Jae Hee Cheon

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

Ulcerative colitis and Crohns disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus

Metformin use has been associated with decreased cancer risk and mortality. However, the effects of metformin on clinical outcomes of colorectal cancer (CRC) are not defined. This study aimed to evaluate the association between metformin use and mortality of CRC in diabetic patients. We identified 595 patients who were diagnosed both CRC and diabetes mellitus. Patients were compared by two groups; 258 diabetic patients taking metformin and 337 diabetic patients not taking metformin. Patients demographics, clinical characteristics, overall mortality and CRC‐specific mortality were analyzed. After a median follow‐up of 41 months, there were 71 total deaths (27.5%) and 55 CRC‐specific deaths (21.3%) among 258 patients who used metformin, compared with 136 total deaths (40.4%) and 104 CRC‐specific deaths (30.9%) among 337 patients who did not use metformin. Metformin use was associated with decreased overall mortality (p = 0.018) and CRC‐specific mortality (p = 0.042) by univariate analysis. After adjustment for clinically relevant factors, metformin use showed lower risk of overall mortality (HR, 0.66; 95% CI 0.476–0.923; p = 0.015) and CRC‐specific mortality (HR, 0.66; 95% CI 0.45–0.975; p = 0.037) in CRC patients with diabetes. Metformin use in CRC patients with diabetes is associated with lower risk of CRC‐specific and overall mortality.

Efficacy and safety of CT-P13, a biosimilar of infliximab, in patients with inflammatory bowel disease: A retrospective multicenter study

The biosimilar of infliximab, CT‐P13, has recently been shown to be equivalent to infliximab in both efficacy and safety in the treatment of rheumatologic diseases. However, no data are available with respect to the drugs efficacy in patients with inflammatory bowel disease (IBD). We aimed to assess the efficacy and safety of CT‐P13 in IBD patients

Plant sterol guggulsterone inhibits nuclear factor-κB signaling in intestinal epithelial cells by blocking IκB kinase and ameliorates acute murine colitis

Background/Aims The plant sterol guggulsterone has been shown to have anti‐inflammatory properties. It remains unknown, however, whether guggulsterone is effective for the treatment of inflammatory bowel disease (IBD). Therefore, we investigated anti‐inflammatory effects of guggulsterone on intestinal epithelial cells (IEC) and on experimental murine colitis models and elucidated its molecular mechanisms. Methods Human Caco‐2 cells and rat non‐transformed IEC‐18 cells were stimulated with interleukin (IL)‐1&bgr; or lipopolysaccharide (LPS) with or without guggulsterone. The effects of guggulsterone on nuclear factor (NF)‐&kgr;B signaling in IEC were examined by intercellular adhesion molecule (ICAM)‐1 real‐time reverse‐transcription polymerase chain reaction, NF‐&kgr;B transcriptional activity assay, Western blotting for I&kgr;B phosphorylation/degradation, electrophoretic mobility shift assay, and in vitro I&kgr;B kinase (IKK) assay. For in vivo study, dextran sulfate sodium (DSS)‐treated mice were fed with or without guggulsterone. Colitis was quantified by disease activity index and evaluation of macroscopic and microscopic findings. Phosphorylation of I&kgr;B and IKK in colon mucosa was assessed by Western blotting and immunohistochemistry. Results Guggulsterone significantly inhibited LPS‐ or IL‐1&bgr;‐induced ICAM‐1 gene expression, NF‐&kgr;B transcriptional activity, I&kgr;B phosphorylation/degradation, and NF‐&kgr;B DNA binding activity in IEC. Moreover, guggulsterone strongly blocked IKK activity. Administration of guggulsterone significantly reduced the severity of DSS‐induced murine colitis as assessed by clinical disease activity score, colon length, and histology. Furthermore, tissue upregulation of I&kgr;B and IKK phosphorylation induced by DSS was attenuated in guggulsterone‐treated mice. Conclusion Guggulsterone blocks NF‐&kgr;B signaling pathway by targeting IKK complex in IEC and attenuates DSS‐induced acute murine colitis, which suggests that guggulsterone could be an attractive therapeutic option in the treatment of IBD.

