Sang Hyoung Park

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.

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)

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.

Clinical features and long-term prognosis of Crohn's disease in Korea

Abstract Objective. Recent studies have suggested that the clinical characteristics and genetic background of Crohns disease (CD) patients differ between Asian and Caucasian individuals. However, the clinical features and course of CD in Asian patients remain unclear. Therefore, we investigated the clinical features and long-term prognosis of CD in a Korean population. Material and methods. We retrospectively analyzed 278 Korean patients with CD first diagnosed at the Asan Medical Center between March 1991 and February 2007. Results. The male-to-female ratio was 2.2:1 and the median age at diagnosis was 23 years. The median duration of follow-up was 71 months (range, 1–210 months). At diagnosis, 187 patients (67.3%) had disease in both small bowel and colon, 68 (24.4%) had isolated small bowel disease, and 23 (8.3%) had isolated colonic disease. The number of patients with stricturing or penetrating behavior as defined by the Montreal classification increased from 87 (31.3%) at diagnosis to 141 (50.7%) at final evaluation. One hundred and thirty patients (46.8%) experienced perianal fistulas before and/or after diagnosis of CD. A total of 71 patients (25.5%) underwent intestinal resection and the cumulative probability of intestinal resection after 1, 5, and 10 years was 15.5%, 25.0%, and 32.8%, respectively. Conclusions. Korean CD patients differed from Western patients in gender distribution, disease location, and perianal fistula occurrence. Korean CD patients may also have better clinical courses than Western patients, as indicated by the lower intestinal resection rate.

Contribution of IL23R but not ATG16L1 to Crohn's disease susceptibility in Koreans

Background: Recent genome‐wide association studies in Caucasian populations identified IL23R and ATG16L1 as susceptibility genes to Crohns disease (CD). We tested 5 IL23R single nucleotide polymorphisms (SNPs) and 12 ATG16L1 SNPs in Korean patients to determine whether these genes are associated with susceptibility to CD in a non‐Caucasian population. Methods: We analyzed 5 IL23R SNPs and 12 ATG16L1 SNPs in 380 patients with CD and 380 healthy controls. Results: Two IL23R gene variants, an intronic SNP rs1004819 and intergenic SNP rs1495465, showed significant associations with CD; the adjusted odds ratio (aOR) for rs1004819 was 1.822 (95% confidence interval [CI] = 1.164–2.852, P = 0.009) and aOR for rs1495965 was 1.650 (95% CI = 1.102–2.471, P = 0.015). The genotype–phenotype analysis showed subphenotype specificity to stricturing and penetrating behaviors. On the other hand, none of the 12 ATG16L1 SNPs showed any positive association with CD in Koreans. The contribution of IL23R variants in Korean CD patients overall is low in comparison with studies of Caucasian. Conclusions: Our data in Koreans support the previous Caucasian reports of an association of the IL23R gene with CD. (Inflamm Bowel Dis 2009)

Long-term Prognosis of Crohn's Disease and Its Temporal Change Between 1981 and 2012: A Hospital-based Cohort Study from Korea

Background:To date, no large-scale studies have evaluated the prognosis of Crohns disease (CD) over a period of 3 decades in non-Caucasian populations. The aims of this study were to update the current information on the long-term prognosis of CD using a large series of patients and to evaluate changes in treatment paradigms over time and their impact on the prognosis of CD in Korea. Methods:We retrospectively analyzed 2043 Korean patients with CD who visited the Asan Medical Center. The study subjects were divided into 3 groups according to the year of diagnosis (cohort 1: 1981–2000, cohort 2: 2001–2005, and cohort 3: 2006–2012). Results:Azathioprine/6-mercaptopurine and anti–tumor necrosis factor agents have been used increasingly more frequently and earlier over the past 30 years, with a 5-year cumulative probability of prescription of 28.9% and 1.4%, respectively, in cohort 1 and 88.1% and 23.7%, respectively, in cohort 3 (P < 0.001). A total of 726 patients (35.5%) underwent intestinal resection, with a cumulative probability of intestinal resection 10, 20, and 30 years after diagnosis of 43.5%, 70.0%, and 76.1%, respectively. The cumulative probability of surgery was significantly lower in cohort 3 than in cohort 1 (P = 0.012). Early use of azathioprine/6-mercaptopurine was significantly associated with delayed need for intestinal resection by multivariate Cox analysis (hazard ratio: 0.63, 95% confidence interval: 0.46–0.85). Conclusions:Korean patients with CD may have a similar clinical course to Westerners, as indicated by the intestinal resection rate. The surgery rate has decreased over time, and early use of azathioprine/6-mercaptopurine was related to its decrease.

Post-marketing study of biosimilar infliximab (CT-P13) to evaluate its safety and efficacy in Korea

Objective: To evaluate the safety and efficacy of CT-P13 (Remsima®) in patients with inflammatory bowel disease (IBD) in South Korea. Methods: This post-marketing study included patients with active moderate-to-severe Crohn’s disease (CD), fistulizing CD (FCD), or moderate-to-severe ulcerative colitis (UC) treated with CT-P13 and followed for 30 weeks. Assessments included treatment-emergent adverse events (TEAEs) and disease-specific clinical response and remission. Results: No unexpected TEAEs were observed in the 173 patients recruited to date. TEAEs occurred in 18.1, 16.7, and 26.9% of CD, FCD, and UC patients, respectively. Treatment-related TEAEs occurred in 10% of patients and were mostly mild-moderate in severity. There were five serious TEAEs (two infusion-related reactions, two infections, one abdominal pain) and no cases of malignancy, pneumonia, or death. Positive outcomes for response/remission were reported regardless of whether patients had received prior infliximab or not. Conclusion: CT-P13 was well tolerated and efficacious in patients with IBD.

Genome-Wide Association Study of Ulcerative Colitis in Koreans Suggests Extensive Overlapping of Genetic Susceptibility With Caucasians

Background:Recent genome-wide association studies and meta-analyses have identified 47 susceptibility loci for ulcerative colitis (UC) in Caucasian populations. A previous genome-wide association study of UC in a Japanese population suggested marginal sharing of susceptibility loci between Caucasian and Asian populations. We performed a genome-wide association studies to identify UC susceptibility loci in a Korean population and further comparative study. Methods:We analyzed 581,060 autosomal single-nucleotide polymorphisms (SNPs) in 388 individuals with UC and 739 control subjects in the discovery stage. For the validation, 64 suggestive SNPs were analyzed in an additional 417 affected individuals and 732 control subjects. Results:Three genetic loci were validated for significant association, and all were previously reported in Caucasians including the major histocompatibility complex region (top SNP, rs9271366; P = 1.03 × 10−18, odds ratio [OR] = 2.10), 16q24.1 (rs16940186; P = 4.39 × 10−10, OR = 1.56), and RNF186-OTUD3-PLA2G2E at chromosome arm 1p36.13 (top SNP, rs4654903 in OTUD3; P = 7.43 × 10−9, OR = 0.64). Although failed to reach genome-wide statistical significance, 2 additional loci previously reported in Caucasians including rs17085007 at chromosome arm 13q12 and JAK2 at chromosome arm 9p24 were significant after Bonferroni correction (Pcorrected = 0.0016 and Pcorrected = 0.0056, respectively). FOS, UBE2L3, the JAK2 gene region, and rs1297265 at chromosome arm 21q21.1 likely play a role in both Crohn’s disease and UC. Conclusions:Our data support the biologic significance of the overlapping loci for UC between Caucasian and Korean populations. Our data suggest that genetic associations for UC tend to overlap more extensively among different ethnic groups than those for Crohn’s disease, which shows well-established dependence on ethnicity.

Diffusion-weighted MR Enterography for Evaluating Crohnʼs Disease: How Does It Add Diagnostically to Conventional MR Enterography?

Background:Diffusion-weighted imaging (DWI) is a novel technique to evaluate bowel inflammation in Crohns disease (CD). It is unknown whether and how DWI adds to the accuracy of conventional magnetic resonance enterography (MRE). Methods:Fifty consecutive adults suspected of CD prospectively underwent clinical assessment, conventional MRE and DWI at b = 900 sec/mm2 without water enema, and ileocolonoscopy within 1 week. MRE images were interpreted with proper blinding. Forty-four patients finally diagnosed with CD (male:female, 34:10; 26.9 ± 6.1 yr) were analyzed. The per-segment accuracy of MRE for diagnosing active CD was assessed in the terminal ileum, right colon, and rectum using location-by-location matching with endoscopy as the reference standard. Results:The study evaluated 58 bowel segments with deep or superficial ulcers, 34 with aphthae, erythema, or edema only, and 35 without inflammation. Conventional MRE + DWI was more sensitive for bowel inflammation than conventional MRE alone (83% [76/92] versus 62% [57/92]; P = 0.001) largely because of additional detection of aphthae, erythema, or edema. The sensitivities for deep and overt ulcers were similar regardless of DWI, ranging from 88% to 97%. Conventional MRE + DWI was less specific than conventional MRE alone (60% [21/35] versus 94% [33/35]; P < 0.001), mostly because of many false positives in the colorectum. Positive DWI findings in the bowel showing active inflammation on conventional MRE were associated with higher Crohns disease endoscopic index of severity score (P = 0.021) and deep ulcers (P = 0.01; diagnostic odds ratio, 12). Conclusions:DWI performed without water enema is not useful for incremental detection of bowel inflammation. DWI may help identify more severe inflammation among bowel segments showing active inflammation on conventional MRE.

The diagnostic value of a digital rectal examination compared with high-resolution anorectal manometry in patients with chronic constipation and fecal incontinence.

Objectives:Digital rectal examination (DRE) is a simple clinical method to diagnose anorectal disorders. High-resolution antorectal manometry (HRAM) based on a spatiotemporal plot is expected to promote improved diagnostic accuracy. However, there are no reports comparing the effectiveness of DRE and HRAM. The aim of our study was therefore to evaluate the diagnostic value of DRE compared with HRAM.Methods:A total of 309 consecutive patients with chronic constipation (n=268) or fecal incontinence (n=41) who underwent a standardized DRE, HRAM, and balloon expulsion test were enrolled in this study. The diagnostic yield of DRE compared with HRAM was determined, and agreement between DRE and HRAM data was evaluated.Results:Of the constipated patients, 207 (77.2%) were diagnosed with dyssynergia using HRAM. The sensitivity, specificity, and positive predictive value of DRE in the diagnosis of dyssynergia were 93.2%, 58.7%, and 91.0%, respectively, and moderate agreement was seen between the two modalities (κ-coefficient =0.542, P<0.001). In patients with fecal incontinence, there was moderate agreement in terms of anal squeeze pressure between the two modalities (κ-coefficient =0.418, P=0.006); however, there was poor agreement for anal resting tone (κ-coefficient =0.079, P=0.368).Conclusions:DRE shows high sensitivity and positive predictive value in detecting dyssynergia compared with HRAM, and could therefore be used as a bedside screening test for the diagnosis of this disorder. Further studies are warranted to evaluate the correlation between DRE and HRAM in assessing anal sphincter pressure.