Suk-Kyun Yang

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.

Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986-2005: a KASID study.

Background: Crohns disease (CD) and ulcerative colitis (UC) are considered rare diseases in developing countries. We have evaluated the incidence and prevalence of CD and UC over time in a district of Seoul, Korea. Methods: A population‐based study was performed from 1986 to 2005 in the Songpa‐Kangdong district of Seoul. To recruit patients as completely as possible, multiple information sources, including all medical facilities in the study area and 3 referral centers nearby but outside the study area, were used. Results: During the 20‐year study period, 138 incident cases of CD (102 men, 36 women) and 341 incident cases of UC (170 men, 171 women) were identified. For the 20‐year period, the adjusted mean annual incidence rates of CD and UC per 100,000 inhabitants were 0.53 (95% CI 0.44–0.62) and 1.51 (95% CI 1.34–1.67), respectively. When analyzed by 5‐year intervals, the mean annual incidence rates of CD and UC increased significantly, from 0.05 and 0.34 per 100,000 inhabitants, respectively, in 1986–1990 to 1.34 and 3.08 per 100,000 inhabitants, respectively, in 2001–2005. The adjusted prevalence rates of CD and UC per 100,000 inhabitants on December 31, 2005, were 11.24 (95% CI 9.29–13.18) and 30.87 (95% CI 27.47–34.27), respectively. Conclusions: The incidence and prevalence of CD and UC in Seoul, Korea, are still low compared with those in Western countries, but are rapidly increasing.

Crohn Disease of the Small Bowel: Comparison of CT Enterography, MR Enterography, and Small-Bowel Follow-Through as Diagnostic Techniques

PURPOSE To prospectively compare the accuracy of computed tomographic (CT) and magnetic resonance (MR) enterography and small-bowel follow-through (SBFT) examination for detection of active small-bowel inflammation and extraenteric complications in patients with Crohn disease (CD). MATERIALS AND METHODS The institutional review board approved the study protocol; informed consent was obtained from all participants. Thirty-one consecutive patients who had CD or who were suspected of having CD underwent CT and MR enterography, SBFT, and ileocolonoscopy. Two independent readers reviewed CT and MR enterographic and SBFT images for presence of active terminal ileitis and extraenteric complications. Accuracy values of CT and MR enterography and SBFT for identification of active terminal ileitis were evaluated with the receiver operating characteristic method, with ileocolonoscopic findings as the reference standard. Sensitivity values of CT and MR enterography and SBFT for detection of extraenteric complications were compared by using the McNemar test, with results of imaging studies, surgery, and physical examination as reference standards. RESULTS The study population included 30 patients (17 men, 13 women; mean age, 29.0 years) with CD. Differences in areas under the receiver operating characteristic curves for CT enterography (0.900 and 0.894), MR enterography (0.933 and 0.950), and SBFT (0.883 and 0.928) for readers 1 and 2, respectively, in the detection of active terminal ileitis were not significant (P > .017). Sensitivity values for detection of extraenteric complications were significantly higher for CT and MR enterography (100% for both) than they were for SBFT (32% for reader 1 and 37% for reader 2) (P < .001). CONCLUSION Because MR enterography has a diagnostic effectiveness comparable to that of CT enterography, this technique has potential to be used as a radiation-free alternative for evaluation of patients with CD.

Incidence and prevalence of ulcerative colitis in the Songpa-Kangdong district, Seoul, Korea, 1986-1997.

Background and Aims : Ulcerative colitis (UC) is regarded as a rare disease in developing countries, but accurate data are generally lacking. We performed the present study to evaluate the incidence and prevalence of UC in Korea.

A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia

Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohns disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; Pcombined = 4.88 × 10−94). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10−4). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.

Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy

We performed a genome-wide association study with 706 individuals with leprosy and 5,581 control individuals and replicated the top 24 SNPs in three independent replication samples, including a total of 3,301 individuals with leprosy and 5,299 control individuals from China. Two loci not previously associated with the disease were identified with genome-wide significance: rs2275606 (combined P = 3.94 × 10−14, OR = 1.30) on 6q24.3 and rs3762318 (combined P = 3.27 × 10−11, OR = 0.69) on 1p31.3. These associations implicate IL23R and RAB32 as new susceptibility genes for leprosy. Furthermore, we identified evidence of interaction between the NOD2 and RIPK2 loci, which is consistent with the biological association of the proteins encoded by these genes (NOD2-RIPK2 complex) in activating the NF-κB pathway as a part of the host defense response to infection. Our findings have expanded the biological functions of IL23R by uncovering its involvement in infectious disease susceptibility and suggest a potential involvement of autophagocytosis in leprosy pathogenesis. The IL23R association supports previous observations of the marked overlap of susceptibility genes for leprosy and Crohns disease, implying common pathogenesis mechanisms.

Clinical Features and Natural History of Ulcerative Colitis in Korea

Background The clinical characteristics of ulcerative colitis (UC) in Asian populations have not been well characterized. We therefore investigated the clinical features and natural history of UC in Korea. Methods We retrospectively analyzed 304 Korean patients with UC first diagnosed at the Asan Medical Center between June 1989 and August 2005. Results The male‐to‐female ratio of the patients was 0.94:1, and their median age at diagnosis was 40.0 years (range, 12‐72 years). At diagnosis, proctitis was noted in 134 patients (44.1%), left‐sided colitis in 69 patients (22.7%), and extensive colitis in 101 patients (33.2%). Disease activity at diagnosis was mild in 149 patients (49.0%), moderate in 125 patients (41.1%), and severe in 26 patients (8.6%). In addition, 4 asymptomatic patients (1.3%) were detected as a result of a screening colonoscopy. Clinical remission after the first attack was documented in 97.4% of patients. The cumulative relapse rate after 1, 5, and 10 years was 30.2%, 72.0%, and 88.4%, respectively. The cumulative risk of proximal extension in patients with proctitis or left‐sided colitis was 33.0% after 5 years and 44.5% after 10 years. The cumulative probability of colectomy was 2.0% after 1 year, 2.8% after 3 years, and 3.3% after 5 to 15 years. The cumulative survival rate after 1, 5, and 10 years was 100%, 99.4%, and 97.4%, respectively. Conclusions The clinical features of Korean UC patients at diagnosis are similar to those of Westerners. However, UC in Koreans may have a milder course than in Westerners, as indicated by the lower rate of colectomy among Koreans. (Inflamm Bowel Dis 2007)

A Prospective Comparison of Standard-Dose CT Enterography and 50% Reduced-Dose CT Enterography With and Without Noise Reduction for Evaluating Crohn Disease

OBJECTIVE The purpose of this study was to prospectively compare standard-dose CT enterography (CTE) and 50% reduced-dose CTE, obtained with and without an image noise reduction method, in the evaluation of Crohn disease. SUBJECTS AND METHODS Ninety-two patients (69 men and 23 women; mean age [± SD], 31.2 ± 9.5 years) with Crohn disease underwent CTE. Using a dual-source scanner equipped with a proprietary noise reduction method (iterative reconstruction in image space [IRIS]), three sets of CTE images were obtained: standard-dose filtered back projection (FBP) (i.e., weighted FBP), low-dose (i.e., 50% reduction) FBP, and low-dose IRIS CTE. Image noise was measured. Two independent radiologists evaluated subjective image quality (1 [worst] to 4 [best]) and findings of active Crohn disease in the terminal small-bowel segment, including mural hyperenhancement, thickening and stratification, comb sign, and increased perienteric fat attenuation (1 [definitely absent] to 5 [definitely present]). RESULTS The mean (± SD) volume CT dose index (CTDI(vol)) was 7.0 ± 0.9 mGy and 3.5 ± 0.5 mGy for standard-dose and low-dose CTE examinations, respectively. The mean (± SD) image noise for standard-dose FBP, low-dose FBP, and low-dose IRIS CTE was 10.6 ± 1.7 HU, 13.9 ± 2.1 HU, and 9.7 ± 1.7 HU, respectively (p < 0.001 for all comparisons). Both assessors found that image quality was poorer with low-dose (mean grade (± SD), 2.3 ± 0.4-2.7 ± 0.5) than in standard-dose (3 ± 0) CTE (p < 0.01), and one found that image quality was poorer with low-dose IRIS (2.3 ± 0.4) than with low-dose FBP (2.7 ± 0.5) CTE (p < 0.01). Low-dose (with or without IRIS) and standard-dose CTE showed ≥ 85% agreement (one-sided 95% CI ≥ 77%) in interpretation of bowel findings. CONCLUSION Low-dose CTE using 50% reduced-dose performed similarly to standard-dose CTE in identifying findings of enteric inflammation of Crohn disease. Although a noise reduction method markedly reduced image noise in half-dose examinations, its effect on image quality was not as great and was reader dependent.