Gene Expression–Based Recurrence Prediction of Hepatitis B Virus–Related Human Hepatocellular Carcinoma

Purpose: The poor prognosis of hepatocellular carcinoma (HCC) is, in part, due to the high rate of recurrence even after “curative resection” of tumors. Therefore, it is axiomatic that the development of an effective prognostic prediction model for HCC recurrence after surgery would, at minimum, help to identify in advance those who would most benefit from the treatment, and at best, provide new therapeutic strategies for patients with a high risk of early recurrence. Experimental Design: For the prediction of the recurrence time in patients with HCC, gene expression profiles were generated in 65 HCC patients with hepatitis B infections. Result: Recurrence-associated gene expression signatures successfully discriminated between patients at high-risk and low-risk of early recurrence (P = 1.9 × 10−6, log-rank test). To test the consistency and robustness of the recurrence signature, we validated its prognostic power in an independent HCC microarray data set. CD24 was identified as a putative biomarker for the prediction of early recurrence. Genetic network analysis suggested that SP1 and peroxisome proliferator–activated receptor-α might have regulatory roles for the early recurrence of HCC. Conclusion: We have identified a gene expression signature that effectively predicted early recurrence of HCC independent of microarray platforms and cohorts, and provided novel biological insights into the mechanisms of tumor recurrence.

Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations

Objective Crohns disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified 163 susceptibility loci to IBD in Caucasians, however there are limited studies in other populations. Methods We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls. Results We confirmed four previously reported loci: TNFSF15, IL23R, the major histocompatibility complex region, and the RNASET2-FGFR1OP-CCR6 region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10−14), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10−10) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10−9), implicating ATG16L2 and/or FCHSD2 as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of ATG16L2 with stronger association (OR=1.61, combined p=2.44×10−12) than rs11235667, suggesting ATG16L2 as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10−5)) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans. Conclusions Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.

Long-term outcome of palliative therapy for malignant colorectal obstruction in patients with unresectable metastatic colorectal cancers: endoscopic stenting versus surgery

BACKGROUND Self-expandable metal stents (SEMSs) provide a promising alternative for initial palliation of malignant bowel obstruction. However, data on the long-term outcomes of SEMSs are limited. OBJECTIVE The aim of this study was to compare the long-term outcomes of endoscopic stenting with those of surgery for palliation in patients with incurable obstructive colorectal cancer. DESIGNS AND SETTING: A retrospective study. PATIENTS From January 2000 to December 2008, patients with incurable obstructive colorectal cancer who were treated with SEMSs (n = 71) or palliative surgery (n = 73) were reviewed. INTERVENTIONS SEMS placement by using through-the-endoscope methods or surgery. MAIN OUTCOME MEASUREMENTS Success rates and complication rates. RESULTS Early success rates in the SEMS group and those in the surgery group were not different (95.8% vs 100%, P = .12), and the SEMS group had fewer early complications than the surgery group (15.5% vs 32.9%, P = .015). Although the patency duration of the first stent in the SEMS group was shorter than that in the surgery group (P < .001), the median patency duration after a second stenting was comparable to that of the surgery group (P = .239). There were more late complications in the SEMS group than in the surgery group (P = .028), but the rates of major complications did not differ between the 2 groups (P = .074). LIMITATIONS Retrospective and single-center study. CONCLUSIONS SEMSs were not only an effective and acceptable therapy for initial palliation of malignant colorectal obstruction, but they also showed long-term efficacy comparable to that with surgery.

Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease

Background and Aims To identify the associations of genetic and epigenetic variations in IL-23R and IL-17A with inflammatory bowel diseases (IBD). Methods The promoter and exon regions of IL-23R and IL-17A were analysed in 727 subjects (201 Crohns disease, 268 ulcerative colitis and 258 healthy controls) using DNA sequencing and denaturing high performance liquid chromatography. Transcription factor binding affinity, IL-17A mRNA expression and methylation of the IL-17A promoter were evaluated in peripheral blood mononuclear cells (PBMC) and Jurkat cells. Results A case–control analysis showed that development of Crohns disease is associated with the IL-23R variant G149R (OR 0.32, 95% CI 0.15 to 0.68) and IL-17A variant IVS1+18G>C (OR 10.65, 95% CI 1.32 to 85.89). Ulcerative colitis patients showed an association with IL-23R variants G149R (OR 0.41, 95% CI 0.21 to 0.76), IVS4+17C>T (OR 2.89, 95% CI 1.20 to 6.96) and Q3H (OR 0.61, 95% CI 0.38 to 0.99), and IL-17A variants −737C>T (OR 1.50, 95% CI 1.06 to 2.13), −197G>A (OR 0.63, 95% CI 0.40 to 0.97) and IVS1+18 G>C (OR 8.93, 95% CI 1.12 to 70.99). The −877G, −737T and −444A risk alleles of IL-17A displayed higher binding affinities with the transcription factor complex and higher expression levels of IL-17A transcripts. DNA hypomethylation of the IL-17A promoter was observed in PBMC from IBD patients with a significant inverse correlation between methylation extent of IVS1+17 and IL-17A mRNA level. Finally, Jurkat cells recovered IL-17A mRNA expression after exposure to demethylating agent. Conclusions The results provide insights into the genetic and epigenetic interactions in the IL-23R/IL-17 axis that are associated with elevated expression of IL-17 and IBD pathogenesis.

Development and Validation of Novel Diagnostic Criteria for Intestinal Behçet's Disease in Korean Patients With Ileocolonic Ulcers

OBJECTIVES:It is difficult to diagnose intestinal Behçets disease (BD) due to various extraintestinal manifestations emerging at different time points in the disease course and a lack of reliable diagnostic criteria. We conducted this study to develop and validate novel diagnostic criteria for intestinal BD.METHODS:Experts from three universities generated the preliminary diagnostic criteria for intestinal BD, and a consensus was reached using a modified Delphi method with 13 gastroenterologists participating. To validate the criteria, we recruited 12,850 consecutive patients who underwent colonoscopic examinations between January 2000 and December 2006 at Severance Hospital, Yonsei University, Seoul, Korea.RESULTS:The novel diagnostic criteria were developed on the basis of two aspects: colonoscopic findings and extraintestinal manifestations. Of the 12,850 patients, 280 with ileocolonic ulcers were enrolled for validation. At the time of initial colonoscopic examinations, patients were categorized for BD status into 4 groups: definite (84 patients), probable (67), suspected (15), and nondiagnostic (114). At the end of the follow-up period (mean, 50.9±25.7 months), intestinal BD was confirmed in 145 patients (51.8%)—84 (100%) from the definite group, 49 (73.1%) from the probable group, 10 (66.7%) from the suspected group, and 2 (1.8%) from the nondiagnostic group. The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the diagnosis probability of these criteria were 98.6, 83.0, 86.1, 98.2, and 91.1%, respectively.CONCLUSIONS:These newly proposed, simple criteria might be useful in diagnosing intestinal BD, especially in patients with ileocolonic ulcers who do not fully satisfy the diagnostic criteria of systemic BD.

Endoscopic resection for undifferentiated early gastric cancer

BACKGROUND AND OBJECTIVE Endoscopic resection (ER) has become an important curative option for early gastric cancer (EGC). However, the application of ER for undifferentiated EGC remains controversial. The aim of this study was to evaluate the clinicopathologic outcomes of ER performed in undifferentiated EGC with special reference to histopathologic subtypes to examine the feasibility of ER in undifferentiated EGC. DESIGN AND SETTING Retrospective, single-center study. PATIENTS From January 2001 to April 2007, 58 lesions in 58 patients with undifferentiated EGC (17 poorly differentiated adenocarcinoma; 41 signet-ring cell carcinoma) were treated by ER at Severance Hospital, Seoul, Korea. MAIN OUTCOME MEASUREMENTS The therapeutic efficacy of ER was assessed according to en bloc resection, histologic complete resection (CR), lateral or vertical cut end-positive (including submucosal invasion), and recurrence rates in 3- to 65-month follow-up periods. RESULTS The en bloc resection and CR rates were 84.5% and 67.2%, respectively. The en bloc and CR rates in poorly differentiated were 82.4% and 58.8%, whereas those in signet-ring cell were 85.4% and 70.7%, respectively. There were no significant differences between poorly differentiated and signet-ring cell. However, all (100%) of the histologic incomplete resections in poorly differentiated were vertical cut end-positive, whereas 83.3% of these resections in signet-ring cell were lateral cut end-positive. The recurrence rate was 5.1% in CR during the follow-up period. LIMITATIONS Retrospective, short-term follow-up period. CONCLUSIONS ER may be a feasible local treatment for undifferentiated EGC if CR can be achieved. However, a different approach is necessary between poorly differentiated and signet-ring cell before ER to prevent incomplete resection.