properties both in humans and mice. Csf1r-iCre Ptger4fl/fl mice showed defective mucosal healing and epithelial barrier regeneration in a model of DSS colitis. Mechanistically, an increased mucosal level of PGE2 triggers chemokine (C-X-C motif) ligand 1 (CXCL1) secretion in monocyte-derived PTGER4+ macrophages via mitogen-activated protein kinases (MAPKs). CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during colitis. Specific therapeutic targeting of macrophages with liposomes loaded with an MAPK agonist augmented the production of CXCL1 in vivo in conditional macrophage PTGER4-deficient mice, restoring their defective epithelial regeneration and favouring mucosal healing. CONCLUSION: PTGER4+ intestinal macrophages are essential for supporting the intestinal stem cell niche and regeneration of the injured epithelium. Our results pave the way for the development of a new class of therapeutic targets to promote macrophage healing functions and favour remission in patients with IBD.

Risk and characteristics of tuberculosis after anti-tumor necrosis factor therapy for inflammatory bowel disease: a hospital-based cohort study from Korea.

BACKGROUND: Anti-tumor necrosis factor (TNF) treatment for inflammatory bowel disease (IBD) increases the risk of tuberculosis (TB) infection. In the present study, we analyzed the clinical characteristics and risks of TB in Korean patients with IBD who received anti-TNF treatment. METHODS: The study included patients with IBD who were treated using anti-TNF agents between January 2001 and June 2018 at the Asan Medical Center. Overall, 1434 patients with ulcerative colitis or Crohn's disease were enrolled. We calculated the incidence of active TB infection after anti-TNF treatment and compared the clinical characteristics of the TB group with those of the non-TB group. RESULTS: Twenty-one patients (1.46%) developed active TB infection, and the incidence rate of active TB was 366.73 per 100,000 person-years. In total, 198 patients (14.9%) were positive for latent tuberculosis infection (LTBI), of whom only eight (4%) did not complete LTBI treatment. The age at which the anti-TNF therapy was started was significantly higher in the TB group than in the non-TB group (HR 1.041, 95% CI 1.014-1.069, p = 0.002), and as age increased, so did the incidence rate of active TB infection (linearity p < 0.001). There was no significant difference in the incidence rate of LTBI between the TB and non-TB groups (HR 0.896, 95% CI 0.262-3.066, p = 0.862). CONCLUSIONS: In patients with IBD, the incidence rate of TB increased with age at anti-TNF therapy initiation. Active treatment of LTBI may lower the incidence of TB in patients with IBD who are to undergo anti-TNF therapy.

Prevalence and risk factors of bowel symptoms in Korean patients with ulcerative colitis in endoscopic remission: a retrospective study.

BACKGROUND: Many patients with ulcerative colitis (UC) in clinical remission frequently complain of bowel symptoms such as increased stool frequency (SF) and rectal bleeding (RB). However, studies on these patient-reported outcomes in patients with inactive UC are limited, especially in Korea. Therefore, we investigated the prevalence and risk factors of bowel symptoms in Korean patients with inactive UC. METHODS: We investigated the prevalence of bowel symptoms in patients with endoscopically quiescent UC between June 1989 and December 2016 using a well-characterized referral center-based cohort. The Mayo clinic score (MCS) was used to evaluate bowel symptoms at the most recent visit near the date of endoscopy. Clinical characteristics of the patients were compared based on the presence or absence of bowel symptoms. RESULTS: Overall, 741 patients with endoscopically quiescent UC were identified, of whom 222 (30%) and 48 (6.5%) had an SF and RB subscore of ≥ 1, respectively. Patients with bowel symptoms (SF + RB ≥ 1; n = 244 [32.9%]) had higher rates of left-sided colitis (E2) or extensive colitis (E3) than patients without bowel symptoms (SF + RB = 0; n = 497 [67.1%]; P = 0.002). Multivariate analysis revealed that female sex (odds ratio [OR]: 1.568; 95% confidence interval [CI]: 1.023-2.402; P = 0.039) and E2 or E3 (OR 1.411; 95% CI 1.020-1.951; P = 0.038) were the significant risk factors for increased SF. CONCLUSIONS: This study revealed that one-third of patients with endoscopically quiescent UC reported increased SF. Female sex and disease extent may be associated with bowel symptoms.

Clinical outcomes and long-term prognosis of perianal Crohn's disease in an Asian population.

BACKGROUND AND AIM: The clinical impact of perianal Crohn's disease (CD) (pCD), a well-known poor prognostic factor of CD, has not been fully evaluated in Asian patients. We investigated the outcomes of CD in Korean patients according to the presence of pCD at CD diagnosis. METHODS: Using 2010-2014 data from the national health insurance claims database, we evaluated the disease course of CD according to the presence of pCD at CD diagnosis. The results were verified in a hospital-based cohort of 2923 patients. RESULTS: The cumulative risk of intestinal resection was lower in patients with pCD at diagnosis than in those without, in the population-based cohort (9.1% vs 14.7% at 5 years after diagnosis, P < 0.001), but it was similar between the two groups in the hospital-based cohort (36.8% vs 36.8% at 10 years after diagnosis, P = 0.950). Moreover, the cumulative risk of behavioral progression was not significantly different between the two groups in the hospital-based cohort (43.4% vs 41.6% at 10 years after diagnosis, P = 0.366). On multivariable analysis, pCD at CD diagnosis was not a predictor of intestinal resection, behavioral progression, CD-related hospital admission, or diverting surgery; however, it was an independent predictor of proctectomy (hazard ratio [HR] 3.210, P < 0.001) and anorectal cancer (HR 3.104, P = 0.047). CONCLUSIONS: Although the presence of pCD increased the risk of proctectomy and anorectal cancer in Asian patients, the clinical impact of pCD on the overall outcomes of patients with CD may be less significant in Asian patients compared with Western patients.