Endoscopic submucosal dissection for treatment of rectal carcinoid tumors

BACKGROUND Conventional EMR has been the endoscopic treatment of choice for rectal carcinoid tumors. However, histologically complete resection often cannot be achieved because the carcinoid tumors are located mainly in the submucosal layer. Endoscopic submucosal dissection (ESD), a new method for large colorectal neoplasm resection, may overcome this problem. OBJECTIVE To compare ESD with EMR for the endoscopic treatment of rectal carcinoid tumors. DESIGN A prospective case series with comparison to retrospective controls. SETTING Tertiary-care center. PATIENTS From January 2007 to January 2009 we prospectively enrolled consecutive patients with rectal carcinoid tumors less than 16 mm in diameter and with no regional lymph node enlargement shown by CT or EUS. For comparison, we retrospectively randomly selected patients who had undergone EMR for treatment of rectal carcinoid tumors between March 2000 and December 2006. INTERVENTION We performed ESD of rectal carcinoid tumors in prospectively enrolled patients. MAIN OUTCOME MEASUREMENTS Rate of en bloc resection, rate of histologically complete resection, incidence of complications, and length of procedures. RESULTS The ESD group contained 31 patients (18 male, 13 female; age range 34-65 years), and the EMR group contained 62 patients (42 male, 20 female; age range 22-77 years). Both groups had similar mean rectal carcinoid tumor diameters (ESD 6.8 +/- 2.4 mm, EMR 7.3 +/- 2.2 mm; P = .106). Resection time was longer in the ESD group than in the EMR group (11.4 +/- 3.7 minutes vs 4.2 +/- 3.2 minutes, P < .001). The en bloc resection rate was 100% (31 of 31) in the ESD group and 95.2% (59 of 62) in the EMR group (P = .213). The histologically complete resection rate was 90.3% (28 of 31) in the ESD group and 71.0% (44 of 62) in the EMR group (P = .035). Suspected perforation occurred in 1 ESD patient (3.2%) and in 1 EMR patient (1.6%), and both patients were successfully managed by conservative measures. Immediate bleeding occurred in 1 ESD patient (3.2%) and in 4 EMR patients (6.5%); all instances of bleeding were controlled endoscopically. LIMITATIONS Retrospective control study and limited experience at a single center. CONCLUSION Compared with EMR, ESD resulted in a higher histologically complete resection rate, had a similar complication rate, and took slightly longer to perform. Given the advantages of complete resection, these findings indicate that ESD may be considered for treatment of rectal carcinoid tumors.

Appendiceal orifice inflammation as a skip lesion in ulcerative colitis: an analysis in relation to medical therapy and disease extent☆☆☆

BACKGROUND Although several reports have claimed that the appendix can be involved as a skip lesion in ulcerative colitis, they do not exclude the possibility that this skip lesion occurs as a result of medical therapy. Also, little is known about the relation between the presence of appendiceal orifice inflammation and the extent of the disease. METHODS The presence of appendiceal orifice inflammation was prospectively assessed both endoscopically and histologically in 94 patients with active ulcerative colitis, the extent of whose disease had not been beyond the hepatic flexure. To evaluate the effect of prior medical therapy on the prevalence of appendiceal orifice inflammation, all cases were divided into two groups. Group A consisted of 66 patients who had been treated before inclusion; group B was composed of 28 patients newly diagnosed at inclusion. RESULTS Appendiceal orifice inflammation was diagnosed in 24 (26%) of 94 patients with active subtotal ulcerative colitis, with no statistical difference observed between group A (23%) and group B (32%). In all 94 patients, the frequency of appendiceal orifice inflammation decreased significantly as the extent of disease increased, i.e., 37% in proctitis (n = 49), 17% in left-sided colitis (n = 36), and 0% in extensive colitis (n = 9) (p < 0.05). CONCLUSIONS Appendiceal orifice inflammation as a skip lesion of ulcerative colitis is not rare, is more frequently observed in patients with less extensive disease, and is not the result of patchy improvement due to medical therapy.