A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH RESULTS: Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 controls from the Japanese population (GWAS-lead variant: rs8098858, p=2.6×10-8). In-silico and in-vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were confirmed in the portal area of the PBC-liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in-vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFN signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis.

Genome-wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease-susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single-nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type-specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune-related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon-gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer-like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type-specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets.

POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (SNP) imputation analysis of a total of 4,045 Japanese individuals (2,060 cases and 1,985 healthy controls). A susceptibility locus on chromosome 3q13.33 (including ARHGAP31, TMEM39A, POGLUT1, TIMMDC1, and CD80) was previously identified both in the European and Chinese populations and was replicated in the Japanese population (OR = 0.7241, P = 3.5 × 10-9). Subsequent in silico and in vitro functional analyses identified rs2293370, previously reported as the top-hit SNP in this locus in the European population, as the primary functional SNP. Moreover, e-QTL analysis indicated that the effector gene of rs2293370 was Protein O-Glucosyltransferase 1 (POGLUT1) (P = 3.4 × 10-8). This is the first study to demonstrate that POGLUT1 and not CD80 is the effector gene regulated by the primary functional SNP rs2293370, and that increased expression of POGLUT1 might be involved in the pathogenesis of PBC.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population.

A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10-9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

A pilot study using an infrared imaging system in prevention of post-endoscopic submucosal dissection ulcer bleeding.

BACKGROUND: Endoscopic submucosal dissection (ESD) for superficial gastric neoplasm is a curative method. The aim of this study was to detect potential nonbleeding visible vessels (NBVVs) by using an infrared imaging (IRI) system. METHODS: A total of 24 patients (25 lesions) were consecutively enrolled between March 2010 and December 2010. The day after ESD, endoscopist A (K.M.), who was blinded to the actual procedure of ESD, performed esophagogastroduodenoscopy (EGD) of the post-ESD ulcer base using the IRI system. Endoscopist A marked gray/blue points in the hard-copy images with the IRI system. After the first procedure, endoscopist B (Y.Y.), who was blinded to the results recorded by endoscopist A, performed a second EGD with white light endoscopy and administered water-jet pressure with the maximum level of an Olympus flushing pump onto the post-ESD ulcer base. This test can cause iatrogenic bleeding via application of pressure to NBVV in the post-ESD ulcer. RESULTS: The IRI system detected 58 gray points and 71 blue points. The post-ESD ulcer was divided into the central area and the peripheral area. There were 14 gray points (24 %) in the central area and 44 gray points (76 %) in the peripheral area. There were 19 blue points (27 %) in the central area and 52 blue points (73 %) in the peripheral area. There was no significant difference when comparing the distribution of gray points and blue points. Bleeding occurred with a water-jet pressure in 11 of 58 gray points and in none of the blue points (P = 0.000478). Among the gray points, bleeding in response to a water-jet pressure occurred in 2 points in the central area and in 9 points in the peripheral area. CONCLUSION: The IRI system detects visible vessels (VVs) that are in no need of coagulation as blue points, and VVs have a potential risk of bleeding as gray points.

Correlation between symptomatic improvement and quality of life in patients with reflux and dyspeptic symptoms.

We investigated the correlation between symptomatic improvement and quality of life in Japanese gastroesophageal reflux disease patients with PPI. Eighty one patients with reflux and dyspeptic symptom were enrolled. The evaluation of the symptom was used he Frequency Scale for the Symptom of GERD in 3 categories: total score of 12 questions, score related to reflux symptoms, and score related to dyspeptic symptoms and the evaluation of the quality of life was use the 8-item Short Form Health Survey in 2 categories, the physical component summary score and mental component summary score. All patients administered rabeprazole 10 mg/day for 8 weeks. We investigated the correlation between symptomatic improvement with proton pump inhibitor and quality of life. Significant symptomatic improvement was seen in the total score of 12 questions (26.7 ± 8.8 â†’ 17.5 ± 5.9, p<0.0001), score related to reflux symptoms (14.9 ± 5.4 â†’ 9.6 ± 3.6, p<0.0001), and score related to dyspeptic symptoms (11.8 ± 4.3 â†’ 8.0 ± 2.9, p<0.0001). Significant improvement in quality of life was seen in the physical component summary score (47.8 ± 6.6 â†’ 50.0 ± 5.9, p = 0.0209) and mental component summary score (47.4 ± 8.5 â†’ 50.4 ± 5.3, p = 0.0133) with proton pump inhibitor. With proton pump inhibitor, a significant positive correlation was seen between the improvement rates in total score of 12 questions, score related to dyspeptic symptoms and in mental component summary score at 8 weeks (total score of 12 questions: r = 0.275, p = 0.0265, score related to dyspeptic symptoms: r = 0.367, p = 0.0027). In conclusion, quality of life was associated with improvement in dyspeptic symptoms with proton pump inhibitor treatment.

The benefit of using narrow-band imaging systems for observation of capillary networks before determining of treatments for early colon cancer.

INTRODUCTION: This study examined whether magnifying endoscopy with narrow-band Imaging observation could be useful selecting the appropriate treatment for early colon cancer. PATIENTS AND METHODS: We analyzed 551 cases of colon tumors excised endoscopically or surgically, comprising 68 with large hyperplastic polyps, 25 traditional serrated adenomas, 141 tubular adenomas, 177 intramucosal cancers and 140 submucosal invasive (SM) cancers. We classified capillary network pattern into four types according to the degree of dilatation, irregularity and distribution of microcapillary features. These results were then compared with the histological findings. RESULTS: The comparison of capillary pattern and histological features showed microcapillary networks by magnifying endoscopy with narrow-band imaging observation in intramucosal lesion or SM cancer with remnant neoplastic glands at the superficial layer. CONCLUSIONS: The remaining microcapillary network was designed to maintain the architecture of neoplastic glands, even in the presence of subumucosal invasion. Consequently, loss of this network could correlate with depth of tumor invasion and histological reaction. Therefore, even if the tumor, remained of network was diagnosed to invade into SM layer, it should be checked up further examination by using magnifying endoscopy with crystal violet staining.

Imaging by Magnifying Endoscopy with NBI Implicates the Remnant Capillary Network As an Indication for Endoscopic Resection in Early Colon Cancer.

Introduction. This study examined whether magnifying endoscopy with NBI observation (ME-NBI) could be useful selecting the appropriate treatment for submucosal invasive cancer (SM cancer). Patients and Methods. We analyzed 515 cases of colon tumors excised endoscopically or surgically. We classified capillary network pattern into four types according to the degree of dilatation, irregularity, and distribution of microcapillary features. Results. The comparison of capillary pattern and histological features revealed microcapillary networks by using confocal laser-scanning microscopy and ME-NBI in intramucosal lesion or SM cancer with remnant neoplastic glands at the superficial layer. In contrast, the network was absent in SM cancer with desmoplastic reactions, which invaded deeper into the submucosal layer. Conclusions. The remaining microcapillary network is designed to maintain the architecture of neoplastic glands. Consequently, loss of this network could correlate with depth of tumor invasion and desmoplastic reaction. Therefore, we can decide the appropriate treatment by using ME-NBI method.

[A case of Budd-Chiari syndrome type IV, successfully treated with percutaneous transluminal angioplasty (PTA)].

A 25-year-old man was admitted to our hospital because of abdominal fullness. Abdominal enhanced CT, ultrasonography, and MRI revealed massive ascites and obstruction of the hepatic veins and the inferior vena cava. Gastrointestinal endoscopy showed F(3) esophageal varices with the so-called "red color sign". A diagnosis of Budd-Chiari syndrome (BCS) was confirmed by angiography which detected membranous obstruction of the hepatic veins. The cause of BCS in this patient was unclear. After treatment with percutaneous transluminal angioplasty (PTA), his ascites and esophageal varices improved.

[Case of lymphangioleiomyomatosis associated with protein-losing gastroenteropathy].

A 29-year-old woman was referred to our hospital for the intensive examination of leg edema and hypoproteinemia. CT scan of showed multiple thin-walled cysts in both lungs, suggesting lymphangioleiomyomatosis. CT scan of the abdomen, lymphoscintigraphy showed enlarged abdominal lymph nodes. Protein loss from the gastrointestinal tract was documented by measurement of the clearance of alpha-1 antitrypsin from the plasma using a 72 h stool collection and (99m)Tc human serum albumin scintigraphy. We thought that secondary lymphangiectasia with lymphangioleiomyomatosis caused protein-losing gastroenteropathy. Dietary therapy resulted in symptomatic improvement.