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179 results on '"Yuki, Hitomi"'

1. 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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2. 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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3. New antimalarials identified by a cell-based phenotypic approach: Structure–activity relationships of 2,3,4,9-tetrahydro-1H-β-carboline derivatives possessing a 2-((coumarin-5-yl)oxy)alkanoyl moiety

Author: Cho, Nobuo, Kikuzato, Ko, Futamura, Yushi, Shimizu, Takeshi, Hayase, Hiroki, Kamisaka, Kikuko, Takaya, Daisuke, Yuki, Hitomi, Honma, Teruki, Niikura, Mamoru, Kobayashi, Fumie, Watanabe, Nobumoto, Osada, Hiroyuki, and Koyama, Hiroo
Published: 2022
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4. Author Correction: Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases

Author: Nishida, Yuya, Yanagisawa, Sachiko, Morita, Rikuri, Shigematsu, Hideki, Shinzawa-Itoh, Kyoko, Yuki, Hitomi, Ogasawara, Satoshi, Shimuta, Ken, Iwamoto, Takashi, Nakabayashi, Chisa, Matsumura, Waka, Kato, Hisakazu, Gopalasingam, Chai, Nagao, Takemasa, Qaqorh, Tasneem, Takahashi, Yusuke, Yamazaki, Satoru, Kamiya, Katsumasa, Harada, Ryuhei, Mizuno, Nobuhiro, Takahashi, Hideyuki, Akeda, Yukihiro, Ohnishi, Makoto, Ishii, Yoshikazu, Kumasaka, Takashi, Murata, Takeshi, Muramoto, Kazumasa, Tosha, Takehiko, Shiro, Yoshitsugu, Honma, Teruki, Shigeta, Yasuteru, Kubo, Minoru, Takashima, Seiji, and Shintani, Yasunori
Published: 2022
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5. Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases

Author: Nishida, Yuya, Yanagisawa, Sachiko, Morita, Rikuri, Shigematsu, Hideki, Shinzawa-Itoh, Kyoko, Yuki, Hitomi, Ogasawara, Satoshi, Shimuta, Ken, Iwamoto, Takashi, Nakabayashi, Chisa, Matsumura, Waka, Kato, Hisakazu, Gopalasingam, Chai, Nagao, Takemasa, Qaqorh, Tasneem, Takahashi, Yusuke, Yamazaki, Satoru, Kamiya, Katsumasa, Harada, Ryuhei, Mizuno, Nobuhiro, Takahashi, Hideyuki, Akeda, Yukihiro, Ohnishi, Makoto, Ishii, Yoshikazu, Kumasaka, Takashi, Murata, Takeshi, Muramoto, Kazumasa, Tosha, Takehiko, Shiro, Yoshitsugu, Honma, Teruki, Shigeta, Yasuteru, Kubo, Minoru, Takashima, Seiji, and Shintani, Yasunori
Published: 2022
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6. Mapping of susceptible variants for cold medicine-related Stevens–Johnson syndrome by whole-genome resequencing

Author: Yosuke Kawai, Yuki Hitomi, Mayumi Ueta, Seik-Soon Khor, Ken Nakatani, Chie Sotozono, Shigeru Kinoshita, Masao Nagasaki, and Katsushi Tokunaga
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract Stevens–Johnson syndrome (SJS) and its severe condition with extensive skin detachment and a poor prognosis, toxic epidermal necrolysis (TEN), are immunologically mediated severe cutaneous reactions of the skin and mucous membranes such as the ocular surface. Genetic variations on the HLA-A and other autosomal genes have been identified as risk factors for cold medicine-related SJS/TEN with severe ocular complications (CM-SJS/TEN with SOC). Using a whole-genome sequencing (WGS) approach, we explored other susceptible variants of CM-SJS/TEN with SOC, especially among rare variants and structural variants (SVs). WGS was performed on samples from 133 patients with CM-SJS/TEN with SOC and 418 healthy controls to obtain single nucleotide polymorphisms (SNPs) and SVs. Genome-wide association tests were performed with these variants. Our genome-wide association test reproduced the associations of the common variants of HLA-A and loci on chromosome 16q12.1. We also identified novel associations of SVs on these loci and an aggregation of rare coding variants on the TPRM8 gene. In silico gene expression analysis on the HLA-A locus revealed that the SNP (rs12202296), which was significantly associated with susceptibility to CM-SJS/TEN with SOC, was correlated to an increase in HLA-A expression levels in the whole blood (P = 2.9 × 10−17), from the GTEx database. The majority of variants that were significantly associated with CM-SJS/TEN with SOC were found in non-coding regions, indicating the regulatory role of genetic variations in the pathogenesis of CM-SJS/TEN with SOC.
Published: 2021
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7. 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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8. Genome-Wide Association Study for Chronic Hepatitis B Infection in the Thai Population

Author: Saeideh Ashouri, Seik-Soon Khor, Yuki Hitomi, Hiromi Sawai, Nao Nishida, Masaya Sugiyama, Yosuke Kawai, Nawarat Posuwan, Pisit Tangkijvanich, Piyawat Komolmit, Makoto Tsuiji, Vorasuk Shotelersuk, Yong Poovorawan, Masashi Mizokami, and Katsushi Tokunaga
Subjects: chronic hepatitis B, GWAS, SNP, HLA, allele, haplotype, Genetics, QH426-470
Abstract: To identify novel host genetic variants that predispose to hepatitis B virus (HBV) persistence, we performed the first genome-wide association study in the Thai population involving 318 cases of chronic hepatitis B and 309 healthy controls after quality control measures. We detected the genome-wide significant association of the HLA class II region (HLA-DPA1/DPB1, rs7770370, p-value = 7.71 × 10−10, OR = 0.49) with HBV chronicity. Subsequent HLA allele imputation revealed HLA-DPA1*01:03 (Pc = 1.21 × 10−6, OR = 0.53), HLA-DPB1*02:01 (Pc = 2.17 × 10−3, OR = 0.50), and HLA-DQB1*06:09 (Pc = 2.17 × 10−2, OR = 0.07) as protective alleles, and HLA-DPA1*02:02 (Pc = 6.32 × 10−5, OR = 1.63), HLA-DPB1*05:01 (Pc = 1.13 × 10−4, OR = 1.72), HLA-DPB1*13:01 (Pc = 4.68 × 10−2, OR = 1.60), and HLA-DQB1*03:03 (Pc = 1.11 × 10−3, OR = 1.84) as risk alleles for HBV persistence. We also detected suggestive associations in the PLSCR1 (rs35766154), PDLIM5 (rs62321986), SGPL1 (rs144998273), and MGST1 (rs1828682) loci. Among single-nucleotide polymorphisms in the PLSCR1 locus, rs1061307 was identified as the primary functional variant by in silico/in vitro functional analysis. In addition to replicating the association of the HLA class II region, we detected novel candidate loci that provide new insights into the pathophysiology of chronic hepatitis B.
Published: 2022
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9. Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia

Author: Hashimoto, Mari, Saito, Yoriko, Nakagawa, Ryo, Ogahara, Ikuko, Takagi, Shinsuke, Takata, Sadaaki, Amitani, Hanae, Endo, Mikiko, Yuki, Hitomi, Ramilowski, Jordan A., Severin, Jessica, Manabe, Ri-ichiroh, Watanabe, Takashi, Ozaki, Kokoro, Kaneko, Akiko, Kajita, Hiroshi, Fujiki, Saera, Sato, Kaori, Honma, Teruki, Uchida, Naoyuki, Fukami, Takehiro, Okazaki, Yasushi, Ohara, Osamu, Shultz, Leonard D., Yamada, Makoto, Taniguchi, Shuichi, Vyas, Paresh, de Hoon, Michiel, Momozawa, Yukihide, and Ishikawa, Fumihiko
Published: 2021
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10. Genomic Heritabilities and Correlations of 17 Traits Related to Obesity and Associated Conditions in the Japanese Population

Author: Olivier Gervais, Kazuko Ueno, Yosuke Kawai, Yuki Hitomi, Kazuharu Misawa, Shunsuke Teraguchi, Yen-Yen Wang, Katsushi Tokunaga, and Masao Nagasaki
Subjects: obesity, heritability, genetic correlation, japanese population, polygenic model analysis, Genetics, QH426-470
Abstract: Over the past few decades, obesity has become a public health issue of global concern. Even though disparities exist between human populations, e.g., the higher liver fat content of the Japanese despite a lower body mass index (BMI), studies on the genetics of obesity still largely focus on populations of European descent, leading to a dearth of genetic data on non-European populations. In this context, this study aimed to establish a broad picture of the genetic attributes of the Japanese population, by examining a representative sample of 18,889 individuals participating in the Tohoku Medical Megabank Project cohort. We applied linear mixed model methods to 17 traits related to obesity and associated diseases to estimate the heritabilities explained by common genetic variants and the genetic correlations between each pair of traits. These analyses allowed us to quantify the SNP heritability of health indicators such as BMI (0.248 ± 0.032) and HDL cholesterol (0.324 ± 0.031), and to provide one of the few estimates of the SNP heritability of cystatin C in unrelated individuals (0.260 ± 0.025). We discuss potential differences between the Japanese and people of European ancestry with respect to the genetic correlations between urinary biomarkers and adiposity traits, for which large estimates were obtained. For instance, the genetic correlations between urine potassium level and the values for weight, BMI, waist circumference, and waist-to-height ratio ranged from 0.290 to 0.559, much higher than the corresponding estimates in the UK Biobank.
Published: 2020
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11. 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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12. Coronin-1 is phosphorylated at Thr-412 by protein kinase Cα in human phagocytic cells

Author: Teruaki Oku, Yutaka Kaneko, Rie Ishii, Yuki Hitomi, Makoto Tsuiji, Satoshi Toyoshima, and Tsutomu Tsuji
Subjects: Coronin-1, Actin-binding protein, Protein kinase C, Phagocytosis, Phagosome-lysosome fusion, Biology (General), QH301-705.5, Biochemistry, QD415-436
Abstract: Coronin-1, a hematopoietic cell-specific actin-binding protein, is thought to be involved in the phagocytic process through its interaction with actin filaments. The dissociation of coronin-1 from phagosomes after its transient accumulation on the phagosome surface is associated with lysosomal fusion. We previously reported that 1) coronin-1 is phosphorylated by protein kinase C (PKC), 2) coronin-1 has two phosphorylation sites, Ser-2 and Thr-412, and 3) Thr-412 of coronin-1 is phosphorylated during phagocytosis. In this study, we examined which PKC isoform is responsible for the phosphorylation of coronin-1 at Thr-412 by using isotype-specific PKC inhibitors and small interfering RNAs (siRNAs). Thr-412 phosphorylation of coronin-1 was suppressed by Gö6976, an inhibitor of PKCα and PKCβI. This phosphorylation was attenuated by siRNA for PKCα, but not by siRNA for PKCβ. Furthermore, Thr-412 of coronin-1 was phosphorylated by recombinant PKCα in vitro, but not by recombinant PKCβ. We next examined the effects of Gö6976 on the intracellular distribution of coronin-1 in HL60 cells during phagocytosis. The confocal fluorescence microscopic observation showed that coronin-1 was not dissociated from phagosomes in Gö6976-treated cells. These results indicate that phosphorylation of coronin-1 at Thr-412 by PKCα regulates intracellular distribution during phagocytosis.
Published: 2021
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13. Small-molecule RAS/RAF Binding Inhibitors Allosterically Disrupt RAF Conformation and Exert Efficacy Against a Broad Spectrum of RAS-driven Cancers

Author: Shima, Fumi, primary, Yoshikawa, Yoko, additional, Makino, Yoshiteru, additional, Kubota, Hirokazu, additional, Kawamura, Takashi, additional, Matsumoto, Shigeyuki, additional, Yuki, Hitomi, additional, Shibaike, Akira, additional, Okamura, Megumi, additional, Okada, Tomoyo, additional, Horikawa, Manabu, additional, Horie, Kazumasa, additional, Koyanagi-Aoi, Michiyo, additional, Aoi, Takashi, additional, Kataoka, Tohru, additional, Honma, Teruki, additional, Kumasaka, Takashi, additional, and Koyama, Hiroo, additional
Published: 2024
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14. 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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15. Identification of a two-SNP PLA2R1 Haplotype and HLA-DRB1 Alleles as Primary Risk Associations in Idiopathic Membranous Nephropathy

Author: Khun Zaw Latt, Kenjiro Honda, Myo Thiri, Yuki Hitomi, Yosuke Omae, Hiromi Sawai, Yosuke Kawai, Shunsuke Teraguchi, Kazuko Ueno, Masao Nagasaki, Akihiko Mabuchi, Hajime Kaga, Atsushi Komatsuda, Katsushi Tokunaga, and Eisei Noiri
Subjects: Idiopathic Membranous Nephropathy, Phospholipase A2 Receptor (PLA2R), Missense SNPs, Single Nucleotide Polymorphisms (SNPs), Additional Risk Allele, Medicine, Science
Abstract: Abstract The associations of single nucleotide polymorphisms (SNPs) in PLA2R1 and HLA-DQA1, as well as HLA-DRB1*15:01-DQB1*06:02 haplotype with idiopathic membranous nephropathy (IMN) is well known. However, the primary associations of these loci still need to be determined. We used Japanese-specific SNP genotyping array and imputation using 2,048 sequenced Japanese samples to fine-map PLA2R1 region in 98 patients and 413 controls. The most significant SNPs were replicated in a separate sample set of 130 patients and 288 controls. A two-SNP haplotype of intronic and missense SNPs showed the strongest association. The intronic SNP is strongly associated with PLA2R1 expression in the Genotype-Tissue Expression (GTEx) database, and the missense SNP is predicted to alter peptide binding with HLA-DRB1*15:01 by the Immune Epitope Database (IEDB). In HLA region, we performed relative predispositional effect (RPE) tests and identified additional risk alleles in both HLA-DRB1 and HLA-DQB1. We collapsed the risk alleles in each of HLA-DRB1 and HLA-DQB1 into single risk alleles. Reciprocal conditioning of these collapsed risk alleles showed more residual significance for HLA-DRB1 collapsed risk than HLA-DQB1 collapsed risk. These results indicate that changes in the expression levels of structurally different PLA2R protein confer risk for IMN in the presence of risk HLA-DRB1 alleles.
Published: 2018
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16. Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen

Author: Yuki, Hitomi, Kikuzato, Ko, Koda, Yasuko, Mikuni, Junko, Tomabechi, Yuri, Kukimoto-Niino, Mutsuko, Tanaka, Akiko, Shirai, Fumiyuki, Shirouzu, Mikako, Koyama, Hiroo, and Honma, Teruki
Published: 2017
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17. 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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18. Support Vector Machine model for hERG inhibitory activities based on the integrated hERG database using descriptor selection by NSGA-II

Author: Ogura, Keiji, Sato, Tomohiro, Yuki, Hitomi, and Honma, Teruki
Published: 2019
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19. Quantum Chemical Interaction Analysis between SARS-CoV-2 Main Protease and Ensitrelvir Compared with Its Initial Screening Hit

Author: Watanabe, Chiduru, primary, Tanaka, Shigenori, additional, Okiyama, Yoshio, additional, Yuki, Hitomi, additional, Ohyama, Tatsuya, additional, Kamisaka, Kikuko, additional, Takaya, Daisuke, additional, Fukuzawa, Kaori, additional, and Honma, Teruki, additional
Published: 2023
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20. Quantum Chemical Interaction Analysis between SARS-CoV-2 Main Protease and Ensitrelvir (Xocova) Compared with Its Initial Screening Hit

Author: Watanabe, Chiduru, primary, Tanaka, Shigenori, additional, Okiyama, Yoshio, additional, Yuki, Hitomi, additional, Ohyama, Tatsuya, additional, Kamisaka, Kikuko, additional, Takaya, Daisuke, additional, Fukuzawa, Kaori, additional, and Honma, Teruki, additional
Published: 2022
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21. Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population

Author: Masao Nagasaki, Yoshihiro Aiba, Minoru Nakamura, Kazuko Ueno, Yuki Hitomi, Yosuke Kawai, Mayumi Ueta, Katsushi Tokunaga, and Olivier Gervais
Subjects: Cholangitis, Population, Single-nucleotide polymorphism, Context (language use), Genome-wide association study, Computational biology, Protein Serine-Threonine Kinases, Quantitative trait locus, Biology, Genome informatics, Quantitative trait, Polymorphism, Single Nucleotide, Genome, Article, 03 medical and health sciences, 0302 clinical medicine, Japan, Genetics, Humans, SNP, education, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, STAT4 Transcription Factor, Heritability, Ether-A-Go-Go Potassium Channels, Liver, 030220 oncology & carcinogenesis
Abstract: While the advent of GWAS more than a decade ago has ushered in remarkable advances in our understanding of complex traits, the limitations of single-SNP analysis have also led to the development of several other approaches. Simulation studies have shown that the regional heritability mapping (RHM) method, which makes use of multiple adjacent SNPs jointly to estimate the genetic effect of a given region of the genome, generally has higher detection power than single-SNP GWAS. However, thus far its use has been mostly limited to agricultural settings, and its potential for the discovery of new genes in human diseases is yet to be fully exploited. In this study, by applying the RHM method to primary biliary cholangitis (PBC) in the Japanese population, we identified three novel loci (STAT4, ULK4, and KCNH5) at the genome-wide significance level, two of which (ULK4 and KCNH5) have not been found associated with PBC in any population previously. Notably, these genes could not be detected by using conventional single-SNP GWAS, highlighting the potential of the RHM method for the detection of new susceptibility loci in human diseases. These findings thereby provide strong empirical evidence that RHM is an effective and practical complementary approach to GWAS in this context. Also, liver tissue mRNA microarray analysis revealed higher gene expression levels in ULK4 in PBC patients (P, 原発性胆汁性胆管炎の新たな遺伝要因を同定 --ヒト全ゲノム領域へのRHM法による世界初の成果--. 京都大学プレスリリース. 2021-04-09.
Published: 2021

22. Identification of novel drug-resistant EGFR mutant inhibitors by in silico screening using comprehensive assessments of protein structures

Author: Sato, Tomohiro, Watanabe, Hisami, Tsuganezawa, Keiko, Yuki, Hitomi, Mikuni, Junko, Yoshikawa, Seiko, Kukimoto-Niino, Mutsuko, Fujimoto, Takako, Terazawa, Yumiko, Wakiyama, Motoaki, Kojima, Hirotatsu, Okabe, Takayoshi, Nagano, Tetsuo, Shirouzu, Mikako, Yokoyama, Shigeyuki, Tanaka, Akiko, and Honma, Teruki
Published: 2012
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23. A Novel Pim-1 Kinase Inhibitor Targeting Residues That Bind the Substrate Peptide

Author: Tsuganezawa, Keiko, Watanabe, Hisami, Parker, Lorien, Yuki, Hitomi, Taruya, Shigenao, Nakagawa, Yukari, Kamei, Daisuke, Mori, Masumi, Ogawa, Naoko, Tomabechi, Yuri, Handa, Noriko, Honma, Teruki, Yokoyama, Shigeyuki, Kojima, Hirotatsu, Okabe, Takayoshi, Nagano, Tetsuo, and Tanaka, Akiko
Published: 2012
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24. Prediction of sites of metabolism in a substrate molecule, instanced by carbamazepine oxidation by CYP3A4

Author: Yuki, Hitomi, Honma, Teruki, Hata, Masayuki, and Hoshino, Tyuji
Published: 2012
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25. Genomic Heritabilities and Correlations of 17 Traits Related to Obesity and Associated Conditions in the Japanese Population

Author: Masao Nagasaki, Olivier Gervais, Kazuharu Misawa, Yuki Hitomi, Shunsuke Teraguchi, Katsushi Tokunaga, Kazuko Ueno, Yen-Yen Wang, and Kawai Yosuke
Subjects: Genetic correlation, Waist, Context (language use), Polygenic model analysis, QH426-470, Biology, Investigations, Body Mass Index, Heritability, 03 medical and health sciences, 0302 clinical medicine, Japan, Genetics, medicine, Humans, Mass index, 030212 general & internal medicine, Obesity, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Japanese population, Genetics of obesity, Genomics, medicine.disease, Cohort, Waist Circumference, Demography
Abstract: Over the past few decades, obesity has become a public health issue of global concern. Even though disparities exist between human populations, e.g., the higher liver fat content of the Japanese despite a lower body mass index (BMI), studies on the genetics of obesity still largely focus on populations of European descent, leading to a dearth of genetic data on non-European populations. In this context, this study aimed to establish a broad picture of the genetic attributes of the Japanese population, by examining a representative sample of 18,889 individuals participating in the Tohoku Medical Megabank Project cohort. We applied linear mixed model methods to 17 traits related to obesity and associated diseases to estimate the heritabilities explained by common genetic variants and the genetic correlations between each pair of traits. These analyses allowed us to quantify the SNP heritability of health indicators such as BMI (0.248 ± 0.032) and HDL cholesterol (0.324 ± 0.031), and to provide one of the few estimates of the SNP heritability of cystatin C in unrelated individuals (0.260 ± 0.025). We discuss potential differences between the Japanese and people of European ancestry with respect to the genetic correlations between urinary biomarkers and adiposity traits, for which large estimates were obtained. For instance, the genetic correlations between urine potassium level and the values for weight, BMI, waist circumference, and waist-to-height ratio ranged from 0.290 to 0.559, much higher than the corresponding estimates in the UK Biobank.
Published: 2020

26. 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
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27. 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
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28. The Genetics of Primary Biliary Cholangitis: A GWAS and Post-GWAS Update

Author: Yuki Hitomi and Minoru Nakamura
Subjects: Genetics, Genetics (clinical)
Abstract: Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which the small intrahepatic bile ducts are destroyed by autoimmune reactions. Among autoimmune diseases, which are polygenic complex traits caused by the combined contribution of genetic and environmental factors, PBC exhibits the strongest involvement of genetic heritability in disease development. As at December 2022, genome-wide association studies (GWASs) and associated meta-analyses identified approximately 70 PBC susceptibility gene loci in various populations, including those of European and East Asian descent. However, the molecular mechanisms through which these susceptibility loci affect the pathogenesis of PBC are not fully understood. This study provides an overview of current data regarding the genetic factors of PBC as well as post-GWAS approaches to identifying primary functional variants and effector genes in disease-susceptibility loci. Possible mechanisms of these genetic factors in the development of PBC are also discussed, focusing on four major disease pathways identified by in silico gene set analyses, namely, (1) antigen presentation by human leukocyte antigens, (2) interleukin-12-related pathways, (3) cellular responses to tumor necrosis factor, and (4) B cell activation, maturation, and differentiation pathways.
Published: 2023
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29. 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

30. 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

31. Molecular and morphological evidence of hybridization between native Ruditapes philippinarum and the introduced Ruditapes form in Japan

Author: Kitada, Shuichi, Fujikake, Chie, Asakura, Yoshiho, Yuki, Hitomi, Nakajima, Kaori, Vargas, Kelley M., Kawashima, Shiori, Hamasaki, Katsuyuki, and Kishino, Hirohisa
Published: 2013
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32. Quantitative prediction of hERG inhibitory activities using support vector regression and the integrated hERG dataset in AMED cardiotoxicity database

Author: Sato, Tomohiro, primary, Yuki, Hitomi, additional, and Honma, Teruki, additional
Published: 2021
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33. Predicting human liver microsomal stability with machine learning techniques

Author: Sakiyama, Yojiro, Yuki, Hitomi, Moriya, Takashi, Hattori, Kazunari, Suzuki, Misaki, Shimada, Kaoru, and Honma, Teruki
Published: 2008
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34. An epoxidation mechanism of carbamazepine by CYP3A4

Author: Hata, Masayuki, Tanaka, Yoshikazu, Kyoda, Naoko, Osakabe, Taisuke, Yuki, Hitomi, Ishii, Itsuko, Kitada, Mitsukazu, Neya, Saburo, and Hoshino, Tyuji
Published: 2008
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35. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author: S. Abiru, John F. Dillon, Yasuhiro Miyake, Piero Portincasa, Giancarlo Spinzi, R. Harvey, T. Ngatchu, Agostino Colli, M. Taniai, K. Flahive, Masanori Abe, B. Hoeroldt, S. Holder, Howard Curtis, María Isabel Colombo, C. MacNicol, Gang Xie, Andrew Chilton, H. Hussaini, Cristina Rigamonti, M. Kato, Shintaro Yagi, G. Abouda, D. Tyrer, Chris D. Evans, Christopher I. Amos, K. Koss, Kazuaki Chayama, P. Premchand, K. Migita, Simon Panter, Marco Marzioni, Silvia Colombo, Konstantinos N. Lazaridis, M. Yagura, Ashley Brown, D. Gocher, Domenico Alvaro, K. Murata, Mark Wright, Piero Luigi Almasio, C. Healey, A. Ciaccio, N. Wheatley, Vincenzo Cardinale, T. Delahooke, Chiara Milani, T. Shewan, W. Stableforth, S. Levi, Mark L. Green, James V. Jones, Y. Baird, Aftab Ala, Burroughs Ak, D. Williams, K. Ario, P. Sanghi, Hemant Gupta, P. Southern, L. Farrington, M. Hamilton, Andrew D. Higham, I. Yabuuchi, H. Yatsuhashi, Lorenzo Morini, T. Yamamoto, Douglas Thorburn, M. Carnahan, N. Nishida, Susan Slininger, M. Koga, K. Honda, Annarosa Floreani, Andrew Douglass, K. Netherton, M. Yasunami, Hirohito Tsubouchi, F. Donato, K. Walker, U. Shmueli, Paolo Muratori, Ray Mathew, J. Maiden, E. Dungca, Subramaniam Ramakrishnan, S. Vyas, Helen Sweeting, Subrata Saha, T. Komeda, T. Komatsu, H. J. Lee, Maria Consiglia Bragazzi, T. Komura, C. Thomas, C. Shallcross, C. Duggan, J. Kordula, F. Muscariu, Lourdes Cumlat, Imran Patanwala, Giulia Cardamone, L. Morgan, J. Brighton, Masao Honda, H. Nakamura, David Jones, Raj Srirajaskanthan, M. E. Gershwin, T. Muro, L. Stafford, N. Fukushima, Graham P. Butcher, Andrea Crosignani, George Lipscomb, K. Hirata, Y. Nagaoki, S. Mann, Paul G. Richardson, David A Elphick, M. Mupudzi, Y. Ohara, E. Grieve, Gayle Clifford, Claudio Tiribelli, M. Quinn, G. Van Duyvenvoorde, E. Archer, Tatsuki Ichikawa, J. Maltby, T. Arinaga-Hino, Simon Williams, A. King, Yasuni Nakanuma, H. Doyle, A. Brind, Nora Cazzagon, H. Ota, Daphne D’Amato, K. Hogben, H. Wooldridge, J. Wilkins, Shuichi Kaneko, L. Hankey, Gordon Wood, Andrew Fraser, K. Martin, A. Naqvi, M. Ninkovic, M. Patel, Yoshihiko Maehara, Kapil Kapur, I. Amey, Vincenza Calvaruso, Kenichi Harada, T. Yamashita, James Neuberger, N. Taylor, T. Lee, J. Featherstone, C. Lawlor, K. Seward, Satoshi Yamagiwa, Andrea Galli, L. Tan, Kentaro Kikuchi, K. Furuta, Mark A. Ainsworth, Hiromasa Ohira, Esther Unitt, Yosuke Kawai, N. Lancaster, D. Simpson, R. Shidrawi, I. Salam, A.J. Bell, Pietro Andreone, J. Ishida, Voi Shim Wong, N Fisher, Andrew C. Douds, R. Penn, Matthew Foxton, A. Watson, Andrew Mason, S. Walsh, Hiromi Ishibashi, Daniel M. Forton, Giovanni Casella, H. Takaki, K. Yamauchi, Pietro Lampertico, Osamu Yokosuka, M. Koda, M. Davies, H. Mitchison, P. Gyawali, G. Bird, M. Hughes, L. Jones, C. Hamilton, A. Hynes, R. Galaska, Fabio Marra, Debasish Das, C. Cowley, A. Fouracres, Yasuhiko Sugawara, E. Mita, T. Saoshiro, Akinobu Taketomi, Robert P. Myers, R. Przemioslo, F. Wright, L. Hobson, L. Currie, J. Allison, J. Hails, Noriyo Yamashiki, Massimo Zuin, C. Grimley, Alessio Gerussi, S. Besley, Stefano Duga, A. Piotrowicz, H. Kouno, L. Dali-kemmery, H. Sakai, M. Mizokami, Stefano Fagiuoli, Amy Davis, Pier Maria Battezzati, Masao Nagasaki, Luigi Muratori, A. Mori, S. Desmennu, S. Jones, R. Abrahams, Keith George, F. Makita, J. Brown, D. Gorard, Satoru Joshita, M. Mills, Pierluigi Toniutto, S. Campbell, J. Butterworth, S. Dyer, Filomena Morisco, Norihiro Kokudo, T. Yapp, C. Shorrock, Floriano Rosina, E. Walker, Shinji Uemoto, H. Takahashi, Simon M. Rushbrook, K. Amor, E. Marshall, J. Browning, S. Batham, Luca Fabris, Paul R. Banim, Meenakshi Narain, M. Harada, Dermot Gleeson, N. Hirashima, M. Kikuchi, T. Nikami, Gideon M. Hirschfield, Carlo Ferrari, G. Prasad, O. Chirag, Katsushi Tokunaga, M. Nasseri, Rosanna Asselta, Y. Lu, Ken Shirabe, D. Sirdefield, George F. Mells, K. Sugi, R. Ayres, G. Whatley, A. Singhal, M. Leoni, N. Sivaramakrishnan, T. 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Gordon, Shotaro Sakisaka, A. Dias, Chin Lye Ch'ng, M. Carter, A. Mandal, Yufang Shi, Takafumi Ichida, N. Masaki, M. Oblak, S. Nagaoka, Kevin Yoong, O. Gervais, Minoru Nakamura, Kazuhiko Nakao, S. Taylor-Robinson, L. Kent, Sushma Saksena, A. Affronti, K. Boulton, R. Ede, H. Pateman, K. Yoshizawa, G. Bray, H. Ebinuma, Yeng Ang, Akio Ido, John Ramage, Richard Sturgess, C. Gray, E. Durant, M. Hayes, A. Saeed, J. Keggans, J. Gitahi, T. Valliani, Edoardo G. Giannini, C. Foale, A. Palegwala, Lory Saveria Crocè, K. Matsushita, S. Shaukat, J. Mclindon, S. Pearson, A. Barnardo, A. Wright, Mirko Tarocchi, R Marley, M. Kent, C. Dickson, A. Gibbins, J. Whiteman, S. Singhal, Richard Aspinall, M. Ito, Laura Cristoferi, Maurizia Rossana Brunetto, J. Booth, A. Bathgate, Morikazu Onji, A. Grant, A. Paton, Y. Aiba, P. Chan, J. Sayer, S. Whalley, T. Mathialahan, J. Gotto, T. Kanda, B. Williams, K. Elliott, P. Raymode, Akinobu Takaki, V. Silvestre, I. Gee, C. Hovell, Graham R. Foster, D. Cotterill, G. 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D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. 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F., Invernizzi, P., Asselta R., Paraboschi E.M., Gerussi A., Cordell H.J., Mells G.F., Sandford R.N., Jones D.E., Nakamura M., Ueno K., Hitomi Y., Kawashima M., Nishida N., Tokunaga K., Nagasaki M., Tanaka A., Tang R., Li Z., Shi Y., Liu X., Xiong M., Hirschfield G., Siminovitch K.A., Walker E., Xie G., Mason A., Myers R., Peltekian K., Ghent C., Atkinson E., Juran B., Lazaridis K., Lu Y., Gu X., Jing K., Amos C., Affronti A., Brunetto M., Coco B., Spinzi G., Elia G., Ferrari C., Lleo A., Muratori L., Muratori P., Portincasa P., Colli A., Bruno S., Colloredo G., Azzaroli F., Andreone P., Bragazzi M., Alvaro D., Cardinale V., Cazzagon N., Rigamonti C., Floreani A., Rosina F., Ciaccio A., Cristoferi L., D'Amato D., Malinverno F., Mancuso C., Massironi S., Milani C., O'Donnell S.E., Ronca V., Barisani D., Lampertico P., Donato F., Fagiuoli S., Almasio P.L., Giannini E., Cursaro C., Colombo M., Valenti L., Miele L., Andriulli A., Niro G.A., Grattagliano I., Morini L., Casella G., Vinci M., Battezzati P.M., Crosignani A., Zuin M., Mattalia A., Calvaruso V., Colombo S., Benedetti A., Marzioni M., Galli A., Marra F., Tarocchi M., Picciotto A., Morisco F., Fabris L., Croce L.S., Tiribelli C., Toniutto P., Strazzabosco M., Ch'ng C.L., Rahman M., Yapp T., Sturgess R., Healey C., Czajkowski M., Gunasekera A., Gyawali P., Premchand P., Kapur K., Marley R., Foster G., Watson A., Dias A., Subhani J., Harvey R., McCorry R., Ramanaden D., Gasem J., Evans R., Mathialahan T., Shorrock C., Lipscomb G., Southern P., Tibble J., Gorard D., Palegwala A., Jones S., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali F., Rees I., Salam I., Narain M., Brown A., Taylor-Robinson S., Williams S., Grellier L., Banim P., Das D., Chilton A., Heneghan M., Curtis H., Gess M., Drake I., Aldersley M., Davies M., Jones R., McNair A., Srirajaskanthan R., Pitcher M., Sen S., Bird G., Barnardo A., Kitchen P., Yoong K., Chirag O., Sivaramakrishnan N., MacFaul G., Jones D., Shah A., Evans C., Saha S., Pollock K., Bramley P., Mukhopadhya A., Fraser A., Mills P., Shallcross C., Campbell S., Bathgate A., Shepherd A., Dillon J., Rushbrook S., Przemioslo R., Macdonald C., Metcalf J., Shmueli U., Davis A., Naqvi A., Lee T., Ryder S.D., Collier J., Klass H., Ninkovic M., Cramp M., Sharer N., Aspinall R., Goggin P., Ghosh D., Douds A., Hoeroldt B., Booth J., Williams E., Hussaini H., Stableforth W., Ayres R., Thorburn D., Marshall E., Burroughs A., Mann S., Lombard M., Richardson P., Patanwala I., Maltby J., Brookes M., Mathew R., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Panter S., Shearman J., Bray G., Butcher G., Forton D., Mclindon J., Cowan M., Whatley G., Mandal A., Gupta H., Sanghi P., Jain S., Pereira S., Prasad G., Watts G., Wright M., Neuberger J., Gordon F., Unitt E., Grant A., Delahooke T., Higham A., Brind A., Cox M., Ramakrishnan S., King A., Collins C., Whalley S., Li A., Fraser J., Bell A., Wong V.S., Singhal A., Gee I., Ang Y., Ransford R., Gotto J., Millson C., Bowles J., Thomas C., Harrison M., Galaska R., Kendall J., Whiteman J., Lawlor C., Gray C., Elliott K., Mulvaney-Jones C., Hobson L., Van Duyvenvoorde G., Loftus A., Seward K., Penn R., Maiden J., Damant R., Hails J., Cloudsdale R., Silvestre V., Glenn S., Dungca E., Wheatley N., Doyle H., