Joo Young Jang

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.

A nucleic acid-hydrolyzing antibody penetrates into cells via caveolae-mediated endocytosis, localizes in the cytosol and exhibits cytotoxicity

Abstract.Many natural anti-DNA antibodies (Abs) have the ability to translocate across the plasma membrane and localize in the nucleus of mammalian cells, frequently leading to cytotoxicity to cells. Herein, we report detailed intracellular trafficking routes and cytotoxicity in HeLa cells for a single chain variable fragment (scFv) Ab, 3D8, which is an anti-DNA Ab capable of hydrolyzing both DNA and RNA. The intracellular penetration of 3D8 scFv occurred by caveolae/lipid raft endocytosis. The time-course chasing experiments revealed that 3D8 scFv escaped directly from the caveosome into the cytosol and remained in the cytosol without further trafficking into endosomes, lysosomes, endoplasmic reticulum, Golgi, or nucleus. The cytosolically localized 3D8 scFv maintained its nuclease activity to hydrolyze cellular RNAs, mainly mRNAs, eventually triggering apoptotic cell death. Our results demonstrate that 3D8 scFv has a unique intracellular trafficking route of localizing in the cytosol, thereby exhibiting cytotoxicity due to its nuclease activity.

Long-term outcomes of pediatric living donor liver transplantation at a single institution

Oh SH, Kim KM, Kim DY, Lee YJ, Rhee KW, Jang JY, Chang SH, Lee SY, Kim J‐S, Choi BH, Park S‐J, Yoon CH, Ko G‐Y, Sung K‐B, Hwang G‐S, Choi K‐T, Yu E, Song G‐W, Ha T‐Y, Moon D‐B, Ahn C‐S, Kim K‐H, Hwang S, Park K‐M, Lee Y‐J, Lee S‐G. Long‐term outcomes of pediatric living donor liver transplantation at a single institution.
Pediatr Transplantation 2010: 14:870–878.

Quantitative Epstein-Barr Virus Viral Load Monitoring in Pediatric Liver Transplantation

The aim of this study was to determine whether the implementation of the quantitative Epstein-Barr virus polymerase chain reaction (qEBV-PCR) test in 2003 decreased the incidence of posttransplant lymphoproliferative disease (PTLD) and PTLD-related mortality. Of the 128 children who underwent liver transplantation between January 1994 and May 2007, 110 (85.9%) survived. Patients were divided into pre (1994 to 2002; n = 86) and post (2003 to 2007; n = 42) EBV-PCR groups. There were no between-group differences in mean age, percentage of patients < 12 months old, or seronegative for EBV. The incidence rates of primary EBV infection in the pre- and post-EBV-PCR groups were 14.0% and 33.3%, respectively (P < .05). In contrast, the pre- and post-EBV-PCR groups showed similar incidences of symptomatic EBV infection (31.3% vs 35.7%; P = .625) and PTLD (10.5% vs 9.5%; P = .869), but different survival rates (80.2% vs 97.6%; P < .001). Five of nine PTLD patients in the pre-EBV-PCR group died of PTLD, but there was no PTLD-related mortality in the post-EBV-PCR group, indicating that PTLD-related mortality decreased after qEBV-PCR monitoring. These findings suggested that frequent EBV viral load monitoring and subsequent modulation of immunosuppression can reduce PTLD and PTLD-related mortality among pediatric liver transplant patients.

Efficacy of Two Triple Eradication Regimens in Children with Helicobacter pylori Infection

Triple therapy with bismuth subsalicylate, amoxicillin, metronidazole (BAM) or with omeprazole, amoxicillin, clarithromycin (OAC) has been commonly used for the eradication of Helicobacter pylori infection. We compared the efficacy of these triple therapies in children with H. pylori infection. We retrospectively analyzed results in 233 children with H. pylori infection and treated with OAC (n=141) or BAM (n=92). Overall eradication rates of triple therapy with OAC and BAM were 74% and 85%, respectively, which showed no statistical difference. Our study showed that the triple therapy with BAM was more effective for the first-line eradication of H. pylori infection in Korean children, but has no statistical difference with OAC regimen.

