Publications by authors named "Nao Nishida"

100 Publications

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

Gastroenterology 2021 Mar 4. Epub 2021 Mar 4.

Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy. Electronic address:

Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease.

Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals).

Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively).

Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
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http://dx.doi.org/10.1053/j.gastro.2021.02.061DOI Listing
March 2021

Importance of HBsAg recognition by HLA molecules as revealed by responsiveness to different hepatitis B vaccines.

Sci Rep 2021 Mar 2;11(1):3703. Epub 2021 Mar 2.

Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, 272-8516, Japan.

Hepatitis B (HB) vaccines (Heptavax-II and Bimmugen) designed based on HBV genotypes A and C are mainly used for vaccination against HB in Japan. To determine whether there are differences in the genetic background associated with vaccine responsiveness, genome-wide association studies were performed on 555 Heptavax-II and 1193 Bimmugen recipients. Further HLA imputation and detailed analysis of the association with HLA genes showed that two haplotypes, DRB1*13:02-DQB1*06:04 and DRB1*04:05-DQB1*04:01, were significantly associated in comparison with high-responders (HBsAb > 100 mIU/mL) for the two HB vaccines. In particular, HLA-DRB1*13:02-DQB1*06:04 haplotype is of great interest in the sense that it could only be detected by direct analysis of the high-responders in vaccination with Heptavax-II or Bimmugen. Compared with healthy controls, DRB1*13:02-DQB1*06:04 was significantly less frequent in high-responders when vaccinated with Heptavax-II, indicating that high antibody titers were less likely to be obtained with Heptavax-II. As Bimmugen and Heptavax-II tended to have high and low vaccine responses to DRB1*13:02, 15 residues were found in the Heptavax-II-derived antigenic peptide predicted to have the most unstable HLA-peptide binding. Further functional analysis of selected hepatitis B patients with HLA haplotypes identified in this study is expected to lead to an understanding of the mechanisms underlying liver disease.
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http://dx.doi.org/10.1038/s41598-021-82986-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925550PMC
March 2021

rs1944919 on chromosome 11q23.1 and its effector genes COLCA1/COLCA2 confer susceptibility to primary biliary cholangitis.

Sci Rep 2021 Feb 25;11(1):4557. Epub 2021 Feb 25.

Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.

Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which intrahepatic bile ducts are destroyed by an autoimmune reaction. Our previous genome-wide association study (GWAS) identified chromosome 11q23.1 as a susceptibility gene locus for PBC in the Japanese population. Here, high-density association mapping based on single nucleotide polymorphism (SNP) imputation and in silico/in vitro functional analyses identified rs1944919 as the primary functional variant. Expression-quantitative trait loci analyses showed that the PBC susceptibility allele of rs1944919 was significantly associated with increased COLCA1/COLCA2 expression levels. Additionally, the effects of rs1944919 on COLCA1/COLCA2 expression levels were confirmed using genotype knock-in versions of cell lines constructed using the CRISPR/Cas9 system and differed between rs1944919-G/G clones and -T/T clones. To our knowledge, this is the first study to demonstrate the contribution of COLCA1/COLCA2 to PBC susceptibility.
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http://dx.doi.org/10.1038/s41598-021-84042-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907150PMC
February 2021

Transmission dynamics of SARS-CoV-2 on the Diamond Princess uncovered using viral genome sequence analysis.

Gene 2021 May 13;779:145496. Epub 2021 Feb 13.

Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan. Electronic address:

An outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred aboard the Diamond Princess cruise ship between her January 20 departure and late February 2020. Here, we used phylodynamic analyses to investigate the transmission dynamics of SARS-CoV-2 during the outbreak. Using a Bayesian coalescent-based method, the estimated mean nucleotide substitution rate of 240 SARS-CoV-2 whole-genome sequences was approximately 7.13 × 10 substitutions per site per year. Population dynamics and the effective reproductive number (R) of SARS-CoV-2 infections were estimated using a Bayesian framework. The estimated origin of the outbreak was January 21, 2020. The infection spread substantially before quarantine on February 5. The R peaked at 6.06 on February 4 and gradually declined to 1.51, suggesting that transmission continued slowly even after quarantine. These findings highlight the high transmissibility of SARS-CoV-2 and the need for effective measures to control outbreaks in confined settings.
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http://dx.doi.org/10.1016/j.gene.2021.145496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880849PMC
May 2021

Serum CCL17 level becomes a predictive marker to distinguish between mild/moderate and severe/critical disease in patients with COVID-19.

Gene 2021 Jan 14;766:145145. Epub 2020 Sep 14.

Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.

COVID-19, a novel coronavirus-related illness, has spread worldwide. Patients with apparently mild/moderate symptoms can suddenly develop severe pneumonia. Therefore, almost all COVID-19 patients require hospitalization, which can reduce limited medical resources in addition to overwhelming medical facilities. To identify predictive markers for the development of severe pneumonia, a comprehensive analysis of serum chemokines and cytokines was conducted using serial serum samples from COVID-19 patients. The expression profiles were analyzed along the time axis. Serum samples of common diseases were enrolled from a BioBank to confirm the usefulness of predictive markers. Five factors, IFN-λ3, IL-6, IP-10, CXCL9, and CCL17, were identified as predicting the onset of severe/critical symptoms. The factors were classified into two categories. Category A included IFN-λ3, IL-6, IP-10, and CXCL9, and their values surged and decreased rapidly before the onset of severe pneumonia. Category B included CCL17, which provided complete separation between the mild/moderate and the severe/critical groups at an early phase of SARS-CoV-2 infection. The five markers provided a high predictive value (area under the receiver operating characteristic curve (AUROC): 0.9-1.0, p < 0.001). Low expression of CCL17 was specifically observed in pre-severe COVID-19 patients compared with other common diseases, and the predictive ability of CCL17 was confirmed in validation samples of COVID-19. The factors identified could be promising prognostic markers to distinguish between mild/moderate and severe/critical patients, enabling triage at an early phase of infection, thus avoiding overwhelming medical facilities.
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http://dx.doi.org/10.1016/j.gene.2020.145145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489253PMC
January 2021

Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation.

Int J Mol Sci 2020 Aug 7;21(16). Epub 2020 Aug 7.

Genome Medical Science Project, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba 272-8516, Japan.

Hepatitis B virus (HBV), a highly persistent pathogen causing hepatocellular carcinoma (HCC), takes full advantage of host machinery, presenting therapeutic targets. Here we aimed to identify novel druggable host cellular factors using the reporter HBV we have recently generated. In an RNAi screen of G protein-coupled receptors (GPCRs), GPCR39 (GPR39) appeared as the top hit to facilitate HBV proliferation. Lentiviral overexpression of active GPR39 proteins and an agonist enhanced HBV replication and transcriptional activities of viral promoters, inducing the expression of CCAAT/enhancer binding protein (CEBP)-β (CEBPB). Meanwhile, GPR39 was uncovered to activate the heat shock response, upregulating the expression of proviral heat shock proteins (HSPs). In addition, glioma-associated oncogene homologue signaling, a recently reported target of GPR39, was suggested to inhibit HBV replication and eventually suppress expression of CEBPB and HSPs. Thus, GPR39 provirally governed intracellular circuits simultaneously affecting the carcinopathogenetic gene functions. GPR39 and the regulated signaling networks would serve as antiviral targets, and strategies with selective inhibitors of GPR39 functions can develop host-targeted antiviral therapies preventing HCC.
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http://dx.doi.org/10.3390/ijms21165661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460832PMC
August 2020

SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype.

Gene 2020 Oct 3;758:144944. Epub 2020 Jul 3.

Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan. Electronic address:

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). The relentless spread and pathogenicity of the virus have become a global public health emergency. One of the striking features of this pandemic is the pronounced impact on specific regions and ethnic groups. In particular, compared with East Asia, where the virus first emerged, SARS-CoV-2 has caused high rates of morbidity and mortality in Europe. This has not been experienced in past global viral infections, such as influenza, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) and is unique to SARS-CoV-2. For this reason, we investigated the involvement of genetic factors associated with SARS-CoV-2 infection with a focus on angiotensin-converting enzyme (ACE)-related genes, because ACE2 is a receptor for SARS-CoV-2. We found that the ACE1 II genotype frequency in a population was significantly negatively correlated with the number of SARS-CoV-2 cases. Similarly, the ACE1 II genotype was negatively correlated with the number of deaths due to SARS-CoV-2 infection. These data suggest that the ACE1 II genotype may influence the prevalence and clinical outcome of COVID-19 and serve as a predictive marker for COVID-19 risk and severity.
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http://dx.doi.org/10.1016/j.gene.2020.144944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833925PMC
October 2020

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

Hepatol Commun 2020 May 15;4(5):724-738. Epub 2020 Mar 15.

Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan.

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 ( < 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 ( < 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. : 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.
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http://dx.doi.org/10.1002/hep4.1497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193132PMC
May 2020

Admixture and natural selection shaped genomes of an Austronesian-speaking population in the Solomon Islands.

Sci Rep 2020 04 23;10(1):6872. Epub 2020 Apr 23.

Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033, Japan.

People in the Solomon Islands today are considered to have derived from Asian- and Papuan-related ancestors. Papuan-related ancestors colonized Near Oceania about 47,000 years ago, and Asian-related ancestors were Austronesian (AN)-speaking population, called Lapita, who migrated from Southeast Asia about 3,500 years ago. These two ancestral populations admixed in Near Oceania before the expansion of Lapita people into Remote Oceania. To understand the impact of the admixture on the adaptation of AN-speaking Melanesians in Near Oceania, we performed the genome-wide single nucleotide polymorphism (SNP) analysis of 21 individuals from Munda, the main town of the New Georgia Islands in the western Solomon Islands. Population samples from Munda were genetically similar to other Solomon Island population samples. The analysis of genetic contribution from the two different ancestries to the Munda genome revealed significantly higher proportions of Asian- and Papuan-related ancestries in the region containing the annexin A1 (ANXA1) gene (Asian component > 82.6%) and in the human leukocyte antigen (HLA) class II region (Papuan component > 85.4%), respectively. These regions were suspected to have undergone natural selection since the time of admixture. Our results suggest that admixture had affected adaptation of AN-speaking Melanesians in the Solomon Islands.
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http://dx.doi.org/10.1038/s41598-020-62866-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181741PMC
April 2020

Histopathological factors affecting the extraction of high quality genomic DNA from tissue sections for next-generation sequencing.

Biomed Rep 2019 Oct 21;11(4):171-180. Epub 2019 Aug 21.

Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.

To enable the widespread application of genomic medicine, the extraction of genomic DNA from thin sections of archived formalin-fixed and paraffin-embedded (FFPE) tissue blocks for next-generation sequencing (NGS) is often necessary. However, there are currently no guidelines available on which specific regions of the microtome sections to use for macrodissection with respect to the histopathological factors observed under microscopic examination. The aim of this study was to clarify the relationship between histopathological factors and DNA quality, and to standardize the macrodissection method for more efficient implementation of NGS. FFPE tissue specimens of 218 patients from the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics study were used to investigate the relationship between 15 histopathological factors and the quantitative ratio of double-stranded DNA (dsDNA) to total nucleic acids, as well as the ∆ crossing point value of each tissue specimen. Multivariate logistic regression analysis revealed that specimen storage of ≥3 years was negatively associated with dsDNA quality (P=0.0007, OR: 4.30, 95% CI: 1.85-10.04). In contrast, the presence of a mucus pool was positively associated with dsDNA quality (P=0.0308, OR: 0.23, 95% CI: 0.06-0.87). Metastatic tumors and longer specimen storage periods were significantly associated with lower ∆Cp values (P=0.0007, OR: 4.43, 95% CI: 1.87-10.49; and P=0.0003, OR: 5.51, 95% CI: 2.18-13.95, respectively). Therefore, macrodissection should not be performed on specimens exhibiting histopathological factors associated with poor DNA quality. In particular, the use of tissue blocks with a storage period of <3 years allows the extraction of genomic DNA suitable for NGS.
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http://dx.doi.org/10.3892/br.2019.1235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759515PMC
October 2019

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

Sci Rep 2019 01 14;9(1):102. Epub 2019 Jan 14.

Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan.

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). 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). 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.
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http://dx.doi.org/10.1038/s41598-018-36490-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331557PMC
January 2019

Genome-Wide Association Study Confirming a Strong Effect of HLA and Identifying Variants in on Chromosome 12q13.13 Associated With Susceptibility to Fulminant Type 1 Diabetes.

Diabetes 2019 03 14;68(3):665-675. Epub 2018 Dec 14.

Department of Endocrinology, Metabolism and Diabetes, Faculty of Medicine, Kindai University, Osaka, Japan

The first genome-wide association study of fulminant type 1 diabetes was performed in Japanese individuals. As previously reported using a candidate gene approach, a strong association was observed with multiple single nucleotide polymorphisms (SNPs) in the HLA region, and the strongest association was observed with rs9268853 in the class II DR region ( = 1.56 × 10, odds ratio [OR] 3.18). In addition, rs11170445 in on chromosome 12q13.13 showed an association at a genome-wide significance level ( = 7.58 × 10, OR 1.96). Fine mapping of the region revealed that rs3782151 in showed the lowest value ( = 4.60 × 10, OR 1.97 [95% CI 1.57-2.48]). The risk allele of rs3782151 is a expression quantitative trait locus for that significantly increases the expression of this gene. was found to be strongly associated with susceptibility to fulminant, but not classical, autoimmune type 1 diabetes, implicating this locus in the distinct phenotype of fulminant type 1 diabetes.
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http://dx.doi.org/10.2337/db18-0314DOI Listing
March 2019

NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional Variants.

Cell Mol Gastroenterol Hepatol 2019 4;7(3):515-532. Epub 2018 Dec 4.

Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.

Background & Aims: Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease that eventually leads to cirrhosis and hepatic failure. We recently identified several susceptibility genes included NFKB1 and MANBA for PBC in the Japanese population by genome-wide association study. However, the primary functional variants in the NFKB1/MANBA region and the molecular mechanism for conferring disease susceptibility to PBC have not yet been clarified.

Methods: We performed high-density association mapping based on a single-nucleotide polymorphism (SNP) imputation analysis, using data from a whole-genome sequence reference panel of 1070 Japanese individuals and the previous genome-wide association study (1389 PBC patients, 1508 healthy controls). Among SNPs (P < 5.0 × 10) in the NFKB1/MANBA region, putative primary functional variants and the molecular mechanism for conferring disease susceptibility to PBC were identified by in silico/in vitro functional analysis.

Results: Among the SNPs in the NFKB1/MANBA region, rs17032850 and rs227361, which changed the binding of transcription factors lymphoid enhancer-binding factor 1 (LEF-1) and retinoid X receptor α (RXRα), respectively, were identified as putative primary functional variants that regulate gene expression. In addition, expression-quantitative trait locus data and gene editing using a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system supported the potential role of rs17032850 and rs227361 in regulating NFKB1 and MANBA expression, respectively.

Conclusions: We identified independent putative primary functional variants in NFKB1/MANBA and showed the distinct molecular mechanism by which each putative primary functional variant conferred susceptibility to PBC. Our approach was useful to dissect the pathogenesis not only of PBC, but also other digestive diseases in which NFKB1/MANBA has been reported as a susceptibility locus.
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http://dx.doi.org/10.1016/j.jcmgh.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396435PMC
June 2019

Association Between High Levels of Hepatitis B Core Antibody and Seroclearance of Hepatitis B e Antigen in Individuals With Chronic Hepatitis B Virus Infection.

Clin Gastroenterol Hepatol 2019 06 26;17(7):1413-1415. Epub 2018 Sep 26.

Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address:

For chronic hepatitis B patients, hepatitis B e antigen (HBeAg) seroclearance signals a transition from an immunologically active phase to an inactive carrier state with a reduction in hepatitis B virus (HBV) DNA levels and a reduced risk of hepatocellular carcinoma (HCC). Predictors of HBeAg seroclearance include lower HBV DNA levels, viral genotype, the precore mutation, and higher serum alanine aminotransferase (ALT) levels..
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http://dx.doi.org/10.1016/j.cgh.2018.09.037DOI Listing
June 2019

A Glycomarker for Short-term Prediction of Hepatocellular Carcinoma: A Longitudinal Study With Serial Measurements.

Clin Transl Gastroenterol 2018 09 20;9(9):183. Epub 2018 Sep 20.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

Objectives: Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA-M2BP) is a glycomarker. The present community-based long-term follow-up study repeatedly determined the serum WFA-M2BP level and examined its short- and long-term associations with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).

Methods: A total of 921 participants with antibodies against HCV seropositive, but seronegative for hepatitis B surface antigen were enrolled from seven townships in Taiwan during 1991-1992. The participants were regularly followed and their serum WFA-M2BP levels were measured at baseline and follow-up. HCC was ascertained through active follow-up and computerized data linkage with the National Cancer Registration System until December 31, 2013. Cox proportional hazards and logistic regression models were applied to estimate the magnitude of associations between serum WFA-M2BP levels and HCC.

Results: During a median follow-up of 21.7 years, 122 new-onset HCC cases were identified. Elevated serum WFA-M2BP levels were associated with an increased risk of HCC (p < 0.001). Patients with increasing changes in serum WFA-M2BP levels, relative to their baseline levels, had a 4.36-fold risk of HCC. The areas under receiver operating curves (AUROCs) of WFA-M2BP for predicting HCC showed that the prediction efficacy was significantly higher while closer to HCC diagnosis (p = 0.024). The AUROC was 0.91 for predicting HCC within 1 year by including the predictors of age, sex, alanine aminotransferase, alpha-fetoprotein (AFP) and WFA-M2BP.

Conclusions: Serum WFA-M2BP level may elevate before HCC onset and is a short-term predictor of HCC among patients infected with HCV.
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http://dx.doi.org/10.1038/s41424-018-0050-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148253PMC
September 2018

Increased expression and altered localization of cathepsin Z are associated with progression to jaundice stage in primary biliary cholangitis.

Sci Rep 2018 08 7;8(1):11808. Epub 2018 Aug 7.

Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan.

Our recent genome-wide association study found that the NELFCD/CTSZ locus was significantly associated with progression of primary biliary cholangitis (PBC) to jaundice stage in the Japanese population. In this study, we investigated the role of cathepsin Z in the etiology and pathology of PBC. Serum cathepsin Z levels were measured using enzyme-linked immunosorbent assay. The expression and localization of cathepsin Z in liver specimens were analyzed by western blotting and immunohistochemistry. In PBC patients, serum cathepsin Z levels were significantly increased with disease progression. In addition, its levels were positively correlated with alanine transaminase, aspartate transaminase and total bilirubin, and were negatively correlated with platelet count and albumin. Cathepsin Z expression was markedly increased in hepatocytes at later stages of PBC, and its localization was altered from the peri-bile canaliculus to the cytoplasm, where a fraction was no longer colocalized with endosomal/lysosomal vesicles. Similar altered expression of cathepsin Z was observed in end-stage of other cholestatic liver diseases including sepsis, obstructive jaundice, and Alagille syndrome. Our results indicate that altered expression and localization of cathepsin Z in hepatocytes are characteristic features of PBC and other cholestatic liver diseases, and are implicated in the progression of PBC.
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http://dx.doi.org/10.1038/s41598-018-30146-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081405PMC
August 2018

NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population.

Sci Rep 2018 05 23;8(1):8071. Epub 2018 May 23.

Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan.

Approximately 10-20% of patients with primary biliary cholangitis (PBC) progress to jaundice stage regardless of treatment with ursodeoxycholic acid and bezafibrate. In this study, we performed a GWAS and a replication study to identify genetic variants associated with jaundice-stage progression in PBC using a total of 1,375 patients (1,202 early-stage and 173 jaundice-stage) in a Japanese population. SNP rs13720, which is located in the 3'UTR of cathepsin Z (CTSZ), showed the strongest association (odds ratio [OR] = 2.15, P = 7.62 × 10) with progression to jaundice stage in GWAS. High-density association mapping at the CTSZ and negative elongation factor complex member C/D (NELFCD) loci, which are located within a strong linkage disequilibrium (LD) block, revealed that an intronic SNP of CTSZ, rs163800, was significantly associated with jaundice-stage progression (OR = 2.16, P = 8.57 × 10). In addition, eQTL analysis and in silico functional analysis indicated that genotypes of rs163800 or variants in strong LD with rs163800 influence expression levels of both NELFCD and CTSZ mRNA. The present novel findings will contribute to dissect the mechanism of PBC progression and also to facilitate the development of therapies for PBC patients who are resistant to current therapies.
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http://dx.doi.org/10.1038/s41598-018-26369-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966418PMC
May 2018

Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma.

Sci Rep 2018 05 21;8(1):7958. Epub 2018 May 21.

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10; rs1110446: OR = 1.79, P = 1.66 × 10; and rs3094137: OR = 1.73, P = 7.09 × 10). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A 33:03 (OR = 1.97, P = 4.58 × 10) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.
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http://dx.doi.org/10.1038/s41598-018-26217-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962604PMC
May 2018

Key HLA-DRB1-DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine.

Hepatology 2018 09 27;68(3):848-858. Epub 2018 Apr 27.

Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.

Approximately 5-10% of individuals who are vaccinated with a hepatitis B (HB) vaccine designed based on the hepatitis B virus (HBV) genotype C fail to acquire protective levels of antibodies. Here, host genetic factors behind low immune response to this HB vaccine were investigated by a genome-wide association study (GWAS) and Human Leukocyte Antigen (HLA) association tests. The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome-wide SNP typing data. The GWAS identified independent associations of HLA-DRB1-DQB1, HLA-DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA-DRB1-DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1-DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1-DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1-DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. Conclusion: The findings in this study clearly show the importance of HLA-DR-DQ (i.e., recognition of a vaccine related HB surface antigen (HBsAg) by specific DR-DQ haplotypes) and BTNL2 molecules (i.e., high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. (Hepatology 2018).
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http://dx.doi.org/10.1002/hep.29876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175380PMC
September 2018

Successful Treatment of Oral Lichen Planus with Direct-Acting Antiviral Agents after Liver Transplantation for Hepatitis C Virus-Associated Hepatocellular Carcinoma.

Case Rep Gastroenterol 2017 Sep-Dec;11(3):701-710. Epub 2017 Nov 29.

Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.

Hepatitis C virus (HCV) infection is frequently associated with various extrahepatic manifestations, such as autoimmune features and immune complex deposit diseases. Oral lichen planus (OLP) is one such extrahepatic manifestation of HCV infection. Recently, direct-acting antivirals (DAA) have proved to be highly effective and safe for the eradication of HCV. Herein, we report a case of OLP accompanied by HCV-related hepatocellular carcinoma (HCC) that disappeared after liver transplantation and achievement of sustained virological response following interferon (IFN)-free treatment with ledipasvir (LDV) and sofosbuvir (SOF). The 50-year-old patient developed erosive OLP during IFN therapy, with hyperthyroidism at 53 years of age and HCC at 55 years. He received immunosuppressive drugs and IFN-free DAA treatment after liver transplantation at 60 years of age, which led to disappearance of the symptoms of OLP. The patient was treated safely and effectively with LDV/SOF, although it is not known whether the disappearance of OLP resulted from the eradication of HCV or the immunosuppressive therapy.
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http://dx.doi.org/10.1159/000484132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803697PMC
November 2017

Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

Br J Cancer 2017 Nov 3;117(10):1450-1458. Epub 2017 Oct 3.

Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan.

Background: Patients with BRAF-mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAF (BRAF mutations) contribute to anti-EGFR antibody resistance.

Methods: This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort.

Results: In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAF (6.0%), and 7 patients with BRAF mutations (4.7%), respectively. The response rates in RAS, BRAF, and BRAF were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAF mutations was 2.4 months, similar to that in RAS or BRAF mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months).

Conclusions: Although BRAF mutations identified were a rare and unestablished molecular subtype, certain BRAF mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.
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http://dx.doi.org/10.1038/bjc.2017.308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680457PMC
November 2017

Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: A genome-wide association study.

Hepatology 2018 02 1;67(2):651-661. Epub 2018 Jan 1.

Academia Sinica, Taipei, Taiwan.

We conducted a genome-wide association study to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We genotyped 502 HCC cases and 749 non-HCC controls using the Axiom-CHB genome-wide array. After identifying single-nucleotide polymorphism clusters located in the human leukocyte antigen (HLA) region which were potentially associated with HCC, HLA-DQB1 genotyping was performed to analyze 994 anti-HCV seropositives collected in the period 1991-2013 in a community-based cohort for evaluating long-term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals of HLA genotypes for determining the aforementioned HCC risk. Eight single-nucleotide polymorphisms in the proximity of HLA-DQB1 were associated with HCC (P < 8.7 × 10 ) in the genome-wide association study. Long-term follow-up showed a significant association with HLA-DQB1*03:01 and DQB1*06:02 (P < 0.05). The adjusted hazard ratios associated with HCC were 0.45 (0.30-0.68) and 2.11 (1.34-3.34) for DQB1*03:01 and DQB1*06:02, respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non-1 genotypes. HLA imputation analyses revealed that HLA-DRB1*15:01, which is in linkage disequilibrium with DQB1*06:02, also increased the risk of HCC (odds ratio, 1.96; 95% confidence interval, 1.31-2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primarily protective and susceptible variants, respectively. Conclusion: HLA-DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA-DQB1 on the risk of HCC. (Hepatology 2018;67:651-661).
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http://dx.doi.org/10.1002/hep.29531DOI Listing
February 2018

Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary cholangitis in a Japanese population.

Sci Rep 2017 09 11;7(1):11093. Epub 2017 Sep 11.

Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, 856-8562, Japan.

Identification of the primary allele(s) in HLA class II associated diseases remains challenging because of a tight linkage between alleles of HLA-DR and -DQ loci. In the present study, we determined the genotypes of seven HLA loci (HLA-A, -B, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) for 1200 Japanese patients with primary biliary cholangitis and 1196 controls. Observation of recombination derivatives facilitated an evaluation of the effects of individual HLA alleles consisting of disease-prone/disease-resistant HLA haplotypes. Consequently, a primary contribution of DQB1*06:04 (odds ratio: 0.19, p = 1.91 × 10), DQB1*03:01 (odds ratio: 0.50, p = 6.76 × 10), DRB1*08:03 (odds ratio: 1.75, p = 1.01 × 10) and DQB1*04:01 (odds ratio: 1.50, p = 9.20 × 10) was suggested. Epistasis of the protective DQB1*06:04 to risk conferred by DRB1*08:03 was demonstrated by subpopulation analysis, implicating the presence of an active immunological mechanism that alleviates pathogenic autoimmune reactions. Further, the contribution of the aforementioned HLA alleles as well as an HLA-DP allele, DPB1*02:01 to the association signals of 304 loci among 4103 SNPs in the HLA region at the genome-wide level of significance (p values less than 5 × 10) was demonstrated by the stepwise exclusion of the individuals possessing these HLA alleles from the comparison.
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http://dx.doi.org/10.1038/s41598-017-11148-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593890PMC
September 2017

Discerning the Origins of the Negritos, First Sundaland People: Deep Divergence and Archaic Admixture.

Genome Biol Evol 2017 08;9(8):2013-2022

Division of Population Genetics, National Institute of Genetics, Mishima, Japan.

Human presence in Southeast Asia dates back to at least 40,000 years ago, when the current islands formed a continental shelf called Sundaland. In the Philippine Islands, Peninsular Malaysia, and Andaman Islands, there exist indigenous groups collectively called Negritos whose ancestry can be traced to the "First Sundaland People." To understand the relationship between these Negrito groups and their demographic histories, we generated genome-wide single nucleotide polymorphism data in the Philippine Negritos and compared them with existing data from other populations. Phylogenetic tree analyses show that Negritos are basal to other East and Southeast Asians, and that they diverged from West Eurasians at least 38,000 years ago. We also found relatively high traces of Denisovan admixture in the Philippine Negritos, but not in the Malaysian and Andamanese groups, suggesting independent introgression and/or parallel losses involving Denisovan introgressed regions. Shared genetic loci between all three Negrito groups could be related to skin pigmentation, height, facial morphology and malarial resistance. These results show the unique status of Negrito groups as descended from the First Sundaland People.
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http://dx.doi.org/10.1093/gbe/evx118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597900PMC
August 2017

Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis.

Sci Rep 2017 06 6;7(1):2904. Epub 2017 Jun 6.

Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.

Numerous genome-wide association studies (GWAS) have been performed to identify susceptibility genes to various human complex diseases. However, in many cases, neither a functional variant nor a disease susceptibility gene have been clarified. Here, we show an efficient approach for identification of a functional variant in a primary biliary cholangitis (PBC)-susceptible region, chromosome 17q12-21 (ORMDL3-GSDMB-ZPBP2-IKZF3). High-density association mapping was carried out based on SNP imputation analysis by using the whole-genome sequence data from a reference panel of 1,070 Japanese individuals (1KJPN), together with genotype data from our previous GWAS (PBC patients: n = 1,389; healthy controls: n = 1,508). Among 23 single nucleotide polymorphisms (SNPs) with P < 1.0 × 10, rs12946510 was identified as the functional variant that influences gene expression via alteration of Forkhead box protein O1 (FOXO1) binding affinity in vitro. Moreover, expression-quantitative trait locus (e-QTL) analyses showed that the PBC susceptibility allele of rs12946510 was significantly associated with lower endogenous expression of ORMDL3 and GSDMB in whole blood and spleen. This study not only identified the functional variant in chr.17q12-21 and its molecular mechanism through which it conferred susceptibility to PBC, but it also illustrated an efficient systematic approach for post-GWAS analysis that is applicable to other complex diseases.
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http://dx.doi.org/10.1038/s41598-017-03067-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460198PMC
June 2017

Role of HLA-DP and HLA-DQ on the clearance of hepatitis B virus and the risk of chronic infection in a multiethnic population.

Liver Int 2017 10 30;37(10):1476-1487. Epub 2017 Mar 30.

Department of Hepatic Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan.

Background & Aims: HBV infection exhibits geographical variation in its distribution in South America. While HBV rates are low in central Argentina, the north-western region exhibits intermediate HBV rates. Unfortunately, the reasons that could explain this difference are still unknown.

Methods: A total of 1440 Argentines were recruited and grouped into HBV patients, HBV-resolved individuals and healthy controls. Genetic ancestry was assessed by analysis of biparental lineages and ancestry autosomal typing. SNPs of HLA-DPA1 (rs3077), HLA-DPB1 (rs9277542), HLA-DQB1 (rs2856718) and HLA-DQB2 (rs7453920) were determined, and HBV genotyping was performed by phylogenetic analysis in HBV patients.

Results: Native American ancestry prevailed in the north-western region when compared with central Argentina (P<.0001). However, no differences were observed among the three groups of each region. The distribution of HBV genotypes revealed significant differences (P<.0001). Three SNPs (rs3077, rs9277542 and rs7453920) showed a significant association with protection against chronic HBV and viral clearance in both regions. The remaining SNP showed a significant association with susceptibility to chronic HBV. The frequency rates of rs3077-T, related to protection against chronic HBV and viral clearance, were lower in north-western Argentina when compared with central Argentina. The same uneven frequency rates were observed for SNP rs9277542.

Conclusions: This is the first study addressing the associations between the HLA-DP and HLA-DQ loci and the protection against chronic HBV and viral clearance in a multiethnic South American population. The uneven distribution of HLA-DP and HLA-DQ supports the HBV epidemiological differences observed in these two regions of Argentina with dissimilar ancestry genetic background.
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http://dx.doi.org/10.1111/liv.13405DOI Listing
October 2017

Genome-Wide Association Study Identifies Risk Variants for Lichen Planus in Patients With Hepatitis C Virus Infection.

Clin Gastroenterol Hepatol 2017 Jun 5;15(6):937-944.e5. Epub 2017 Jan 5.

Department of Virology, Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Background & Aims: There is a close relationship between hepatitis C virus (HCV) infection and lichen planus, a chronic inflammatory mucocutaneous disease. We performed a genome-wide association study (GWAS) to identify genetic variants associated with HCV-related lichen planus.

Methods: We conducted a GWAS of 261 patients with HCV infection treated at a tertiary medical center in Japan from October 2007 through January 2013; a total of 71 had lichen planus and 190 had normal oral mucosa. We validated our findings in a GWAS of 38 patients with HCV-associated lichen planus and 7 HCV-infected patients with normal oral mucosa treated at a medical center in Italy.

Results: Single-nucleotide polymorphisms in NRP2 (rs884000) and IGFBP4 (rs538399) were associated with risk of HCV-associated lichen planus (P < 1 × 10). We also found an association between a single-nucleotide polymorphism in the HLA-DR/DQ genes (rs9461799) and susceptibility to HCV-associated lichen planus. The odds ratios for the minor alleles of rs884000, rs538399, and rs9461799 were 3.25 (95% confidence interval, 1.95-5.41), 0.40 (95% confidence interval, 0.25-0.63), and 2.15 (95% confidence interval, 1.41-3.28), respectively.

Conclusions: In a GWAS of Japanese patients with HCV infection, we replicated associations between previously reported polymorphisms in HLA class II genes and risk for lichen planus. We also identified single-nucleotide polymorphisms in NRP2 and IGFBP4 loci that increase and reduce risk of lichen planus, respectively. These genetic variants might be used to identify patients with HCV infection who are at risk for lichen planus.
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http://dx.doi.org/10.1016/j.cgh.2016.12.029DOI Listing
June 2017

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

Hum Mol Genet 2017 02;26(3):650-659

Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan.

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.
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http://dx.doi.org/10.1093/hmg/ddw406DOI Listing
February 2017

Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection.

Gut 2018 02 27;67(2):362-371. Epub 2016 Oct 27.

The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

Objective: The clinical significance of polymorphisms in the interleukin-28B gene encoding interferon (IFN)-λ3, which has antiviral effects, is known in chronic HCV but not in HBV infection. Thus, we measured IFN-λ3 levels in patients with HBV and investigated its clinical significance and association with nucleos(t)ide (NUC) analogue administration.

Design: Serum IFN-λ3 level was measured in 254 patients with HBV with varying clinical conditions using our own high sensitivity method. The resulting values were compared with various clinical variables. In addition, cell lines originating from various organs were cultured with NUCs, and the production of IFN-λ3 was evaluated.

Results: Higher serum IFN-λ3 levels were detected in the patients treated with nucleotide analogues (adefovir or tenofovir) compared with those treated with nucleoside analogues (lamivudine or entecavir). There were no other differences in the clinical background between the two groups. A rise in the serum IFN-λ3 levels was observed during additional administration of the nucleotide analogues. In vitro experiments showed that the nucleotide analogues directly and dose-dependently induced IFN-λ3 production only in colon cancer cells. Furthermore, the supernatant from cultured adefovir-treated colon cancer cells significantly induced IFN-stimulated genes (ISGs) and inhibited hepatitis B surface antigen (HBsAg) production in hepatoma cells, as compared with the supernatant from entecavir-treated cells.

Conclusions: We discovered that the nucleotide analogues show an additional pharmacological effect by inducing IFN-λ3 production, which further induces ISGs and results in a reduction of HBsAg production. These findings provide novel insights for HBV treatment and suggest IFN-λ3 induction as a possible target.
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http://dx.doi.org/10.1136/gutjnl-2016-312653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868296PMC
February 2018

Genome-Wide Association Study Identifies ZNF354C Variants Associated with Depression from Interferon-Based Therapy for Chronic Hepatitis C.

PLoS One 2016 10;11(10):e0164418. Epub 2016 Oct 10.

Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

The therapeutic use of interferon (IFN) is known to cause depression that frequently interrupts treatment. To identify genetic variants associated with IFN-induced depression, we conducted a genome-wide association study (GWAS) of 224 Japanese chronic hepatitis C patients receiving IFN-based therapy in a multicenter prospective study and stratified them into two groups according to the Beck Depression Inventory, Second Edition (BDI-II) score. In the GWAS stage, we selected 42 candidate single nucleotide polymorphisms (SNPs) to perform replication analysis in an independent set of 160 subjects. The SNP rs1863918 in strong linkage disequilibrium with SNPs located around the Zinc finger 354C (ZNF354C) gene on chromosome 5 showed a significant association when the results of GWAS and replication were combined (odds ratio = 2.55, P = 7.89×10-8 in the allele frequency model), suggesting that the rs1863918 T allele was associated with IFN-induced depression. Furthermore, logistic regression analysis showed that rs1863918 T allele, a history of depression, and younger age were independent predictive factors for IFN-induced depression. Interestingly, western blotting and immunofluorescence showed that ZNF354C was highly expressed in the hippocampus in mice, a region implicated in the pathology of psychiatric symptoms. In conclusion, we identified rs1863918 as significantly associated with IFN-induced depression, and revealed that the candidate gene ZNF354C is highly expressed in the hippocampus of mice. Our data might be useful for elucidating the pathogenic mechanisms of depression induced by drugs including IFN.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164418PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056723PMC
April 2017