Hee Shang Youn

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.

Monoclonal Antibodies against Helicobacter pylori Cross‐React with Human Tissue

H. pylori is a causative agent of chronic gastritis. However, the pathogenic mechanism by which H. pylori induces chronic inflammation and epithelial injuries in the gastric and duodenal mucosa is not well known. Investigators have recently reported that some monoclonal antibodies against H. pylori cross‐react with the gastric epithelial cells. So, there exists the possibility that the autoimmune mechanism may be involved in the pathogenesis of chronic gastritis caused by H. pylori. The purpose of his study is to investigate whether the antibodies against H. pylori react with human tissues or not, using a large panel of monoclonal antibodies.

Invasiveness of Helicobacter pylori into Human Gastric Mucosa

Background. Helicobacter pylori has generally been observed only in the gastric mucous layer or in the spaces between gastric mucus‐secreting cells and not in the gastric epithelial cells or in the lamina propria. The purpose of this study is to determine whether H. pylori invades the gastric mucosa, using an immunoelectron microscopical examination of human gastric mucosa infected with H. pylori.

Immunochip Analysis Identification of 6 Additional Susceptibility Loci for Crohn's Disease in Koreans

Background:Crohns disease (CD) is an intractable inflammatory bowel disease of unknown cause. Recent genome-wide association studies of CD in Korean and Japanese populations suggested marginal sharing of susceptibility loci between Caucasian and Asian populations. As the 7 identified loci altogether explain 5.31% of the risk for CD, the objective of this study was to identify additional CD susceptibility loci in the Korean population. Methods:Using the ImmunoChip custom single-nucleotide polymorphism array designed for dense genotyping of 186 loci identified through GWAS, we analyzed 722 individuals with CD and 461 controls for 96,048 SNP markers in the discovery stage, followed by validation in an additional 948 affected individuals and 977 controls. Results:We confirmed 6 previously reported loci in Caucasian: GPR35 at 2q37 (rs3749172; P = 5.30 × 10−11, odds ratio [OR] = 1.45), ZNF365 at 10q21 (rs224143; P = 2.20 × 10−9, OR = 1.38), ZMIZ1 at 10q22 (rs1250569; P = 3.05 × 10−7, OR = 1.30), NKX2-3 at 10q24 (rs4409764; P = 7.93 × 10−8, OR = 1.32), PTPN2 at 18p11 (rs514000; P = 9.00 × 10−8, OR = 1.33), and USP25 at 21q11 (rs2823256; P = 2.49 × 10−7, OR = 1.35), bringing the number of known CD loci (including 3 in the HLA) in Koreans to 15. The 6 additional loci increased the total genetic variance for CD risk from 5.31% to 7.27% in Koreans. Conclusions:Although the different genetic backgrounds of CD between Asian and Western countries has been well established for the major susceptibility genes, our findings of overlapping associations offer new insights into the genetic architecture of CD.

Gut Microbiota and Clinical Disease: Obesity and Nonalcoholic Fatty Liver Disease

The prevalence of obesity is increasing worldwide. Obesity can cause hyperlipidemia, hypertension, cardiovascular diseases, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Many environmental or genetic factors have been suggested to contribute to the development of obesity, but there is no satisfactory explanation for its increased prevalence. This review discusses the latest updates on the role of the gut microbiota in obesity and NAFLD.

Prevalence of human parechovirus and enterovirus in cerebrospinal fluid samples in children in Jinju, Korea.

Purpose Human parechovirus (HPeV) and enterovirus (EV) are causative agents of a sepsis-like illness in neonates and of infections of the central nervous system in young children. The objectives of this study were to assess the prevalence of HPeV3 and EV infection in young children with a sepsis-like illness or with meningitis in Jinju, Korea. Methods Cerebrospinal fluid (CSF) samples were collected from 267 patients (age range, 1 day to 5 years) and assessed for HPeV and EV by performing reverse transcription polymerase chain reaction assay. Amplification products of the VP3/VP1 region of HPeV and of the VP1 region of EV were sequenced to identify the virus type. Results HPeV and EV were detected in 3.4% and 7.5% of the total CSF samples assessed, respectively. The age distribution of EV-positive patients (median age, 1.4 months) had a significantly broader range than that of HPeV-positive patients (median age, 7.8 months). The peak seasons for HPeV and EV infection were spring and summer, respectively. The clinical symptoms for HPeV and EV infection were similar, and fever was the most common symptom. Pleocytosis was detected in 22.2% of HPeV-positive patients and 35.5% of EV-positive patients. The VP3/VP1 gene sequence of the nine Korean strains clustered most closely with the Japanese strain (AB759202). Conclusion The data indicate that HPeV infection is predominant in young infants (<6 months) and that meningitis without pleocytosis was caused by both HPeV and EV infection in children.