Lack of common NOD2 mutations in Korean pediatric patients with inflammatory bowel disease

Crohn’s disease (CD) and ulcerative colitis (UC) are idiopathic chronic inflammatory disorders of the gastrointestinal tract. Genetic susceptibility of the host is known as a risk factor playing an important role in the pathogenesis. NOD2 gene variants are widely suspected of increasing susceptibility to CD in the Caucasian and Jewish populations. The prevalence of these diseases is increasing around the world and in Korea in particular. Here, we investigated whether the main NOD2 gene mutations are related to CD and UC in Korean children.

Living Donor Liver Transplantation in a Korean Child with Glycogen Storage Disease Type IV and a GBE1 Mutation

Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease caused by a deficient glycogen branching enzyme (GBE), encoded by the GBE1 gene, resulting in the accumulation of abnormal glycogen deposits in the liver and other tissues. We treated a 20-month-old girl who presented with progressive liver cirrhosis and was diagnosed with GSD-IV, as confirmed by GBE1 gene mutation analysis, and underwent living related heterozygous donor liver transplantation. Direct sequencing of the GBE1 gene revealed that the patient was compound heterozygous for a known c.1571G>A (p.Gly264Glu) mutation a novel c.791G>A (Arg524Gln) mutation. This is the first report of a Korean patient with GSD-IV confirmed by mutation analysis, who was treated successfully by liver transplantation.

Appendiceal Orifice Inflammation in an 8-Year-Old Girl with Ulcerative Colitis Complicating Wilson's Disease

Appendiceal orifice inflammation (AOI) may occur as a skipped lesion in ulcerative colitis (UC). Cases of ulcerative colitis complicated by Wilsons disease have also been reported. We report herein a case of AOI that occurred as a missed lesion in an 8-year-old girl with UC complicating Wilsons disease, which is rare in children.

Association of TNFSF15 polymorphisms in Korean children with Crohn's disease

Genome‐wide association studies have identified tumor necrosis factor superfamily member 15 (TNFSF15) as a Crohns disease (CD)‐related gene. The aim of this study was to evaluate the association between five TNFSF15 polymorphisms and CD in Korean children and analyze their genotypes in relation to phenotype.

The Significance of Interleukin 12 and Interferon-Gamma in Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome and Crohn’s Disease

We read with great interest the contribution by Unverdi et al.1 They reported a case of thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) that presented with Crohn’s disease (CD) and presumed microthrombosis triggered by autoimmune disorders to be the main cause in the development of TTP/HUS and CD. The first report of HUS in patients with CD also described thrombosis at the microvascular level and increased coagulability as an important mechanism involved in the two diseases.2 However, we would like to add another possible pathomechanism of TTP/HUS associated with CD. According to a previous report by Takatsuka et al.,3 interleukin (IL)-12, the T helper (Th) cell-associated cytokine, significantly increased in the patients with thrombotic microangiopathy after bone marrow transplantation (BMT) (p < 0.05), while those without microangiopathy did not show an increase in IL-12. Kakishita4 also showed that TTP and HUS after BMT could be predicted at an early stage by any increase in plasma IL-12, assuming that TTP might be related to inflammation or autoimmunity. Recently, Strober et al.5 studied the role of proinflammatory cytokines responsible for the inflammation underlying CD and announced that not only IL-12 but also interferon-gamma (IFN-γ) induced by IL-12driven Th1 cells during the development of Th17 differentiation is an important proinflammatory cytokine in CD. This explicates that anti-IL-12p40, an antibody that inhibits both the Th1 and Th17 responses, and anti-IFN-γ administration can logically be the most potent agents of anti-inflammatory cytokine for the treatment of CD. Therefore, it is possible that IL-12 and Th1mediated IFN-γ may play the central role in the pathogenesis of TTP/HUS associated with CD, and it would be helpful to measure IL-12 and IFN-γ levels during the course of the disease. However, further studies are necessary to elucidate which cytokines between Th1 and Th17 response are more active in the inflammation of TTP/HUS associated with CD. The relationship between IL-12 and IFN-γ levels and the severity of TTP/HUS or CD should also be further evaluated in the future.