ABSTRACT
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.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Humans , Colitis, Ulcerative/genetics , Crohn Disease/genetics , Genome-Wide Association Study , Genetic Predisposition to Disease , Genetic Loci , Polymorphism, Single Nucleotide/genetics , Tumor Necrosis Factor Ligand Superfamily Member 15/genetics , Carrier Proteins/genetics , Membrane Proteins/genetics , Ubiquitin-Specific Proteases/geneticsABSTRACT
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.
Subject(s)
Crohn Disease , Leprosy , Humans , Genome-Wide Association Study , Crohn Disease/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide/genetics , Asian People/genetics , Genetic Loci , Leprosy/genetics , Case-Control Studies , Tumor Necrosis Factor Ligand Superfamily Member 15/geneticsABSTRACT
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.
Subject(s)
Crohn Disease , Immunologic Memory , Memory T Cells , Th17 Cells , Humans , Crohn Disease/immunology , Crohn Disease/genetics , Crohn Disease/pathology , Th17 Cells/immunology , Th17 Cells/metabolism , Memory T Cells/immunology , Memory T Cells/metabolism , Male , Female , Adult , Middle Aged , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Biomarkers , Gene Expression Profiling , Young AdultABSTRACT
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.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Sarcopenia , Humans , Male , Female , Sarcopenia/diagnostic imaging , Sarcopenia/epidemiology , Inflammatory Bowel Diseases/diagnosis , Colitis, Ulcerative/complications , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/epidemiology , Crohn Disease/complications , Crohn Disease/diagnosis , Crohn Disease/epidemiology , Colectomy , Disease Progression , Republic of Korea/epidemiologyABSTRACT
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.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Hip Fractures , Inflammatory Bowel Diseases , Adrenal Cortex Hormones , Case-Control Studies , Colitis, Ulcerative/complications , Colitis, Ulcerative/epidemiology , Female , Hip Fractures/epidemiology , Hip Fractures/etiology , Humans , Incidence , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/epidemiology , Male , Risk FactorsABSTRACT
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.
Subject(s)
Inflammatory Bowel Diseases/complications , Parkinson Disease/etiology , Gastrointestinal Microbiome , Genetic Predisposition to Disease/genetics , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/physiopathology , Parkinson Disease/genetics , Parkinson Disease/physiopathology , Risk FactorsABSTRACT
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.
Subject(s)
Inflammatory Bowel Diseases/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/metabolism , Macrophage Activation , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Animals , Cell Differentiation , Chemokine CXCL1/metabolism , Disease Models, Animal , Mice , Regeneration , Signal TransductionABSTRACT
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.
Subject(s)
Inflammatory Bowel Diseases , Tuberculosis , Cohort Studies , Hospitals , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/epidemiology , Infliximab/adverse effects , Republic of Korea/epidemiology , Tuberculosis/epidemiology , Tumor Necrosis Factor InhibitorsABSTRACT
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.
Subject(s)
Colitis, Ulcerative , Colitis, Ulcerative/epidemiology , Endoscopy , Female , Humans , Prevalence , Republic of Korea/epidemiology , Retrospective Studies , Risk FactorsABSTRACT
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.
Subject(s)
Crohn Disease/diagnosis , Adult , Anus Neoplasms/epidemiology , Anus Neoplasms/etiology , Asian People , Cohort Studies , Crohn Disease/complications , Crohn Disease/epidemiology , Crohn Disease/surgery , Female , Humans , Male , Proctectomy , Prognosis , Rectal Neoplasms/epidemiology , Rectal Neoplasms/etiology , Risk , Time Factors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Previous studies have shown vitamin D status to be associated with disease activity in patients with inflammatory bowel disease (IBD), but its influence on the clinical course of IBD has not been established. AIMS: We aimed to analyze whether the serum 25-hydroxyvitamin D3 [25(OH)D] status is associated with clinical characteristics and affects the risk of surgery in patients with IBD. METHODS: From the IBD registry of the Asan Medical Center, we identified all patients who had at least one 25(OH)D measurement; we then analyzed the association between clinical factors and 25(OH)D status. 25(OH)D was considered borderline deficient, deficient, and severely deficient at levels of < 30, < 20, and < 10 ng/mL, respectively. RESULTS: We included 711 Crohn's disease (CD) and 764 ulcerative colitis (UC) patients who had not undergone surgery before 25(OH)D was measured. Both in CD and in UC patients, reduced 25(OH)D was associated with higher disease activity scores and CRP levels (p < 0.001). Severe 25(OH)D deficiency was associated with ileocolonic disease and complicated behavior in CD (p < 0.05) and was relevant to the disease extent in UC (p < 0.001). Additionally, severe 25(OH)D deficiency was associated with CMV colitis in patients with UC (p < 0.001). In multivariable analysis, severe deficiency of 25(OH)D was an independent risk factor for surgery in both CD (HR 1.93, 95% confidence interval [CI] 1.38-2.70) and UC (HR 2.77, 95% CI 1.14-6.74). CONCLUSION: Severe 25(OH)D deficiency may be a marker of a more aggressive clinical course of IBD.
Subject(s)
Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/metabolism , Severity of Illness Index , Vitamin D Deficiency/diagnosis , Vitamin D Deficiency/metabolism , Vitamin D/metabolism , Adolescent , Adult , Cohort Studies , Female , Humans , Inflammatory Bowel Diseases/epidemiology , Male , Middle Aged , Registries , Vitamin D Deficiency/epidemiology , Young AdultABSTRACT
Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRß1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12]).
Subject(s)
Colitis, Ulcerative/genetics , Crohn Disease/genetics , Genetic Predisposition to Disease , HLA-DRB1 Chains/genetics , Inflammatory Bowel Diseases/genetics , Alleles , Amino Acid Substitution/genetics , Amino Acids/chemistry , Amino Acids/genetics , Asian People/genetics , Colitis, Ulcerative/pathology , Crohn Disease/pathology , Female , Genetic Association Studies , Genotype , HLA-DRB1 Chains/chemistry , Haplotypes/genetics , Humans , Inflammatory Bowel Diseases/pathology , Japan , Male , Protein Conformation , Republic of KoreaABSTRACT
BACKGROUND AND AIM: Fucosyltransferase 2 (FUT2) at 19q13 is a well-established susceptibility locus for Crohn's disease (CD) in Caucasians. FUT2 encodes α-1,2-fucosyltransferase that regulates the secretion of the α-1-2-N-acetylgalactosaminyltransferase and α-1-3-galactosyltransferase (ABO) antigens in both the gastrointestinal mucosa and secretory glands. Given that CD is thought to arise from dysregulated mucosal immune responses to the gut flora and both the ABO blood group and the FUT2 secretor status affect the composition of the gut microbiota, the goal of this study was to evaluate the associations of variants of FUT2 and ABO with CD in Koreans. METHODS: Three single-nucleotide polymorphisms from the FUT2 and ABO genes were genotyped in 1735 patients with CD and 8074 healthy controls. RESULTS: The FUT2 non-secretor allele showed genome-wide significant association with CD in Koreans (rs1047781, odds ratio [OR] = 1.30, Pcombined = 3.52 × 10-12 ). The ABO locus showed genome-wide significant association with CD in Asians (Pmeta = 2.35 × 10-8 ). A moderate association was observed with the A and B groups (OR = 1.40, P = 2.26 × 10-6 ; and OR = 1.32, P = 1.92 × 10-4 , respectively) compared with the O group. Following stratification on the basis of FUT2 genotype, carriers of the secretor O blood group were significantly protective against CD than were those of the secretor non-O blood group (OR = 0.63, 95% confidence interval = 0.54-0.73, P = 2.86 × 10-9 ). CONCLUSIONS: These are the first results indicating that the O blood group and FUT2 secretor status are protective factors against CD in Asians.
Subject(s)
ABO Blood-Group System/genetics , Crohn Disease/genetics , Fucosyltransferases/genetics , Galactosyltransferases/genetics , Asian People , Genome-Wide Association Study , Genotype , Humans , Galactoside 2-alpha-L-fucosyltransferaseABSTRACT
BACKGROUND: Little is known about the natural history of perianal fistulas in Asian populations with Crohn's disease (CD). AIMS: We investigated the incidence and outcomes of perianal CD (pCD) in Korean CD patients. METHODS: A nationwide population-based cohort of 6265 CD patients diagnosed in 2010-2014 was analyzed to investigate the incidence and outcomes of pCD. The results were validated in a hospital-based cohort of 2923 CD patients diagnosed in 1981-2015. Factors associated with pCD development were analyzed. The incidence and outcomes of pCD were compared between the prebiologic and biologic eras. RESULTS: pCD occurred in 39.2% of the population-based cohort and 56.1% of the hospital-based cohort during the median follow-up of 4.2 and 8.5 years, respectively. The cumulative incidence of pCD was 40.0% at 5 years after CD diagnosis in the population-based cohort and 62.5% at 20 years in the hospital-based cohort. In multivariate analysis, pCD development was positively associated with male sex, younger age and colonic involvement at diagnosis, early diagnosis, and CD diagnosis in the prebiologic era. The cumulative probability of proctectomy at 10, 20, and 30 years after pCD diagnosis was 2.9%, 12.2%, and 16.2%, respectively. The cumulative incidence of pCD occurring after CD diagnosis and the cumulative probability of proctectomy were significantly lower in the biologic era than in the prebiologic era (p < 0.001 and p = 0.03, respectively). CONCLUSIONS: Compared with Western patients with CD, Korean patients show a high incidence of pCD but have a low probability of proctectomy, suggesting the favorable course of pCD.
Subject(s)
Asian People , Crohn Disease/epidemiology , Population Surveillance , Rectal Fistula/epidemiology , Cohort Studies , Crohn Disease/diagnosis , Crohn Disease/surgery , Female , Follow-Up Studies , Hospitalization/trends , Humans , Incidence , Male , Population Surveillance/methods , Rectal Fistula/diagnosis , Rectal Fistula/surgery , Republic of Korea/epidemiology , Risk Factors , Treatment OutcomeABSTRACT
BACKGROUND AND AIM: Tobacco smoking is a risk factor for gastrointestinal disorders, causing mucosal damage and impairing immune responses. However, smoking has been found to be protective against ulcerative colitis (UC). Human leukocyte antigen (HLA) is a major susceptibility locus for UC, and HLA-DRB1*15:02 has the strongest effect in Asians. This study investigated the effects of smoking on the association between HLA and UC. METHODS: The study enrolled 882 patients with UC, including 526 never, 151 current, and 205 former smokers, and 3091 healthy controls, including 2124 never, 502 current, and 465 former smokers. Smoking-stratified analyses of HLA data were performed using a case-control approach. RESULTS: In a case-control approach, HLA-DRB1*15:02 was associated with UC in never smokers (ORnever smokers = 3.20, Pnever smokers = 7.88 × 10-23 ) but not in current or former smokers (Pcurrent smokers = 0.72 and Pformer smokers = 0.33, respectively). In current smokers, HLA-DQB1*06 was associated with UC (ORcurrent smokers = 2.59, Pcurrent smokers = 6.39 × 10-12 ). No variants reached genome-wide significance in former smokers. CONCLUSIONS: An association between UC and HLA-DRB1*15:02 was limited to never smokers. Our findings highlight that tobacco smoking modifies the effects of HLA on the risk of UC.
Subject(s)
Colitis, Ulcerative/genetics , Gene-Environment Interaction , HLA-DRB1 Chains/genetics , Non-Smokers , Smokers , Smoking/genetics , Adult , Aged , Case-Control Studies , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/immunology , Female , HLA-DRB1 Chains/immunology , Humans , Male , Middle Aged , Risk Assessment , Risk Factors , Smoking/adverse effects , Smoking/immunology , Smoking CessationABSTRACT
BACKGROUND AND AIM: Anti-tumor necrosis factor (TNF) agents, such as infliximab (IFX), have been increasingly used to induce and maintain disease remission in patients with Crohn's disease (CD). Despite a considerable non-response rate, little is known about the genetic predictors of response to anti-TNF therapy in CD. Our aim in this study was to investigate the genetic factors associated with response to anti-TNF therapy in patients with CD. METHODS: We performed a two-stage genome-wide association study (GWAS) to identify loci influencing the response to IFX among Korean patients with CD, comprising 42 good responders with mucosal healing and 70 non-responders. The achievement of mucosal healing was assessed by endoscopy and imaging. The functional significance of TRAP1 (TNF receptor associated protein 1) was examined using dextran sodium sulfate-induced colitis model in TRAP1 transgenic mice. RESULTS: The GWAS identified rs2158962, an intronic single nucleotide polymorphism (SNP) of TRAP1, significantly associated with mucosal healing (odds ratio = 4.94; Pcombined = 1.35 × 10-7 ). In the dextran sodium sulfate-induced acute colitis, TRAP1 transgenic mice showed a better response to IFX than the wild-type mice. CONCLUSIONS: The TRAP1 gene is associated with mucosal healing in CD patients following IFX therapy. Identifying the genetic predictors of mucosal healing to anti-TNF therapy can prevent patients from exposure to ineffective therapies.
Subject(s)
Crohn Disease/drug therapy , HSP90 Heat-Shock Proteins/physiology , Infliximab/therapeutic use , Intestinal Mucosa/drug effects , Wound Healing/drug effects , Adolescent , Adult , Animals , Crohn Disease/genetics , Crohn Disease/physiopathology , Female , Gastrointestinal Agents/therapeutic use , Gene Expression Regulation/physiology , Genome-Wide Association Study , Genotype , HSP90 Heat-Shock Proteins/genetics , Humans , Intestinal Mucosa/physiology , Male , Mice, Transgenic , Phenotype , Polymorphism, Single Nucleotide , RNA, Messenger/genetics , Registries , Wound Healing/genetics , Young AdultABSTRACT
BACKGROUND AND AIM: The risk and clinical impact of perianal disease (PAD) in ulcerative colitis (UC) patients have not been fully evaluated. We investigated the incidence of PAD in UC patients and compared clinical characteristics and outcomes of UC according to the presence of PAD. METHODS: We performed a nationwide population-based cohort study and a hospital-based cohort study. Using the 2010-2014 data from the Korean National Health Insurance claims database, we calculated incidence rates and standardized incidence ratios of PAD in UC patients compared with the general population. We evaluated the clinical characteristics and outcomes of UC patients with PAD in both population-based and hospital-based cohorts. To reduce clinically meaningful confounding factors, we also conducted matched analyses. RESULTS: In the population-based cohort, the incidence rate and standardized incidence ratio of PAD in UC patients were 3.74/1000 person-years (95% confidence interval, 3.25-4.31) and 2.88 (95% confidence interval, 2.50-3.32), respectively. In the hospital-based cohort, the cumulative probabilities of PAD at 1, 5, 10, and 20 years after diagnosis were 1.0%, 2.3%, 4.0%, and 6.3%, respectively. In both population-based and hospital-based cohorts, UC patients with PAD showed higher proportions of corticosteroid use and extensive colitis at diagnosis. The requirements for anti-tumor necrosis factor agents and colectomy were significantly higher in UC patients with PAD before and after matched analysis. CONCLUSIONS: The risk of PAD is higher in UC patients than in the general population. UC patients with PAD have distinct clinical features and poor outcomes, as indicated by the greater need for UC-related medications and colectomy.
Subject(s)
Anus Diseases/epidemiology , Anus Diseases/etiology , Colitis, Ulcerative/complications , Colitis, Ulcerative/epidemiology , Adolescent , Adrenal Cortex Hormones/adverse effects , Adult , Aged , Child , Child, Preschool , Cohort Studies , Colectomy/statistics & numerical data , Drug Utilization/statistics & numerical data , Female , Hospitals/statistics & numerical data , Humans , Incidence , Infant , Male , Middle Aged , Population , Prognosis , Republic of Korea/epidemiology , Risk , Time Factors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Young AdultABSTRACT
BACKGROUND & AIMS: Few data are available on risk of herpes zoster (HZ) infection in Asian patients with inflammatory bowel diseases (IBD). We investigated whether patients with IBD in Korea have an increased risk of HZ and sought to identify risk factors for infection. METHODS: We performed a nationwide population-based study and a hospital-based, nested case-control study. Using the 2009-2013 data from the Korean national health insurance claims database, we calculated incidence rates and standardized incidence ratios (SIRs) of HZ infection in patients with IBD compared with the entire Korean population. In the nested case-control study, within a hospital-based cohort, 300 patients with IBD and HZ infection were matched with 895 patients with IBD without HZ. RESULTS: In the nationwide population-based study, the incidence rate and SIR of HZ infection in patients with IBD were 18.34/1000 person-years and 1.48 (95% CI, 1.42-1.54), respectively. The SIR for HZ infection was higher in patients with Crohn's disease than in patients with ulcerative colitis (1.90 vs 1.36; P < .001) and higher in male patients than female patients (1.63 vs 1.33; P < .001). The incidence rate of HZ increased with age (P trend < .001), whereas the SIR of HZ infection decreased with age (P trend < .001). In the nested case-control study, corticosteroid use was associated with HZ infection (for ulcerative colitis, adjusted odds ratio, 2.44; 95% CI, 1.18-5.05 and for Crohn's disease, adjusted odds ratio, 2.70; 95% CI 1.25-5.83). CONCLUSIONS: In a population-based study in Korea, we found patients with IBD to have an increased risk for HZ infection-especially among patients who are male, younger, or have Crohn's disease. Corticosteroid use increases risk of HZ infection in patients with IBD.
Subject(s)
Herpes Zoster/epidemiology , Inflammatory Bowel Diseases/complications , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Case-Control Studies , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infant, Newborn , Korea/epidemiology , Male , Middle Aged , Risk Assessment , Risk Factors , Sex Factors , Young AdultABSTRACT
BACKGROUND AND AIM: Smoking cessation is known to improve the course of Crohn's disease (CD). However, the factors associated with smoking cessation after CD diagnosis have not been well established. METHODS: Clinical characteristics and change in smoking status were evaluated in 445 current smokers at the time of CD diagnosis. Patients were classified into three subgroups based on their final smoking status and time of smoking cessation: non-quitters, quitters at diagnosis, and quitters during follow-up. RESULTS: The overall smoking cessation rate was 55.7% (248 of 445 patients). The diagnosis of CD was the main reason for quitting (41.5%, 103 of 248 patients). Smoking cessation at the time of CD diagnosis was associated with intestinal resection within 3 months from CD diagnosis (odds ratio [OR] 2.355, 95% confidence interval [CI] 1.348-4.116, P = 0.003), light smoking (OR 2.041, 95% CI 1.157-3.602, P = 0.014), and initiation of smoking before 18 years of age (OR 0.570, 95% CI 0.327-0.994, P = 0.047). Light smoking (OR 1.762, 95% CI 1.019-3.144, P = 0.043) and initiation of smoking before 18 years (OR 0.588, 95% CI 0.381-0.908, P = 0.017) were also associated with overall smoking cessation. CONCLUSION: Quitters after CD diagnosis, including quitters at diagnosis and quitters during follow-up, had features distinct from those of non-quitters. Given the motivation at CD diagnosis, a detailed history of smoking habits should be taken and all current smokers should be encouraged to quit smoking at the time of CD diagnosis.
Subject(s)
Crohn Disease/psychology , Smoking Cessation/psychology , Adult , Age Factors , Crohn Disease/diagnosis , Crohn Disease/surgery , Female , Follow-Up Studies , Humans , Male , Motivation , Prospective Studies , Smoking Cessation/statistics & numerical data , Young AdultABSTRACT
BACKGROUND AND AIM: CDKN2A/CDKN2B locus on 9p21 is reported to be associated with various diseases, including cancer and cardiovascular and inflammatory diseases. Significant downregulation of CDKN2B-AS1 in inflamed colon tissue of inflammatory bowel disease (IBD) cases was reported in Europeans. This study aimed to confirm the suggestive association of CDKN2A/CDKN2B with IBD identified in our recent genome-wide association study (GWAS). METHODS: We examined the association of CDKN2A/CDKN2B locus with IBD in an additional sample of 574 IBD cases and 542 controls, totaling 4068 cases and 8074 controls. In silico study was performed at various levels for functional annotation of the causal variant. Co-localization of the GWAS association signals and the corresponding expression quantitative trait loci in IBD-related tissues was evaluated using eCAVIAR. RESULTS: An expanded GWAS showed genome-wide significant association of rs3731257 at 9p21 with IBD (odds ratio = 1.17, 95% confidence interval = 1.12-1.22, Pcombined = 5.68 × 10-9 ) and Crohn's disease (odds ratio = 1.22, 95% confidence interval = 1.15-1.28, Pcombined = 8.85 × 10-9 ) in the Korean population. Co-localization study suggested that both CDKN2B-AS1 and CDKN2A might be functionally associated with the locus in the small intestine. CONCLUSIONS: rs3731257 in CDKN2A/CDKN2B is an IBD-susceptible locus in Koreans, with a suggestive role for small intestine-specific gene regulation. Our findings suggested that alterations of the CDKN2A/CDKN2B locus could affect the pathophysiology of IBD.