Yuta Fuyuno

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.

Long-term effect of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic resection of early gastric cancer.

BACKGROUND A prospective, randomized trial proved that Helicobacter pylori eradication significantly reduces the incidence of metachronous gastric cancer during a 3-year follow-up. OBJECTIVE To investigate the long-term effect of H pylori eradication on the incidence of metachronous gastric cancer after endoscopic resection of early gastric cancer. DESIGN Retrospective, multicenter study. SETTING Kyushu University Hospital and 6 other hospitals in Fukuoka Prefecture, Japan. PATIENTS AND INTERVENTIONS Follow-up data for 268 H pylori-positive patients who had undergone endoscopic resection of early gastric cancer were retrospectively investigated. A total of 177 patients underwent successful H pylori eradication (eradicated group), whereas 91 had persistent H pylori infection (persistent group). MAIN OUTCOME MEASUREMENTS The incidence of metachronous gastric cancer was compared in these 2 groups. RESULTS When the follow-up period was censored at 5 years, the incidence rate in the eradicated group was lower than that observed in the persistent group (P = .007). During the overall follow-up period ranging from 1.1 to 11.1 years (median 3.0 years), metachronous gastric cancer developed in 13 patients (14.3%) in the persistent group and in 15 patients (8.5%) in the eradicated group (P = .262, log-rank test). Based on a multivariate logistic regression analysis, baseline severe mucosal atrophy and a follow-up of more than 5 years were found to be independent risk factors for the development of metachronous gastric cancer. LIMITATIONS Retrospective study. CONCLUSIONS H pylori eradication does not reduce the incidence of metachronous gastric cancer. H pylori eradication should be performed before the progression of gastric mucosal atrophy.

A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter

Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn’s disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of “chronic enteropathy associated with SLCO2A1 gene” (CEAS).

Giant Inflammatory Polyposis of the Cecum With Repeated Intussusception in Ulcerative Colitis: Report of a Case

Giant Inflammatory Polyposis of the Cecum With Repeated Intussusception in Ulcerative Colitis: Report of a Case

A genome-wide association study of late-onset Alzheimer's disease in a Japanese population

Objective Although a number of genome-wide association studies (GWASs) of late-onset Alzheimer’s disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations. Design To discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-&egr;4 status to eliminate the established effect of APOE region. Results Our data indicated that 18p11.32 (rs1992269, P=9.77×10−7), CNTNAP2 (rs802571, P=1.26×10−6), and 12q24.23 (rs11613092, P=6.85×10−6) were suggestive loci for susceptibility to LOAD. Conclusion We identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective.

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn's disease in the Japanese population

We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn’s diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10−2 and P=8.40 × 10−3, respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10−2, P=3.88 × 10−2 and P=2.04 × 10−2, respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.

Therapeutic Strategy for Crohn's Disease with a Loss of Response to Infliximab: A Single-Center Retrospective Study

Background/Aims: Infliximab (IFX) is an effective treatment for maintaining clinical remission in patients with initially moderate-to-severe Crohns disease (CD). However, a certain number of patients become unresponsive to IFX, subsequently requiring intensified therapy. The aim of this study was to compare the short- and long-term therapeutic efficacy of intensified regimens in CD patients who fail to respond to IFX. Methods: The clinical courses of 33 CD patients who failed to respond to treatment with IFX were investigated retrospectively. An intensified regimen involving doubling the dose of IFX was chosen in 13 patients (DD group) versus shortening the IFX interval in 13 patients (SI group) and switching to adalimumab (ADA) in 7 patients (SA group). Results: The clinical response and rate of clinical remission at 4 weeks were 62 and 54% in the DD group, 77 and 62% in the SI group and 57 and 43% in the SA group, respectively (p = 0.59 for clinical response, p = 0.90 for clinical remission). The rate of sustained remission at 48 weeks was 44% in the DD group, 54% in the SI group and 33% in the SA group (p = 0.88). Conclusion: The short- and long-term efficacy of doubling the dose of IFX, shortening the interval of IFX or switching to ADA is similar for CD patients who no longer respond to IFX.

Comparison of the microbial community structure between inflamed and non-inflamed sites in patients with ulcerative colitis

The gut microbiota is suggested to play an important role in the pathogenesis of ulcerative colitis (UC). However, interindividual and spatial variations hamper the identification of UC‐related changes. We thus investigated paired mucosa‐associated microbiota obtained from both inflamed and non‐inflamed sites of UC patients and corresponding sites of non‐inflammatory bowel disease (IBD) controls.

Genetic analysis is helpful for the diagnosis of small bowel ulceration

The widespread use of capsule endoscopy and balloon-assisted endoscopy has provided easy access for detailed mucosal assessment of the small intestine. However, the diagnosis of rare small bowel diseases, such as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE), remains difficult because clinical and morphological features of these diseases are obscure even for gastroenterologists. In an issue of this journal in 2017, Hwang et al reviewed and summarized clinical and radiographic features of 20 patients with an established diagnosis of CMUSE. Recently, recessive mutations in the PLA2G4A and SLCO2A1 genes have been shown to cause small intestinal diseases. The small bowel ulcers in each disease mimic those in the other and furthermore those found in nonsteroidal anti-inflammatory drug-induced enteropathy. These recent and novel findings suggest that a clinical diagnosis exclusively based on the characteristics of small bowel lesions is possibly imprecise. Genetic analyses seem to be inevitable for the diagnosis of rare small bowel disorders such as CMUSE.

Capsule endoscopy findings for the diagnosis of Crohn’s disease: a nationwide case–control study

BackgroundCapsule endoscopy can be used to identify the early stage of small bowel Crohn’s disease (CD). We evaluated significant small bowel capsule endoscopy (SBCE) findings that can lead to early diagnosis of CD.MethodsWe retrospectively accumulated clinical and SBCE data of 108 patients (63 with and 45 without CD). Types of small bowel mucosal injuries, including erosion, ulceration, and cobblestone appearance, and the alignment of diminutive lesions were compared between patients with and without CD. Inter- and intra-observer agreement in the determination of lesions was assessed in 25 pairs of SBCE from the two groups.ResultsUnder SBCE, cobblestone appearance (33% vs. 2%, p < 0.0001), longitudinal ulcers (78% vs. 20%, p < 0.0001), and irregular ulcers (84% vs. 60%, p < 0.01) were more frequently found in patients with CD. Linear erosion (90% vs. 38%, p < 0.0001) and irregular erosion (89% vs. 64%, p < 0.005) were also more frequent in patients with CD. Furthermore, circumferential (75% vs. 9%, p < 0.0001) and longitudinal (56% vs. 7%, p < 0.0001) alignment of diminutive lesions, mainly observed in the 1st tertile of the small bowel, was more frequent in patients with CD. Good intra-observer agreement was found for ulcers, cobblestone appearance, and lesion alignment. However, inter-observer agreement of SBCE findings differed among observers.ConclusionsCircumferential or longitudinal alignment of diminutive lesions, especially in the upper small bowel, may be a diagnostic clue for CD under SBCE, while inter-observer variations should be cautiously considered when using SBCE.