Correlation between Positive Rate and Number of Biopsy Samples on Urease Test in Childhood Helicobacter pylori Infection

To identify the correlation between the number of gastric biopsy samples and the positive rate, we compared the results of urease test using one and three biopsy samples from each 255 children who underwent gastroduodenoscopy at Gyeongsang National University Hospital. The children were divided into three age groups: 0-4, 5-9, and 10-15 yr. The gastric endoscopic biopsies were subjected to the urease test. That is, one and three gastric antral biopsy samples were collected from the same child. The results of urease test were classified into three grades: Grade 0 (no change), 1 (6-24 hr), 2 (1-6 hr), and 3 (<1 hr). The positive rate of urease test was increased by the age with no respect to the number of gastric biopsy samples (one biopsy P = 0.001, three biopsy P < 0.001). The positive rate of the urease test was higher on three biopsy samples as compared with one biopsy sample (P < 0.001). The difference between one and three biopsy samples was higher in the children aged 0-9 yr. Our results indicate that the urease test might be a more accurate diagnostic modality when it is performed on three or more biopsy samples in children.

Association between Gastric pH and Helicobacter pylori Infection in Children.

Purpose To assess gastric pH and its relationship with urease-test positivity and histological findings in children with Helicobacter pylori infection. Methods Fasting gastric juices and endoscopic antral biopsy specimens were collected from 562 children and subjected to the urease test and histopathological examination. The subjects were divided into 3 age groups: 0-4, 5-9, and 10-15 years. The histopathological grade was assessed using the Updated Sydney System, while the gastric juice pH was determined using a pH meter. Results The median gastric juice pH did not differ significantly among the age groups (p=0.655). The proportion of individuals with gastric pH >4.0 was 1.3% in the 0-4 years group, 6.1% in the 5-9 years group, and 8.2% in 10-15 years (p=0.101). The proportions of moderate and severe chronic gastritis, active gastritis, and H. pylori infiltration increased with age (p<0.005). Urease-test positivity was higher in children with hypochlorhydria (77.8%) than in those with normal gastric pH (31.7%) (p<0.001). Chronic and active gastritis were more severe in the former than the latter (p<0.001), but the degree of H. pylori infiltration did not differ (20.9% vs. 38.9%; p=0.186). Conclusion Gastric pH while fasting is normal in most children regardless of age. Urease-test positivity may be related to hypochlorhydria in children, and hypochlorhydria is in turn related to H. pylori infection.

Antibiotics resistance of Helicobacter pylori and treatment modalities in children with H. pylori infection

Pediatric infection with Helicobacter pylori may occur early in childhood and persist lifelong. Global pediatric clinical studies have reported a decreasing tendency in the overall rate of H. pylori eradication. In pediatric patients with H. pylori infection, pediatric patients with peptic ulcer, and the first-degree relatives of patients with a history of gastric cancer, it is commonly recommended that H. pylori strains be eradicated. Antibiotic drug resistance to H. pylori, which has been reported to vary widely between geographic regions, is mainly associated with treatment failure in these patients. It is therefore imperative that the antibiotic resistance rates of H. pylori in children and adolescents be meticulously monitored across countries and throughout geographic regions. This paper particularly focuses on the antibiotic drug resistance of H. pylori and the thearpy of pediatric H. pylori infection cases.

Correlations between the CagA Antigen and Serum Levels of Anti-Helicobacter pylori IgG and IgA in Children

We tested correlations between anti-Helicobacter pylori IgG and IgA levels and the urease test, anti-CagA protein antibody, degree of gastritis, and age. In total, 509 children (0–15 years) were enrolled. Subjects were stratified as 0–4 years (n = 132), 5–9 years (n = 274), and 10–15 years (n = 103) and subjected to the urease test, histopathology, ELISA, and western blot using whole-cell lysates of H. pylori strain 51. The positivity rate in the urease test (P = 0.003), the degree of chronic gastritis (P = 0.021), and H. pylori infiltration (P < 0.001) increased with age. The median titer for anti-H. pylori IgG was 732.5 IU/mL at 0–4 years, 689.0 IU/mL at 5–9 years, and 966.0 IU/mL at 10–15 years (P < 0.001); the median titer for anti-H. pylori IgA was 61.0 IU/mL at 0–4 years, 63.5 IU/mL at 5–9 years, and 75.0 IU/mL at 10–15 years (P < 0.001). The CagA-positivity rate was 26.5% at 0–4 years, 36.5% at 5–9 years, and 46.6% at 10–15 years for IgG (P = 0.036), and 11.3% at 0–4 years, 18.6% at 5–9 years, and 23.3% at 10–15 years for IgA (P < 0.001). Anti-H. pylori IgG and IgA titers increased with the urease test grade, chronic gastritis degree, active gastritis, and H. pylori infiltration. Presence of CagA-positivity is well correlated with a high urease test grade and high anti-H. pylori IgG/IgA levels.