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1. The NBDC-DDBJ imputation server facilitates the use of controlled access reference panel datasets in Japan

Author

Tsuyoshi Hachiya, Manabu Ishii, Yosuke Kawai, Seik-Soon Khor, Minae Kawashima, Licht Toyo-Oka, Nobutaka Mitsuhashi, Asami Fukuda, Yuichi Kodama, Takatomo Fujisawa, Katsushi Tokunaga, and Toshihisa Takagi

Subjects
Genetics, QH426-470, Life, QH501-531
Abstract

Abstract Accurate genotype imputation requires large-scale reference panel datasets. When conducting genotype imputation on the Japanese population, researchers can use such datasets under collaborative studies or controlled access conditions in public databases. We developed the NBDC-DDBJ imputation server, which securely provides users with a web user interface to execute genotype imputation on the server. Our benchmarking analysis showed that the accuracy of genotype imputation was improved by leveraging controlled access datasets to increase the number of haplotypes available for analysis compared to using publicly available reference panels such as the 1000 Genomes Project. The NBDC-DDBJ imputation server facilitates the use of controlled access datasets for accurate genotype imputation.

Published
2022
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2. TogoVar: A comprehensive Japanese genetic variation database

Author

Nobutaka Mitsuhashi, Licht Toyo-oka, Toshiaki Katayama, Minae Kawashima, Shuichi Kawashima, Kazunori Miyazaki, and Toshihisa Takagi

Subjects
Genetics, QH426-470, Life, QH501-531
Abstract

Genomic database: Genetic variation patterns in Japan A comprehensive database of genome sequence differences found in Japanese individuals is helping researchers uncover the genetic basis of diseases occurring in the Japanese population. Nobutaka Mitsuhashi from the Database Center for Life Science in Chiba, Japan, and colleagues describe the development of TogoVar, a web-based resource that includes genetic data from more than 200,000 Japanese individuals, plus many others of non-Japanese ancestry for comparison. From the millions of tracked DNA differences, many associated with disease, researchers can search for genetic variants of interest and find information on variant frequency, clinical importance, genomic context, related publications, and more. First established in 2018, TogoVar ( https://togovar.org ) now provides a one-stop shop for researchers looking to interpret genomic variation data in Japanese populations.

Published
2022
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3. rs2013278 in the multiple immunological-trait susceptibility locus CD28 regulates the production of non-functional splicing isoforms

Author

Yuki Hitomi, Yoshihiro Aiba, Kazuko Ueno, Nao Nishida, Yosuke Kawai, Minae Kawashima, Makoto Tsuiji, Chisato Iwabuchi, Sanami Takada, Noriko Miyake, Masao Nagasaki, Katsushi Tokunaga, and Minoru Nakamura

Subjects
Immunological-trait, Genome-wide association study (GWAS), CD28, Primary functional variant, Alternative splicing, Linkage disequilibrium, Medicine, Genetics, QH426-470
Abstract

Abstract Background Ligation of CD28 with ligands such as CD80 or CD86 provides a critical second signal alongside antigen presentation by class II major histocompatibility complex expressed on antigen-presenting cells through the T cell antigen receptor for naïve T cell activation. A number of studies suggested that CD28 plays an important role in the pathogenesis of various human diseases. Recent genome-wide association studies (GWASs) identified CD28 as a susceptibility locus for lymphocyte and eosinophil counts, multiple sclerosis, ulcerative colitis, celiac disease, rheumatoid arthritis, asthma, and primary biliary cholangitis. However, the primary functional variant and molecular mechanisms of disease susceptibility in this locus remain to be elucidated. This study aimed to identify the primary functional variant from thousands of genetic variants in the CD28 locus and elucidate its functional effect on the CD28 molecule. Results Among the genetic variants exhibiting stronger linkage disequilibrium (LD) with all GWAS-lead variants in the CD28 locus, rs2013278, located in the Rbfox binding motif related to splicing regulation, was identified as a primary functional variant related to multiple immunological traits. Relative endogenous expression levels of CD28 splicing isoforms (CD28i and CD28Δex2) compared with full-length CD28 in allele knock-in cell lines generated using CRISPR/Cas9 were directly regulated by rs2013278 (P

Published
2022
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4. Novel HLA allele associations with susceptibility, staging, symptomatic state, autoimmune hepatitis and hepatocellular carcinoma events for primary biliary cholangitis in the Japanese population

Author

Seik-Soon Khor, Kazuko Ueno, Nao Nishida, Minae Kawashima, Yosuke Kawai, Yoshihiro Aiba, Yuki Hitomi, Masao Nagasaki, Minoru Nakamura, and Katsushi Tokunaga

Subjects
primary biliary cholangitis, HLA, autoimmune hepatitis, hepatocellular carcinoma, Scheuer staging system, Immunologic diseases. Allergy, RC581-607
Abstract

Primary biliary cholangitis (PBC) is a rare autoimmune disease with a clear predisposition for human leukocyte antigen (HLA)-DR/DQ-associated loss of immune tolerance for the E2 component of the pyruvate dehydrogenase complex. Three-field-resolution HLA imputation of 1,670 Japanese PBC patients and 2,328 healthy controls was conducted using Japanese population-specific HLA reference panels. Eighteen previously reported Japanese PBC-associated HLA alleles were confirmed and extended to 3-field-resolution, including HLA-DRB1*08:03 to HLA-DRB1*08:03:02, HLA-DQB1*03:01 to HLA-DQB1*03:01:01, HLA-DQB1*04:01 to HLA-DQB1*04:01:01 and HLA-DQB1*06:04 to HLA-DQB1*06:04:01. In addition, additional significant novel HLA alleles were identified, including 3 novel susceptible HLA-DQA1 alleles: HLA-DQA1*03:03:01, HLA-DQA1*04:01:01, HLA-DQA1*01:04:01 and 1 novel protective HLA-DQA1 allele, HLA-DQA1*05:05:01. In addition, PBC patients carrying HLA-DRB1*15:01:01 and HLA-DQA1*03:03:01 would have a higher predisposition toward developing concomitant autoimmune hepatitis (AIH). Further, late-stage and symptomatic PBC shared the same susceptible HLA alleles of HLA-A*26:01:01, HLA-DRB1*09:01:02 and HLA-DQB1*03:03:02. Lastly, HLA-DPB1*05:01:01 was identified as a potential risk HLA allele for development of hepatocellular carcinoma (HCC) in PBC patients. In conclusion, we have extended the current knowledge of HLA allele associations to 3-field resolution and identified novel HLA allele associations with predisposition risk, staging, symptomatic state, and AIH and HCC events for Japanese PBC patients.

Published
2023
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5. rs1944919 on chromosome 11q23.1 and its effector genes COLCA1/COLCA2 confer susceptibility to primary biliary cholangitis

Author

Yuki Hitomi, Yoshihiro Aiba, Yosuke Kawai, Kaname Kojima, Kazuko Ueno, Nao Nishida, Minae Kawashima, Olivier Gervais, Seik-Soon Khor, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura, and Makoto Tsuiji

Subjects
Medicine, Science
Abstract

Abstract 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.

Published
2021
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6. Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

Author

Kazuko Ueno, Yoshihiro Aiba, Yuki Hitomi, Shinji Shimoda, Hitomi Nakamura, Olivier Gervais, Yosuke Kawai, Minae Kawashima, Nao Nishida, Seik‐Soon Kohn, Kaname Kojima, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ohta, Takuya Komura, Satoru Tsuruta, Kazuhiko Yamauchi, Tatsuro Kobata, Amane Kitasato, Tamotsu Kuroki, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Kiyoshi Migita, Hiromasa Ohira, Atsushi Tanaka, Hajime Takikawa, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura, and PBC‐GWAS Consortium in Japan

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

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 2 versus controls (P

Published
2020
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7. The Data Use Ontology to streamline responsible access to human biomedical datasets

Author

Jonathan Lawson, Moran N. Cabili, Giselle Kerry, Tiffany Boughtwood, Adrian Thorogood, Pinar Alper, Sarion R. Bowers, Rebecca R. Boyles, Anthony J. Brookes, Matthew Brush, Tony Burdett, Hayley Clissold, Stacey Donnelly, Stephanie O.M. Dyke, Mallory A. Freeberg, Melissa A. Haendel, Chihiro Hata, Petr Holub, Francis Jeanson, Aina Jene, Minae Kawashima, Shuichi Kawashima, Melissa Konopko, Irene Kyomugisha, Haoyuan Li, Mikael Linden, Laura Lyman Rodriguez, Mizuki Morita, Nicola Mulder, Jean Muller, Satoshi Nagaie, Jamal Nasir, Soichi Ogishima, Vivian Ota Wang, Laura D. Paglione, Ravi N. Pandya, Helen Parkinson, Anthony A. Philippakis, Fabian Prasser, Jordi Rambla, Kathy Reinold, Gregory A. Rushton, Andrea Saltzman, Gary Saunders, Heidi J. Sofia, John D. Spalding, Morris A. Swertz, Ilia Tulchinsky, Esther J. van Enckevort, Susheel Varma, Craig Voisin, Natsuko Yamamoto, Chisato Yamasaki, Lyndon Zass, Jaime M. Guidry Auvil, Tommi H. Nyrönen, and Mélanie Courtot

Subjects
data access, consent, FAIR, ontology, GA4GH, standard, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Human biomedical datasets that are critical for research and clinical studies to benefit human health also often contain sensitive or potentially identifying information of individual participants. Thus, care must be taken when they are processed and made available to comply with ethical and regulatory frameworks and informed consent data conditions. To enable and streamline data access for these biomedical datasets, the Global Alliance for Genomics and Health (GA4GH) Data Use and Researcher Identities (DURI) work stream developed and approved the Data Use Ontology (DUO) standard. DUO is a hierarchical vocabulary of human and machine-readable data use terms that consistently and unambiguously represents a dataset’s allowable data uses. DUO has been implemented by major international stakeholders such as the Broad and Sanger Institutes and is currently used in annotation of over 200,000 datasets worldwide. Using DUO in data management and access facilitates researchers’ discovery and access of relevant datasets. DUO annotations increase the FAIRness of datasets and support data linkages using common data use profiles when integrating the data for secondary analyses. DUO is implemented in the Web Ontology Language (OWL) and, to increase community awareness and engagement, hosted in an open, centralized GitHub repository. DUO, together with the GA4GH Passport standard, offers a new, efficient, and streamlined data authorization and access framework that has enabled increased sharing of biomedical datasets worldwide.

Published
2021
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8. NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional VariantsSummary

Author

Yuki Hitomi, Ken Nakatani, Kaname Kojima, Nao Nishida, Yosuke Kawai, Minae Kawashima, Yoshihiro Aiba, Masao Nagasaki, Minoru Nakamura, and Katsushi Tokunaga

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

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 × 10-7) 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. Keywords: PBC, GWAS, Disease Susceptibility Gene, e-QTL, CRISPR/Cas9

Published
2019
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9. Are minor alleles more likely to be risk alleles?

Author

Takashi Kido, Weronika Sikora-Wohlfeld, Minae Kawashima, Shinichi Kikuchi, Naoyuki Kamatani, Anil Patwardhan, Richard Chen, Marina Sirota, Keiichi Kodama, Dexter Hadley, and Atul J. Butte

Subjects
GWASs, Complex diseases, Minor alleles, Risk alleles, Negative natural selection, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele. Methods Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion. Results Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs 50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (

Published
2018
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10. Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis

Author

Yuki Hitomi, Kaname Kojima, Minae Kawashima, Yosuke Kawai, Nao Nishida, Yoshihiro Aiba, Michio Yasunami, Masao Nagasaki, Minoru Nakamura, and Katsushi Tokunaga

Subjects
Medicine, Science
Abstract

Abstract 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

Published
2017
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11. Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array.

Author

Mayuko Tamura, Tsuyoshi Isojima, Minae Kawashima, Hideki Yoshida, Keiko Yamamoto, Taichi Kitaoka, Noriyuki Namba, Akira Oka, Keiichi Ozono, Katsushi Tokunaga, and Sachiko Kitanaka

Subjects
Medicine, Science
Abstract

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD).Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12.A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium.This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

Published
2015
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12. New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia.

Author

Nao Nishida, Hiromi Sawai, Koichi Kashiwase, Mutsuhiko Minami, Masaya Sugiyama, Wai-Kay Seto, Man-Fung Yuen, Nawarat Posuwan, Yong Poovorawan, Sang Hoon Ahn, Kwang-Hyub Han, Kentaro Matsuura, Yasuhito Tanaka, Masayuki Kurosaki, Yasuhiro Asahina, Namiki Izumi, Jong-Hon Kang, Shuhei Hige, Tatsuya Ide, Kazuhide Yamamoto, Isao Sakaida, Yoshikazu Murawaki, Yoshito Itoh, Akihiro Tamori, Etsuro Orito, Yoichi Hiasa, Masao Honda, Shuichi Kaneko, Eiji Mita, Kazuyuki Suzuki, Keisuke Hino, Eiji Tanaka, Satoshi Mochida, Masaaki Watanabe, Yuichiro Eguchi, Naohiko Masaki, Kazumoto Murata, Masaaki Korenaga, Yoriko Mawatari, Jun Ohashi, Minae Kawashima, Katsushi Tokunaga, and Masashi Mizokami

Subjects
Medicine, Science
Abstract

Previous studies have revealed the association between SNPs located on human leukocyte antigen (HLA) class II genes, including HLA-DP and HLA-DQ, and chronic hepatitis B virus (HBV) infection, mainly in Asian populations. HLA-DP alleles or haplotypes associated with chronic HBV infection or disease progression have not been fully identified in Asian populations. We performed trans-ethnic association analyses of HLA-DPA1, HLA-DPB1 alleles and haplotypes with hepatitis B virus infection and disease progression among Asian populations comprising Japanese, Korean, Hong Kong, and Thai subjects. To assess the association between HLA-DP and chronic HBV infection and disease progression, we conducted high-resolution (4-digit) HLA-DPA1 and HLA-DPB1 genotyping in a total of 3,167 samples, including HBV patients, HBV-resolved individuals and healthy controls. Trans-ethnic association analyses among Asian populations identified a new risk allele HLA-DPB1*09 ∶ 01 (P = 1.36 × 10(-6); OR= 1.97; 95% CI, 1.50-2.59) and a new protective allele DPB1*02 ∶ 01 (P = 5.22 × 10(-6); OR = 0.68; 95% CI, 0.58-0.81) to chronic HBV infection, in addition to the previously reported alleles. Moreover, DPB1*02 ∶ 01 was also associated with a decreased risk of disease progression in chronic HBV patients among Asian populations (P = 1.55 × 10(-7); OR = 0.50; 95% CI, 0.39-0.65). Trans-ethnic association analyses identified Asian-specific associations of HLA-DP alleles and haplotypes with HBV infection or disease progression. The present findings will serve as a base for future functional studies of HLA-DP molecules in order to understand the pathogenesis of HBV infection and the development of hepatocellular carcinoma.

Published
2014
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13. Evolutionary analysis of classical HLA class I and II genes suggests that recent positive selection acted on DPB1*04:01 in Japanese population.

Author

Minae Kawashima, Jun Ohashi, Nao Nishida, and Katsushi Tokunaga

Subjects
Medicine, Science
Abstract

The human leukocyte antigen (HLA) genes exhibit the highest degree of polymorphism in the human genome. This high degree of variation at classical HLA class I and class II loci has been maintained by balancing selection for a long evolutionary time. However, little is known about recent positive selection acting on specific HLA alleles in a local population. To detect the signature of recent positive selection, we genotyped six HLA loci, HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 in 418 Japanese subjects, and then assessed the haplotype homozygosity (HH) of each HLA allele. There were 120 HLA alleles across the six loci. Among the 80 HLA alleles with frequencies of more than 1%, DPB1*04∶01, which had a frequency of 6.1%, showed exceptionally high HH (0.53). This finding raises the possibility that recent positive selection has acted on DPB1*04∶01. The DPB1*04∶01 allele, which was present in the most common 6-locus HLA haplotype (4.4%), A*33∶03-C*14∶03-B*44∶03-DRB1*13∶02-DQB1*06∶04-DPB1*04∶01, seems to have flowed from the Korean peninsula to the Japanese archipelago in the Yayoi period. A stochastic simulation approach indicated that the strong linkage disequilibrium between DQB1*06∶04 and DPB1*04∶01 observed in Japanese cannot be explained without positive selection favoring DPB1*04∶01. The selection coefficient of DPB1*04∶01 was estimated as 0.041 (95% credible interval 0.021-0.077). Our results suggest that DPB1*04∶01 has recently undergone strong positive selection in Japanese population.

Published
2012
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14. Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean.

Author

Nao Nishida, Hiromi Sawai, Kentaro Matsuura, Masaya Sugiyama, Sang Hoon Ahn, Jun Yong Park, Shuhei Hige, Jong-Hon Kang, Kazuyuki Suzuki, Masayuki Kurosaki, Yasuhiro Asahina, Satoshi Mochida, Masaaki Watanabe, Eiji Tanaka, Masao Honda, Shuichi Kaneko, Etsuro Orito, Yoshito Itoh, Eiji Mita, Akihiro Tamori, Yoshikazu Murawaki, Yoichi Hiasa, Isao Sakaida, Masaaki Korenaga, Keisuke Hino, Tatsuya Ide, Minae Kawashima, Yoriko Mawatari, Megumi Sageshima, Yuko Ogasawara, Asako Koike, Namiki Izumi, Kwang-Hyub Han, Yasuhito Tanaka, Katsushi Tokunaga, and Masashi Mizokami

Subjects
Medicine, Science
Abstract

Hepatitis B virus (HBV) infection can lead to serious liver diseases, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC); however, about 85-90% of infected individuals become inactive carriers with sustained biochemical remission and very low risk of LC or HCC. To identify host genetic factors contributing to HBV clearance, we conducted genome-wide association studies (GWAS) and replication analysis using samples from HBV carriers and spontaneously HBV-resolved Japanese and Korean individuals. Association analysis in the Japanese and Korean data identified the HLA-DPA1 and HLA-DPB1 genes with P(meta) = 1.89×10⁻¹² for rs3077 and P(meta) = 9.69×10⁻¹⁰ for rs9277542. We also found that the HLA-DPA1 and HLA-DPB1 genes were significantly associated with protective effects against chronic hepatitis B (CHB) in Japanese, Korean and other Asian populations, including Chinese and Thai individuals (P(meta) = 4.40×10⁻¹⁹ for rs3077 and P(meta) = 1.28×10⁻¹⁵ for rs9277542). These results suggest that the associations between the HLA-DP locus and the protective effects against persistent HBV infection and with clearance of HBV were replicated widely in East Asian populations; however, there are no reports of GWAS in Caucasian or African populations. Based on the GWAS in this study, there were no significant SNPs associated with HCC development. To clarify the pathogenesis of CHB and the mechanisms of HBV clearance, further studies are necessary, including functional analyses of the HLA-DP molecule.

Published
2012
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15. Polymorphism located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype confer susceptibility to CNS hypersomnias (essential hypersomnia).

Author

Taku Miyagawa, Makoto Honda, Minae Kawashima, Mihoko Shimada, Susumu Tanaka, Yutaka Honda, and Katsushi Tokunaga

Subjects
Medicine, Science
Abstract

BackgroundSNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy.Principal findingsEHS was significantly associated with SNP rs5770917 (P(allele) = 3.6x10(-3); OR = 1.56; 95% c.i.: 1.12-2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (P(positivity) = 9.2x10(-11); OR = 3.97; 95% c.i.: 2.55-6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS.ConclusionCPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy.

Published
2009
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16. Corrigendum to: 'An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs' [J Hepatol 75 (2021) 572-581]

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, and George F. Mells

Subjects
Hepatology
Published
2023

17. Corrigendum to 'An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs' [J Hepatol 2021;75(3):572-581]

Author

Heather J, Cordell, James J, Fryett, Kazuko, Ueno, Rebecca, Darlay, Yoshihiro, Aiba, Yuki, Hitomi, Minae, Kawashima, Nao, Nishida, Seik-Soon, Khor, Olivier, Gervai, Yosuke, Kawai, Masao, Nagasaki, Katsushi, Tokunaga, Ruqi, Tang, Yongyong, Shi, Zhiqiang, Li, Brian D, Juran, Elizabeth J, Atkinson, Alessio, Gerussi, Marco, Carbone, Rosanna, Asselta, Angela, Cheung, Mariza, de Andrade, Aris, Bara, Julie, Horowitz, Manuel A R, Ferreira, Dylan, Sun, David E, Jone, Steven, Flack, Ann, Spicer, Victoria L, Mulcahy, Jinyoung, Byun, Younghun, Han, Richard N, Sandford, Konstantinos N, Lazaridi, Christopher I, Amo, Gideon M, Hirschfield, Michael F, Seldin, Pietro, Invernizzi, Katherine A, Siminovitch, Xiong, Ma, Minoru, Nakamura, George F, Mell, Siminovitch, Katherine A., Hirschfield, Gideon M., Mason, Andrew, Vincent, Catherine, Xie, Gang, Zhang, Jinyi, Tang, Ruqi, Ma, Xiong, Li, Zhiqiang, Shi, Yongyong, Affronti, Andrea, Almasio, Piero L., Alvaro, Domenico, Andreone, Pietro, Andriulli, Angelo, Azzaroli, Francesco, Battezzati, Pier Maria, Benedetti, Antonio, Bragazzi, Maria Consiglia, Brunetto, Maurizia, Bruno, Savino, Calvaruso, Vincenza, Cardinale, Vincenzo, Casella, Giovanni, Cazzagon, Nora, Ciaccio, Antonio, Coco, Barbara, Colli, Agostino, Colloredo, Guido, Colombo, Massimo, Colombo, Silvia, Cristoferi, Laura, Cursaro, Carmela, Saveria Crocè, Lory, Crosignani, Andrea, D’Amato, Daphne, Donato, Francesca, Elia, Gianfranco, Fabris, Luca, Fagiuoli, Stefano, Ferrari, Carlo, Floreani, Annarosa, Galli, Andrea, Giannini, Edoardo, Grattagliano, Ignazio, Lampertico, Pietro, Lleo, Ana, Malinverno, Federica, Mancuso, Clara, Marra, Fabio, Marzioni, Marco, Massironi, Sara, Mattalia, Alberto, Miele, Luca, Milani, Chiara, Morini, Lorenzo, Morisco, Filomena, Muratori, Luigi, Muratori, Paolo, Niro, Grazia A., O’Donnell, Sarah, Picciotto, Antonio, Portincasa, Piero, Rigamonti, Cristina, Ronca, Vincenzo, Rosina, Floriano, Spinzi, Giancarlo, Strazzabosco, Mario, Tarocchi, Mirko, Tiribelli, Claudio, Toniutto, Pierluigi, Valenti, Luca, Vinci, Maria, Zuin, Massimo, Consortium, Japan-PBC-GWAS, PBC Consortium, U, Consortium, UK-PBC, Luca, Miele (ORCID:0000-0003-3464-0068), Heather J, Cordell, James J, Fryett, Kazuko, Ueno, Rebecca, Darlay, Yoshihiro, Aiba, Yuki, Hitomi, Minae, Kawashima, Nao, Nishida, Seik-Soon, Khor, Olivier, Gervai, Yosuke, Kawai, Masao, Nagasaki, Katsushi, Tokunaga, Ruqi, Tang, Yongyong, Shi, Zhiqiang, Li, Brian D, Juran, Elizabeth J, Atkinson, Alessio, Gerussi, Marco, Carbone, Rosanna, Asselta, Angela, Cheung, Mariza, de Andrade, Aris, Bara, Julie, Horowitz, Manuel A R, Ferreira, Dylan, Sun, David E, Jone, Steven, Flack, Ann, Spicer, Victoria L, Mulcahy, Jinyoung, Byun, Younghun, Han, Richard N, Sandford, Konstantinos N, Lazaridi, Christopher I, Amo, Gideon M, Hirschfield, Michael F, Seldin, Pietro, Invernizzi, Katherine A, Siminovitch, Xiong, Ma, Minoru, Nakamura, George F, Mell, Siminovitch, Katherine A., Hirschfield, Gideon M., Mason, Andrew, Vincent, Catherine, Xie, Gang, Zhang, Jinyi, Tang, Ruqi, Ma, Xiong, Li, Zhiqiang, Shi, Yongyong, Affronti, Andrea, Almasio, Piero L., Alvaro, Domenico, Andreone, Pietro, Andriulli, Angelo, Azzaroli, Francesco, Battezzati, Pier Maria, Benedetti, Antonio, Bragazzi, Maria Consiglia, Brunetto, Maurizia, Bruno, Savino, Calvaruso, Vincenza, Cardinale, Vincenzo, Casella, Giovanni, Cazzagon, Nora, Ciaccio, Antonio, Coco, Barbara, Colli, Agostino, Colloredo, Guido, Colombo, Massimo, Colombo, Silvia, Cristoferi, Laura, Cursaro, Carmela, Saveria Crocè, Lory, Crosignani, Andrea, D’Amato, Daphne, Donato, Francesca, Elia, Gianfranco, Fabris, Luca, Fagiuoli, Stefano, Ferrari, Carlo, Floreani, Annarosa, Galli, Andrea, Giannini, Edoardo, Grattagliano, Ignazio, Lampertico, Pietro, Lleo, Ana, Malinverno, Federica, Mancuso, Clara, Marra, Fabio, Marzioni, Marco, Massironi, Sara, Mattalia, Alberto, Miele, Luca, Milani, Chiara, Morini, Lorenzo, Morisco, Filomena, Muratori, Luigi, Muratori, Paolo, Niro, Grazia A., O’Donnell, Sarah, Picciotto, Antonio, Portincasa, Piero, Rigamonti, Cristina, Ronca, Vincenzo, Rosina, Floriano, Spinzi, Giancarlo, Strazzabosco, Mario, Tarocchi, Mirko, Tiribelli, Claudio, Toniutto, Pierluigi, Valenti, Luca, Vinci, Maria, Zuin, Massimo, Consortium, Japan-PBC-GWAS, PBC Consortium, U, Consortium, UK-PBC, and Luca, Miele (ORCID:0000-0003-3464-0068)

Abstract

N/A

Published
2022

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

Author

Toshiki Nikami, Hitomi Nakamura, Takuya Komura, Yuki Hitomi, Kiyoshi Migita, Atsushi Naganuma, Amane Kitasato, Olivier Gervais, Hiroshi Kouno, Atsumasa Komori, Hiromasa Ohira, Minae Kawashima, Hajime Ohta, Seigo Abiru, Yosuke Kawai, Shinji Katsushima, Kaname Yoshizawa, Kazuko Ueno, Hideo Nishimura, Masao Nagasaki, Tamotsu Kuroki, Tatsuji Komatsu, Katsushi Tokunaga, Hajime Takikawa, Shinya Nagaoka, Kazuhiko Yamauchi, Tomohiko Mannami, Seik-Soon Kohn, Kouki Matsushita, Tatsuro Kobata, Hirotaka Kouno, Nao Nishida, Satoru Tsuruta, Fujio Makita, Atsushi Tanaka, Hiroshi Yatsuhashi, Shinji Shimoda, Yoshihiro Aiba, Kazuhiro Sugi, Kaname Kojima, and Minoru Nakamura

Subjects
Messenger RNA, CD40, Hepatology, Microarray analysis techniques, Cell, Genome-wide association study, Original Articles, Computational biology, Biology, medicine.anatomical_structure, Gene expression, medicine, biology.protein, lcsh:Diseases of the digestive system. Gastroenterology, Original Article, lcsh:RC799-869, Gene, Genetic association
Abstract

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 2 versus controls (P

Published
2020

19. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byun, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, Maria Consiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton V.J. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris D.J. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom J.W. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch'ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, and Charles Millson

Subjects
Science & Technology, Hepatology, Gastroenterology & Hepatology, Italian PBC Study Group, Japan-PBC-GWAS Consortium, UK-PBC Consortium, Chinese PBC Consortium, 1103 Clinical Sciences, US PBC Consortium, Canadian PBC Consortium, Life Sciences & Biomedicine, PBC Consortia, 1117 Public Health and Health Services
Published
2021

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

Author

Nao Nishida, Kaname Kojima, Ken Nakatani, Yuki Hitomi, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura, Yoshihiro Aiba, and Minae Kawashima

Subjects
0301 basic medicine, EMSA, electrophoretic mobility shift assay, Genome-wide association study, PBC, Linkage Disequilibrium, Pathogenesis, Jurkat Cells, PCR, polymerase chain reaction, 0302 clinical medicine, Risk Factors, Chromosome Segregation, GWAS, Association mapping, Original Research, Genetics, education.field_of_study, Liver Cirrhosis, Biliary, Gastroenterology, Hep G2 Cells, e-QTL, 3. Good health, 1KJPN, whole-genome sequence reference panel of 1070 Japanese individuals, 030211 gastroenterology & hepatology, CRISPR/Cas9, clustered regularly interspaced short palindromic repeat, SNP, single-nucleotide polymorphism, LD, linkage disequilibrium, Population, NF-κB, nuclear factor-κB, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Disease Susceptibility Gene, 03 medical and health sciences, Asian People, Humans, SNP, PDC-E2, E2 component of the pyruvate dehydrogenase complex, Genetic Predisposition to Disease, lcsh:RC799-869, GWAS, genome-wide association study, education, CRISPR/Cas9, Alleles, Hepatology, LEF-1, lymphoid enhancer-binding factor 1, beta-Mannosidase, NF-kappa B p50 Subunit, Th, T-helper type, RXRα, retinoid X receptor α, 030104 developmental biology, Amino Acid Substitution, Gene Expression Regulation, Genetic Loci, lcsh:Diseases of the digestive system. Gastroenterology, PBC, primary biliary cholangitis, Imputation (genetics), Transcription Factors
Abstract

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 × 10-7) 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., Graphical abstract

Published
2019

21. The Data Use Ontology to streamline responsible access to human biomedical datasets

Author

Heidi J. Sofia, Kathy Reinold, Petr Holub, Gregory A. Rushton, Sarion R. Bowers, Melissa A. Konopko, Anthony J. Brookes, Chihiro Hata, Jaime M. Guidry Auvil, Giselle Kerry, Stephanie O. M. Dyke, Rebecca R. Boyles, Tony Burdett, Mallory A. Freeberg, Fabian Prasser, Soichi Ogishima, Jordi Rambla, Aina Jene, Matthew Brush, Mélanie Courtot, Ilia Tulchinsky, Esther van Enckevort, Minae Kawashima, Moran N. Cabili, Jonathan Lawson, Laura A.D. Paglione, Helen Parkinson, Tommi Nyrönen, Adrian Thorogood, Satoshi Nagaie, Craig Voisin, Anthony A. Philippakis, Pinar Alper, Haoyuan Li, Susheel Varma, John Dylan Spalding, Hayley L. Clissold, Gary I. Saunders, Natsuko Yamamoto, Nicola Mulder, Morris A. Swertz, Ravi N. Pandya, Melissa Haendel, Mikael Linden, Mizuki Morita, Vivian Ota Wang, Jean Muller, Chisato Yamasaki, Lyndon Zass, Francis Jeanson, Irene Kyomugisha, Stacey Donnelly, Tiffany Boughtwood, Laura Lyman Rodriguez, Jamal Nasir, Andrea Saltzman, and Shuichi Kawashima

Subjects
secondary data use, Vocabulary, Technology, Computer science, media_common.quotation_subject, Data management, data restrictions, Ontology (information science), Biochemistry, biophysics & molecular biology [F05] [Life sciences], Ontologia, Biochemistry, Genetics and Molecular Biology (miscellaneous), 03 medical and health sciences, Annotation, 0302 clinical medicine, data access, Conjunts de dades, Genetics, ontology, Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant], automated data access, 030304 developmental biology, media_common, FAIR, Computer science [C05] [Engineering, computing & technology], 0303 health sciences, business.industry, Authorization, GA4GH, standard, Ontology language, Sciences informatiques [C05] [Ingénierie, informatique & technologie], controlled access, Data science, 3. Good health, Data access, Community awareness, consent, business, 030217 neurology & neurosurgery
Abstract

Summary Human biomedical datasets that are critical for research and clinical studies to benefit human health also often contain sensitive or potentially identifying information of individual participants. Thus, care must be taken when they are processed and made available to comply with ethical and regulatory frameworks and informed consent data conditions. To enable and streamline data access for these biomedical datasets, the Global Alliance for Genomics and Health (GA4GH) Data Use and Researcher Identities (DURI) work stream developed and approved the Data Use Ontology (DUO) standard. DUO is a hierarchical vocabulary of human and machine-readable data use terms that consistently and unambiguously represents a dataset’s allowable data uses. DUO has been implemented by major international stakeholders such as the Broad and Sanger Institutes and is currently used in annotation of over 200,000 datasets worldwide. Using DUO in data management and access facilitates researchers’ discovery and access of relevant datasets. DUO annotations increase the FAIRness of datasets and support data linkages using common data use profiles when integrating the data for secondary analyses. DUO is implemented in the Web Ontology Language (OWL) and, to increase community awareness and engagement, hosted in an open, centralized GitHub repository. DUO, together with the GA4GH Passport standard, offers a new, efficient, and streamlined data authorization and access framework that has enabled increased sharing of biomedical datasets worldwide., Graphical abstract, Highlights Biomedical advances depend on the efficient and compliant re-use of sensitive human data The Data Use Ontology standardizes terms and definitions for consented data uses The Data Use Ontology facilitates discovery of, request for, and access to datasets Over 200,000 datasets worldwide have been annotated using the Data Use Ontology, The GA4GH Data Use Ontology (DUO) provides unambiguous, machine-readable standard language for consent forms and the data sharing policies they represent. Lawson et al. describe the DUO standard and implementations throughout the data access workflow to expedite data access while maintaining or improving compliant processes.

Published
2021
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22. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. 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Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Medical Research Council (MRC), LiveR North, Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .

Subjects
Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Published
2021

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

Author

Minoru Nakamura, Yoshihiro Aiba, Nao Nishida, Yosuke Kawai, Kaname Kojima, Makoto Tsuiji, Yuki Hitomi, Katsushi Tokunaga, Seik-Soon Khor, Olivier Gervais, Minae Kawashima, Kazuko Ueno, and Masao Nagasaki

Subjects
Science, Intrahepatic bile ducts, Gene Expression, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, Genotype, Immunogenetics, SNP, Humans, Genetic Predisposition to Disease, Association mapping, Gene, Alleles, Genetic Association Studies, Genetics, Multidisciplinary, Liver Cirrhosis, Biliary, Chromosomes, Human, Pair 11, Genetic Variation, Epistasis, Genetic, Genomics, Neoplasm Proteins, Primary biliary cirrhosis, Medicine, RNA, Genome-Wide Association Study
Abstract

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.

Published
2020

24. rs9459874 and rs1012656 in CCR6/FGFR1OP confer susceptibility to primary biliary cholangitis

Author

Yuki Hitomi, Yoshihiro Aiba, Kazuko Ueno, Nao Nishida, Yosuke Kawai, Minae Kawashima, Michio Yasunami, Olivier Gervais, Masahiro Ito, Heather J. Cordell, George F. Mells, Masao Nagasaki, Katsushi Tokunaga, Makoto Tsuiji, and Minoru Nakamura

Subjects
Receptors, CCR6, Asian People, Liver Cirrhosis, Biliary, Proto-Oncogene Proteins, Immunology, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease that appears to be strongly influenced by genetic factors. Recently, an international meta-analysis of genome-wide association studies (GWAS) identified CC-Motif Chemokine Receptor-6 (CCR6) and FGFR1 Oncogene-Partner (FGFR1OP) as PBC-susceptibility genes. However, the lead single nucleotide polymorphisms (SNPs) of CCR6/FGFR1OP showed low linkage disequilibrium with each other in East Asian and European populations. Additionally, the primary functional variants and the molecular mechanisms responsible for PBC-susceptibility remain unclear. Here, among the PBC-susceptibility SNPs identified by high-density association mapping in our previous meta-GWAS (Patients: n = 10,516; healthy controls: n = 20,772) within the CCR6/FGFR1OP locus, rs9459874 and rs1012656 were identified as primary functional variants. These functional variants accounted for the effects of GWAS-identified lead SNPs in CCR6/FGFR1OP. Additionally, the roles of rs9459874 and rs1012656 in regulating FGFR1OP transcription and CCR6 translation, respectively, were supported by expression quantitative trait loci (eQTL) analysis and gene editing technology using the CRISPR/Cas9 system. Immunohistochemistry showed higher expression of CCR6 protein in the livers of patients with PBC than in those of a non-diseased control. In conclusion, we identified primary functional variants in CCR6/FGFR1OP and revealed the molecular mechanisms by which these variants confer PBC-susceptibility in an eQTL-dependent or -independent manner. The approach in this study is applicable for the elucidation of the pathogenesis of other autoimmune disorders in which CCR6/FGFR1OP is known as a susceptibility locus, as well as PBC.

Published
2022

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

Author

Kenichi Harada, S. Tamura, Yosuke Kawai, Shinji Shimoda, Noriyo Yamashiki, Atsumasa Komori, Atsushi Tanaka, Tomoharu Yoshizumi, Tomohiro Tanaka, Mitsuhisa Takatsuki, Minoru Nakamura, Yoshihiro Aiba, Nao Nishida, Masao Nagasaki, Kaname Kojima, Shintaro Yagi, Norihiro Kokudo, Yuji Soejima, Yoshihiko Maehara, Yuki Hitomi, Akira Mori, Katsushi Tokunaga, Susumu Eguchi, Shinji Uemoto, Minae Kawashima, Hitomi Nakamura, and Kazuko Ueno

Subjects
Genetic Markers, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Linkage disequilibrium, Genotype, Quantitative Trait Loci, Jaundice, lcsh:Medicine, Genome-wide association study, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, 03 medical and health sciences, Japan, Internal medicine, Humans, Medicine, SNP, Genetic Predisposition to Disease, Association mapping, lcsh:Science, Multidisciplinary, Liver Cirrhosis, Biliary, business.industry, Cathepsin Z, lcsh:R, Odds ratio, Middle Aged, Prognosis, 030104 developmental biology, Expression quantitative trait loci, Disease Progression, Female, lcsh:Q, medicine.symptom, business, Genome-Wide Association Study, Transcription Factors
Abstract

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 × 10−7) 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 × 10−8). 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.

Published
2018

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

Author

Nao Nishida, Minae Kawashima, Yuki Hitomi, Minoru Nakamura, Hitomi Nakamura, Michio Yasunami, and Katsushi Tokunaga

Subjects
Male, 0301 basic medicine, Linkage disequilibrium, Genotype, Cholangitis, lcsh:Medicine, Single-nucleotide polymorphism, Comorbidity, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Severity of Illness Index, Article, Linkage Disequilibrium, 03 medical and health sciences, Gene Frequency, Japan, HLA-DQ, HLA-DQ beta-Chains, Humans, Genetic Predisposition to Disease, lcsh:Science, Allele frequency, Alleles, Genetic Association Studies, Aged, Disease Resistance, Genetics, Multidisciplinary, Haplotype, lcsh:R, Odds ratio, Middle Aged, Patient Outcome Assessment, 030104 developmental biology, Haplotypes, Case-Control Studies, Immunology, Female, lcsh:Q
Abstract

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 × 10−22), DQB1*03:01 (odds ratio: 0.50, p = 6.76 × 10−10), DRB1*08:03 (odds ratio: 1.75, p = 1.01 × 10−7) and DQB1*04:01 (odds ratio: 1.50, p = 9.20 × 10−6) 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 × 10−8) was demonstrated by the stepwise exclusion of the individuals possessing these HLA alleles from the comparison.

Published
2017

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

Author

Takeaki Sato, Hironori Sakai, Tatsuki Ichikawa, Atsushi Naganuma, Atsushi Tanaka, Tatsuo Kanda, Hirotoshi Ebinuma, Masataka Seike, Hidetaka Shibata, Tatsuji Komatsu, Mikio Zeniya, Shinji Uemoto, Toshiki Nikami, Yoko Nakamura, Osamu Yokosuka, Yoshiyuki Ueno, Masaru Harada, Masao Nagasaki, Keisuke Ario, Yuki Hitomi, Haruhiro Yamashita, Yutaka Mano, Michio Senju, Makiko Taniai, Kazuhiko Yamauchi, Satoshi Yamagiwa, Makoto Nakamuta, Fujio Makita, Kazuhiro Sugi, Kouki Matsushita, Kiyoshi Migita, Masahiro Ito, Noriaki Naeshiro, Hajime Takikawa, Kaname Kojima, Noboru Hirashima, Norihiro Kokudo, Shinji Katsushima, Shinya Nagaoka, Hironao Takahashi, Kuniaki Arai, Kazumoto Murata, Etsuko Hashimoto, Masanori Abe, Tsutomu Yamashita, Naohiko Masaki, Minoru Nakamura, Hiroshi Kouno, Atsumasa Komori, Kiyoshi Furuta, Shinji Shimoda, Kaname Yoshizawa, Yoshihiko Maehara, Iwao Yabuuchi, Seigo Abiru, Shotaro Sakisaka, Rie Sugimoto, Hideo Nishimura, Takashi Himoto, Yasuaki Takeyama, Yosuke Kawai, Hiromasa Ohira, Satoru Joshita, Yusuke Shimada, Katsushi Tokunaga, Masahiro Kikuchi, Minae Kawashima, Masao Honda, Hiroshi Kamitsukasa, Toshiki Komeda, Yoshihiro Aiba, Eiji Mita, Hajime Ohta, Nao Nishida, Kazuhiko Nakao, Hiroshi Yatsuhashi, Takeji Umemura, Masaharu Koda, Seiji Tsunematsu, Hirotaka Kouno, Teruko Arinaga-Hino, Kazuko Ueno, Masaaki Shimada, Hitomi Nakamura, Shuichi Kaneko, and Akinobu Takaki

Subjects
0301 basic medicine, Adult, Male, In silico, lcsh:Medicine, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Pathogenesis, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Japan, SNP, Humans, lcsh:Science, Gene, Aged, Genetics, Aged, 80 and over, Multidisciplinary, Effector, Liver Cirrhosis, Biliary, lcsh:R, Middle Aged, 030104 developmental biology, Glucosyltransferases, lcsh:Q, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Article, Scientific reports.9 :102(2019)

Published
2019

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

Author

Seigo Abiru, Yoshihiro Aiba, Minoru Nakamura, Shinji Shimoda, Takashi Suematsu, Kenichi Harada, Masahiro Ito, Hitomi Nakamura, Nao Nishida, Hiroshi Yatsuhashi, Shinichi Aishima, Katsushi Tokunaga, Kiyoshi Migita, Atsumasa Komori, Minae Kawashima, Yuki Hitomi, Mitsuhisa Takatsuki, Shinya Nagaoka, and Susumu Eguchi

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Bilirubin, Jaundice, lcsh:Medicine, Aspartate transaminase, Endosomes, digestive system, Article, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Alagille syndrome, medicine, Humans, lcsh:Science, Aged, Blood Cells, Multidisciplinary, biology, Liver Cirrhosis, Biliary, business.industry, lcsh:R, Cathepsin Z, Albumin, Middle Aged, medicine.disease, Immunohistochemistry, digestive system diseases, 030104 developmental biology, Endocrinology, Alanine transaminase, chemistry, Hepatocytes, biology.protein, Female, lcsh:Q, medicine.symptom, Lysosomes, business, Genome-Wide Association Study
Abstract

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.

Published
2018

30. Are minor alleles more likely to be risk alleles?

Author

Richard Chen, Marina Sirota, Naoyuki Kamatani, Weronika Sikora-Wohlfeld, Takashi Kido, Keiichi Kodama, Minae Kawashima, Shinichi Kikuchi, Dexter Hadley, Atul J. Butte, and Anil Patwardhan

Subjects
0301 basic medicine, lcsh:Internal medicine, Linkage disequilibrium, lcsh:QH426-470, Evolution, Oncology and Carcinogenesis, Genome-wide association study, Medical Biochemistry and Metabolomics, Biology, Linkage Disequilibrium, Evolution, Molecular, Databases, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Genetic, Databases, Genetic, GWASs, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Allele, lcsh:RC31-1245, Allele frequency, Alleles, Genetics (clinical), Genetic association, Genetics & Heredity, Risk alleles, Prevention, Human Genome, Molecular, Computational Biology, Minor alleles, Human genetics, 3. Good health, Minor allele frequency, lcsh:Genetics, 030104 developmental biology, Mendelian inheritance, symbols, Complex diseases, Negative natural selection, 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract

Background Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele. Methods Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion. Results Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs 50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (

Published
2018

31. Additional file 9: Table S1. of Are minor alleles more likely to be risk alleles?

Author

Kido, Takashi, Sikora-Wohlfeld, Weronika, Minae Kawashima, Kikuchi, Shinichi, Kamatani, Naoyuki, Patwardhan, Anil, Chen, Richard, Sirota, Marina, Kodama, Keiichi, Hadley, Dexter, and Butte, Atul

Abstract

Comparisons of observed and expected proportions of SNVs whose risk alleles are minor alleles in sudden cardiac arrest. Table S2. Comparisons of observed and expected proportions of SNVs whose risk alleles are minor alleles in systemic lupus erythematosus. (DOCX 16 kb)

Published
2018
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32. Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

Author

Minae Kawashima, Hitomi Nakamura, Yuta Fuyuno, Motohiro Esaki, Masakazu Takazoe, Yoshihiro Aiba, Satoshi Motoya, Michiaki Kubo, Nao Nishida, Katsushi Tokunaga, Takayuki Matsumoto, Keiko Yamazaki, Yasuo Suzuki, Atsushi Takahashi, Atsumasa Komori, Yuki Hitomi, Minoru Nakamura, Toshiyuki Matsui, and Takaaki Kawaguchi

Subjects
Adult, Male, medicine.medical_specialty, Disease, Biology, Polymorphism, Single Nucleotide, Young Adult, Primary biliary cirrhosis, Asian People, Crohn Disease, Japan, Molecular genetics, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetics (clinical), Aged, Aged, 80 and over, Crohn's disease, Liver Cirrhosis, Biliary, Middle Aged, medicine.disease, digestive system diseases, Genetic epidemiology, Statistical genetics, Immunology, Medical genetics, Female, Pharmacogenetics, Genome-Wide Association Study
Abstract

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.

Published
2015

33. Human primary biliary cirrhosis-susceptible allele of rs4979462 enhances TNFSF15 expression by binding NF-1

Author

Minae Kawashima, Katsushi Tokunaga, Mika Matsuhashi, Minoru Nakamura, Nao Nishida, Hitoshi Okazaki, Yoshihiro Aiba, and Yuki Hitomi

Subjects
Male, Tumor Necrosis Factor Ligand Superfamily Member 15, In silico, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Jurkat Cells, Genetics, Humans, Electrophoretic mobility shift assay, Allele, Alleles, Genetics (clinical), Genetic association, Neurofibromin 1, Liver Cirrhosis, Biliary, Molecular biology, Gene Expression Regulation, Case-Control Studies, Female, Genome-Wide Association Study, Protein Binding
Abstract

A genome-wide association study (GWAS) identified tumor necrosis factor superfamily member 15 (TNFSF15) as the strongest associated gene with susceptibility to primary biliary cirrhosis (PBC) outside the HLA loci in the Japanese population. However, causal functional variants of the TNFSF15 locus and the molecular mechanism underlying disease susceptibility have not been clarified. Here, to identify the functional causal variants of the TNFSF15 locus, integrated analysis comprising in silico analysis, a case–control association study and in vitro functional analysis was performed. Initially, 32 functional candidate single-nucleotide polymorphisms (SNPs) in the expression regulatory motifs, the coding region, or the untranslated regions (UTRs) of the TNFSF15 locus were selected by in silico analysis. By the case–control association studies using PBC patients (n = 1279) and healthy controls (n = 1091) in the Japanese population, rs4979462 [P = 1.85 × 10−14 (our previous study)], rs56211063 (P = 2.21 × 10−14), and rs55768522 (r 2 = 1 with rs4979462) were likely candidates for causal variants. Among these SNPs, rs4979462 was identified as the causal variant by in vitro functional analysis using luciferase assay and electrophoretic mobility shift assay (EMSA). Super-shift assay clarified that PBC-susceptible allele of rs4979462 generated a novel NF-1 binding site. Moreover, higher endogenous TNFSF15 protein and mRNA expression levels were observed in individuals with the PBC-susceptible allele of rs4979462. This study identified the causal variant for PBC susceptibility in the TNFSF15 locus and clarified its underlying molecular mechanism. TNFSF15 and NF-1 are considered to be potential targets for the treatment of PBC.

Published
2015

34. High-accuracy imputation for HLA class I and II genes based on high-resolution SNP data of population-specific references

Author

Minae Kawashima, Nao Nishida, Yang W, Naoyuki Kamatani, Hiromi Toyoda, Shigeo Kamitsuji, Hiromi Sawai, Katsushi Tokunaga, Seik-Soon Khor, Taku Miyagawa, Makoto Honda, and Xiuwen Zheng

Subjects
Linkage disequilibrium, Genotype, Population, Genome-wide association study, Human leukocyte antigen, Computational biology, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Asian People, Gene Frequency, Genetics, Humans, education, Alleles, Genetic association, Pharmacology, education.field_of_study, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Sample size determination, Case-Control Studies, Molecular Medicine, Original Article, Imputation (genetics), Genome-Wide Association Study, Statistical Imputation
Abstract

Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5-98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.

Published
2015

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

Author

Minae Kawashima, Masao Nagasaki, Kaname Kojima, Minoru Nakamura, Nao Nishida, Yuki Hitomi, Yosuke Kawai, Katsushi Tokunaga, Yoshihiro Aiba, and Michio Yasunami

Subjects
0301 basic medicine, Genotype, Science, Gene Expression, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Models, Biological, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genes, Reporter, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, Nucleotide Motifs, Association mapping, Alleles, Genetic Association Studies, Genetic association, Genetics, Multidisciplinary, Binding Sites, Base Sequence, Forkhead Box Protein O1, Liver Cirrhosis, Biliary, Computational Biology, Genetic Variation, Membrane Proteins, Neoplasm Proteins, 030104 developmental biology, Mutation, Medicine, Imputation (genetics), Chromosomes, Human, Pair 17, Genome-Wide Association Study, Protein Binding
Abstract

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 −8, 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.

Published
2017

37. The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome

Author

Tetsuya Horita, Shinji Morimoto, Tamao Kitaori, Yosuke Omae, Daisuke Fujita, Minae Kawashima, Mayumi Sugiura-Ogasawara, Kinue Katano, Hiromi Sawai, Seik-Soon Khor, Yasuhiko Ozaki, Shinji Katsuragi, Tomio Fujita, Licht Toyo-oka, Eriko Morishita, Atsuko Murashima, Katsushi Tokunaga, and Tatsuya Atsumi

Subjects
0301 basic medicine, Adult, Abortion, Habitual, Genotype, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Biology, Bioinformatics, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Antiphospholipid syndrome, HLA Antigens, Pregnancy, Genetics, medicine, SNP, Humans, Genetic Predisposition to Disease, Genetics (clinical), Alleles, Genetic association, Lupus anticoagulant, 030219 obstetrics & reproductive medicine, Middle Aged, medicine.disease, Antiphospholipid Syndrome, Genotype frequency, 030104 developmental biology, Phenotype, Genetic epidemiology, Antibodies, Anticardiolipin, Case-Control Studies, Lupus Coagulation Inhibitor, Female, Genome-Wide Association Study
Abstract

Antiphospholipid syndrome (APS) is the most important treatable cause of recurrent pregnancy loss. The live birth rate is limited to only 70–80% in patients with APS undergoing established anticoagulant therapy. Lupus anticoagulant (LA), but not anticardiolipin antibody (aCL), was found to predict adverse pregnancy outcome. Recent genome-wide association studies (GWAS) of APS focusing on aCL have shown that several molecules may be involved. This is the first GWAS for obstetric APS focusing on LA. A GWAS was performed to compare 115 Japanese patients with obstetric APS, diagnosed according to criteria of the International Congress on APS, and 419 healthy individuals. Allele or genotype frequencies were compared in a total of 426 344 single-nucleotide polymorphisms (SNPs). Imputation analyses were also performed for the candidate regions detected by the GWAS. One SNP (rs2288493) located on the 3′-UTR of TSHR showed an experiment-wide significant APS association (P=7.85E-08, OR=6.18) under a recessive model after Bonferroni correction considering the number of analyzed SNPs. Another SNP (rs79154414) located around the C1D showed a genome-wide significant APS association (P=4.84E-08, OR=6.20) under an allelic model after applying the SNP imputation. Our findings demonstrate that a specific genotype of TSHR and C1D genes can be a risk factor for obstetric APS.

Published
2016

38. The inclusion of genomic data in the 2015 revision of Japan’s Protection of Personal Information Act: protection of wider range of genomic data as our next challenge

Author

Joshua Wittig, Kazuto Kato, Takanori Fujita, Natsuko Yamamoto, Minae Kawashima, and Masatomo Suzuki

Subjects
0301 basic medicine, Information management, Genome, Human, Information Management, business.industry, Genomic data, Internet privacy, Genomics, Health records, Security Measures, 03 medical and health sciences, 030104 developmental biology, Health Records, Personal, Japan, Political science, Genetics, Humans, Genetic Privacy, business, Inclusion (education), Personally identifiable information, Confidentiality, Genetics (clinical)
Published
2018

39. THU-025-Pathway-analysis using datasets of GWAS and microarray identified IFNG as the most significant upstream-regulator in primary biliary cholangitis

Author

Yoshihiro Aiba, Kazuko Ueno Ueno, Kaname Kojima, Minae Kawashima, Yosuke Kawai, Minoru Nakamura, Katsushi Tokunaga, Masao Nagasaki, Atsushi Tanaka, Seigo Abiru, Olivier Gervais, Atsumasa Komori, Nao Nishida, Shinji Shimoda, Hiroshi Yatsuhashi, Shinya Nagaoka, and Yuki Hitomi

Subjects
Hepatology, Microarray, Regulator, Genome-wide association study, Upstream (networking), Computational biology, Biology, Pathway analysis
Published
2019

40. Poster Sessions

Author

E Orito, JH Kang, Makoto Honda, S Mochida, S Kaneko, KH Han, E Mita, Kentaro Matsuura, Sung-Ku Ahn, M Sugiyama, K Kashiwase, Masayuki Kurosaki, T Ide, Yasuhiro Asahina, Namiki Izumi, Masaaki Korenaga, A Tamori, Y Itoh, Yoshio Tanaka, Mamoru Watanabe, K Hino, Y Hiasa, Nao Nishida, Kaoru Suzuki, Manabu Minami, Y Poovorawan, Hiromi Sawai, Ken Yamamoto, Shuhei Hige, Y Eguchi, M. F. Yuen, W.-K. Seto, Minae Kawashima, E Tanaka, Y Mawatari, M Mizokami, Koji Tokunaga, Isao Sakaida, and Y Murawaki

Subjects
0303 health sciences, medicine.medical_specialty, Hepatology, business.industry, Cost effectiveness, Gastroenterology, Virus, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Chronic hepatitis, 030220 oncology & carcinogenesis, Boceprevir, Internal medicine, Genotype, medicine, business, 030304 developmental biology
Abstract

This journal suppl. entitled: Special Issue: The 64th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2013

Published
2013

41. Systematic evaluation of personal genome services for Japanese individuals

Author

Naoyuki Kamatani, Minae Kawashima, Atul J. Butte, Takashi Kido, Melanie Swan, and Seiji Nishino

Subjects
Genome, Human, MEDLINE, Genome-wide association study, Single-nucleotide polymorphism, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Genome, Personal Health Services, Asian People, Genetics, Humans, SNP, Genetic Testing, Risk assessment, Genetics (clinical), Selection (genetic algorithm), Personal genomics, Demography
Abstract

Disease risk prediction (DRP) is one of the most important challenges in personal genome research. Although many direct-to-consumer genetic test (DTC) companies have begun to offer personal genome services for DRP, there is still no consensus on what constitutes a gold-standard service. Here, we systematically evaluated the distributions of DRPs from three DTC companies, that is, 23andMe, Navigenics and deCODEme, for 22 diseases using three Japanese samples. We systematically quantified and analyzed the differences between each DTC company's DRPs. Our independency test showed that the overall prediction results were correlated with each other, but not perfectly matched; less than onethird mismatching of the opposite direction occurred in eight diseases. Moreover, we found that the differences could mainly be attributed to four factors: (1) single nucleotide polymorphism (SNP) selection, (2) average risk estimation, (3) the disease risk calculation algorithm and (4) ethnicity adjustment. In particular, only 7.1% of SNPs over 22 diseases were reviewed by all three companies. Therefore, development of a universal core SNPs list for non-Caucasian samples will be important for achieving better prediction capacity for Japanese samples. This systematic methodology provides useful insights for improving the capacity of DRPs in future personal genome services.

Published
2013

42. Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy

Author

Kaname Kojima, Huimin Zhang, Honglei Wang, Xi'an Fu, Chuan Wang, Hong Liu, Hyunchul Choi, Katsushi Tokunaga, Yonghu Sun, Licht Toyo-oka, Suk-Kyun Yang, Masao Nagasaki, Fangfang Bao, Olaf Rötzschke, Zhenhua Yue, Minae Kawashima, Jianjun Liu, Minoru Nakamura, Furen Zhang, Yuki Hitomi, Byong Duk Ye, Myunghee Hong, Anand Kumar Andiappan, Kyuyoung Song, Yosua Denise, Astrid Irwanto, Yongxiang Yu, and Gongqi Yu

Subjects
Male, Tumor Necrosis Factor Ligand Superfamily Member 15, 0301 basic medicine, medicine.medical_treatment, Locus (genetics), Disease, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Crohn Disease, Leprosy, Databases, Genetic, Genotype, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Allele, Gene, Crohn's disease, Multidisciplinary, Liver Cirrhosis, Biliary, medicine.disease, 030104 developmental biology, Cytokine, Organ Specificity, Immunology, Female
Abstract

Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn’s disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r2 = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC.

Published
2016

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

Author

Kazuaki Chayama, Masao Honda, Yoshiyuki Ueno, Masaru Harada, Norihiro Kokudo, Hajime Ota, Yoshihiro Aiba, Shinji Shimoda, Atsushi Naganuma, Kenichi Harada, Shotaro Sakisaka, Katsushi Tokunaga, Satoshi Yamagiwa, Toyokichi Muro, Fujio Makita, Kazuhiko Yamauchi, Masao Nagasaki, Tatsuji Komatsu, Hideo Nishimura, Yuki Hitomi, Nao Nishida, Hidetaka Shibata, Kazuhide Yamamoto, Hiromi Ishibashi, Takafumi Ichida, Tsutomu Yamashita, Keisuke Ario, Kazuhiko Nakao, Masanori Abe, Hirotaka Kouno, Kiyoshi Furuta, Makoto Nakamuta, Yasuhiro Miyake, Hiroto Egawa, Yosuke Kawai, Seigo Abiru, Michio Senju, Makiko Taniai, Yukio Ohara, Yoshihiko Maehara, Atsushi Tanaka, Hiroshi Yatsuhashi, Masahiro Kikuchi, Noboru Hirashima, Kazuhiro Sugi, Kaname Kojima, Shintaro Yagi, Hitomi Nakamura, Nobuyoshi Fukushima, Masashi Mizokami, Kiyoshi Migita, Hirotoshi Ebinuma, Kaname Yoshizawa, Kazumoto Murata, Takashi Himoto, Eiichi Takesaki, Naohiro Takahashi, Hiroshi Kouno, Toshiki Nikami, Atsumasa Komori, Tomohiro Tanaka, Shinji Uemoto, Yoko Nakamura, Kouki Matsushita, Hajime Takikawa, Akira Mori, Masahiro Ito, Toshiki Komeda, Hiromasa Ohira, S. Tamura, Etsuko Hashimoto, Naohiko Masaki, Osamu Yokosuka, Ken Shirabe, Shinya Nagaoka, Michio Yasunami, Takeji Umemura, Masaaki Shimada, Masataka Seike, Mikio Zeniya, Shuichi Kaneko, Haruhiro Yamashita, Minae Kawashima, Motoyuki Kohjima, Hiroshi Mano, Minoru Nakamura, Satoru Joshita, and Tatsuo Kanda

Subjects
0301 basic medicine, Male, Genotype, General Population Cohort, Genome-wide association study, Locus (genetics), Disease, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Asian People, Japan, Protein Kinase C beta, Genetics, Genetic predisposition, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Liver Cirrhosis, Biliary, General Medicine, Odds ratio, Japanese population, digestive system diseases, 030104 developmental biology, Female, Genome-Wide Association Study
Abstract

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.

Published
2016

45. Genome-wide Association Study Identifies TNFSF15 and POU2AF1 as Susceptibility Loci for Primary Biliary Cirrhosis in the Japanese Population

Author

Yoshihiko Maehara, Nobuyoshi Fukushima, Makoto Nakamuta, Kuniaki Arai, Noboru Hirashima, Hajime Takikawa, Kentaro Kikuchi, Yasuhiko Sugawara, Hiromasa Ohira, Shintaro Yagi, Yoshihiro Aiba, Akinobu Taketomi, Masakazu Kobayashi, Toshiki Komeda, Kazuhiro Sugi, Hirotoshi Ebinuma, Ken Shirabe, Jinya Ishida, Tatsuki Ichikawa, Minoru Nakamura, Katsuji Hirano, Hiromi Ishibashi, Kyoko Monoe, Eiichi Takesaki, Tatsuji Komatsu, Koichi Honda, Yasuni Nakanuma, Makiko Taniai, Masao Honda, Yasuhiro Miyake, Satoshi Yamagiwa, Kiyoshi Migita, Michiyasu Yagura, Toyokichi Muro, Yasuaki Takeyama, Kenichi Harada, Kazuhide Yamamoto, Atsushi Tanaka, Masanori Abe, Michiaki Koga, Yukio Watanabe, Masaaki Shimada, Morikazu Onji, Noriyo Yamashiki, Teru Kumagi, Masahiro Ito, Michio Yasunami, S. Tamura, Masataka Seike, Shuichi Kaneko, Takeji Umemura, Mikio Zeniya, Etsuko Hashimoto, Atsumasai Komori, Keisuke Ario, Naohiko Masaki, Nao Nishida, Norihiro Kokudo, Hiroki Takahashi, Kaname Yoshizawa, Hiroshi Yatsuhashi, Akira Mori, Takafumi Ichida, Kazuhiko Nakao, Hirohito Tsubouchi, Masashi Mizokami, Katsushi Tokunaga, Shinji Uemoto, Yoko Nakamura, Minae Kawashima, Hitomi Nakamura, Takeo Saoshiro, Keiichi Hirata, Satoru Joshita, Shinji Shimoda, Shotaro Sakisaka, Hirotaka Kouno, Hirotsugu Kouno, Hajime Ota, and Yoshiyuki Ueno

Subjects
Adult, Male, Tumor Necrosis Factor Ligand Superfamily Member 15, Genome-wide association study, Human leukocyte antigen, Biology, White People, Young Adult, Primary biliary cirrhosis, Asian People, HLA Antigens, Report, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Genetics(clinical), STAT4, Genetics (clinical), Aged, Aged, 80 and over, B-Lymphocytes, Polymorphism, Genetic, Liver Cirrhosis, Biliary, Tumor Necrosis Factor-alpha, Case-control study, NF-kappa B p50 Subunit, Cell Differentiation, Odds ratio, Middle Aged, STAT4 Transcription Factor, medicine.disease, IKZF3, Genetic Loci, Case-Control Studies, Immunology, Trans-Activators, Female, Genome-Wide Association Study
Abstract

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

Published
2012

46. Abnormally Low Serum Acylcarnitine Levels in Narcolepsy Patients

Author

Makoto Honda, Susumu Tanaka, Minae Kawashima, Taku Miyagawa, Mihoko Shimada, Katsushi Tokunaga, Hiroko Miyadera, and Yutaka Honda

Subjects
Adult, Male, medicine.medical_specialty, Genotype, Cataplexy, Gene Expression, Excessive daytime sleepiness, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Carnitine, Physiology (medical), Internal medicine, medicine, Humans, Carnitine O-palmitoyltransferase, Narcolepsy, Sleep disorder, Carnitine O-Palmitoyltransferase, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Case-control study, Middle Aged, medicine.disease, Serum Acylcarnitine in Narcolpesy Patients, Endocrinology, Case-Control Studies, Female, Neurology (clinical), medicine.symptom, business, medicine.drug
Abstract

BACKGROUND Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and REM sleep abnormalities. A genome-wide association study identified a novel narcolepsy-related single nucleotide polymorphism (SNP), rs5770917, which is located adjacent to CPT1B (carnitine palmitoyltransferase 1B). In this study, we analyzed the CPT1B expression level and measured the carnitine fractions in blood samples obtained from narcolepsy patients and control subjects to test the hypothesis that fatty acid β-oxidation is altered in narcolepsy. METHODOLOGY AND RESULTS We measured CPT1B mRNA expression in white blood cells of 38 narcolepsy patients and 56 healthy control subjects. The serum carnitine fractions (total carnitine, free carnitine, and acylcarnitine) were measured in the 38 narcolepsy patients and in 30 of 56 control subjects. Stepwise multiple regression analysis revealed that the risk allele (C) for SNP rs5770917 was significantly associated with decreased CPT1B mRNA expression (P = 1.0 × 10(-9)), and the CPT1B expression was higher in the narcolepsy patients than in the controls (P = 0.005). The acylcarnitine levels were abnormally low in 21% of the narcolepsy patients while those of all the controls were within the normal range. Stepwise multiple regression analysis using the dichotomous variable for acylcarnitine (normal or abnormal) as an objective variable revealed that the diagnosis of narcolepsy but not CPT1B expression level and BMI was associated with abnormally low acylcarnitine levels (P = 0.006). CONCLUSIONS Our results indicate that multiple factors are involved in the regulation of serum acylcarnitine levels. Abnormally low levels of acylcarnitine observed in narcolepsy suggest dysfunctional fatty acid β-oxidation pathway.

Published
2011

47. An approach based on a genome-wide association study reveals candidate loci for narcolepsy

Author

Makoto Honda, Taku Miyagawa, Katsushi Tokunaga, Yutaka Honda, Mihoko Shimada, Susumu Tanaka, and Minae Kawashima

Subjects
Candidate gene, Linkage disequilibrium, Calcium Channels, L-Type, Genotype, Cataplexy, Receptors, Antigen, T-Cell, alpha-beta, Excessive daytime sleepiness, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Gene Frequency, HLA-DQ Antigens, Genetics, medicine, HLA-DQ beta-Chains, Humans, Genetic Predisposition to Disease, Poly-ADP-Ribose Binding Proteins, Genetics (clinical), Narcolepsy, Genetic association, Sleep disorder, Chi-Square Distribution, Membrane Glycoproteins, NFATC Transcription Factors, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, DNA Polymerase II, HLA-DR Antigens, medicine.disease, Cytokines, medicine.symptom, Carrier Proteins, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and a pathological manifestation of rapid eye movement during sleep. Narcoleptic pathogenesis is triggered by both genetic and environmental factors. Recently, development of genome-wide association studies (GWAS) has identified new genetic factors, with many more susceptibility genes yet to be elucidated. Using a new approach that consists of a combination of GWAS and an extensive database search for candidate genes, we picked up 202 candidate genes and performed a replication study in 222 narcoleptic patients and 380 controls. Statistical analysis indicated that six genes, NFATC2, SCP2, CACNA1C, TCRA, POLE, and FAM3D, were associated with narcolepsy (P < 0.001). Some of these associations were further supported by gene expression analyses and an association study in essential hypersomnia (EHS), CNS hypersonia similar to narcolepsy. This novel approach will be applicable to other GWAS in the search of disease-related susceptibility genes.

Published
2010

48. Absence of anti-aquaporin-4 antibodies in narcolepsy

Author

Minae Kawashima, Makoto Honda, and Susumu Tanaka

Subjects
medicine.medical_specialty, Sleep disorder, Neuromyelitis optica, Neurology, biology, Physiology, business.industry, Autoantibody, medicine.disease, Pathophysiology, Neuropsychology and Physiological Psychology, Cerebrospinal fluid, Endocrinology, Physiology (medical), Internal medicine, mental disorders, medicine, biology.protein, sense organs, Antibody, business, Narcolepsy
Abstract

Narcolepsy is a chronic sleep disorder, and dysfunction in hypocretinergic neurotransmission has been shown to underlie the pathophysiology of this disorder. Recently, two neuromyelitis optica patients with hypersomnia, hypothalamic lesions, serum anti-aquaporin-4 (AQP4) antibodies, and reduced cerebrospinal fluid hypocretin levels were reported. We hypothesized that anti-AQP4 antibodies induce hypocretin dysfunction leading to hypersomonia in a subgroup of narcolepsy or hypersomnia patients. In this study, we screened for anti-AQP4 antibodies in sera from 251 patients with narcolepsy, 34 with other hypersomnias, and 200 healthy controls by using the radioligand binding assay method. A positive result for anti-AQP4 antibodies was found only in one healthy control subject. All the hypersomnia patients were negative for this antibody. Our results indicated that anti-AQP4 antibody is not useful as a diagnostic marker for narcolepsy and other hypersomnias.

Published
2009

49. Appropriate data cleaning methods for genome-wide association study

Author

Takeshi Otowa, Katsushi Tokunaga, Nao Nishida, Yoshio Momose, Asako Koike, Yuji Okazaki, Taku Miyagawa, Shoji Tsuji, Akihiro Fujimoto, Tsukasa Sasaki, Jun Gotoh, Minae Kawashima, Jun Ohashi, Yasuo Nakahara, Ryosuke Kimura, and Hisashi Tanii

Subjects
Genetics, Mahalanobis distance, Genotype, Genome, Human, Computational Biology, Single-nucleotide polymorphism, Genome-wide association study, Computational biology, Biology, Polymorphism, Single Nucleotide, Minor allele frequency, Asian People, Gene Frequency, Humans, SNP, Genotyping, Allele frequency, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Genetic association
Abstract

Genome-wide association studies (GWAS) using a large number of single nucleotide polymorphisms (SNPs) have successfully been applied to identify genetic variants of common diseases. However, genotyping using the new array technologies is often associated with spurious results that could unfavorably affect analyses of GWAS. Consequently, data cleaning is of paramount importance in excluding spurious genotyping results. In this study, we investigated the criteria required for the appropriate cleaning of 389 unrelated healthy Japanese samples analyzed using the GeneChip Human Mapping 500K Array Set for GWAS. The samples were randomly subdivided into two groups, and the allele frequencies in the groups were compared for individual SNPs as a quasi-case-control study. Then, observed results were filtered by four parameters (SNP call rate, confidence score obtained using the Bayesian Robust Linear Model with Mahalanobis genotype-calling algorithm, Hardy-Weinberg equilibrium, and minor allele frequency) and assessed for deviation from the null hypothesis. We found that appropriate data cleaning could be achieved using these four parameters. Our findings offer an avenue for obtaining appropriate data from GWAS.

Published
2008

50. Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array

Author

Minae Kawashima, Akira Oka, Sachiko Kitanaka, Hideki Yoshida, Katsushi Tokunaga, Keiko Yamamoto, Tsuyoshi Isojima, Mayuko Tamura, Taichi Kitaoka, Noriyuki Namba, and Keiichi Ozono

Subjects
Heterozygote, Nonsense mutation, lcsh:Medicine, Administration, Oral, Single-nucleotide polymorphism, Consanguinity, Biology, Polymorphism, Single Nucleotide, Loss of heterozygosity, medicine, SNP, Humans, Vitamin D, lcsh:Science, Chromosome 12, Alleles, Growth Disorders, Genetics, Multidisciplinary, Chromosomes, Human, Pair 12, Genome, Human, Hydroxycholecalciferols, lcsh:R, Homozygote, Alopecia, Uniparental Disomy, medicine.disease, Uniparental disomy, Body Height, Rickets, Hypophosphatemic, Child, Preschool, Dietary Supplements, Mutation, lcsh:Q, Calcium, Female, SNP array, Research Article
Abstract

Context Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD). Objective Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12. Materials and Methods A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array. Results The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father’s allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium. Conclusions This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

Published
2015

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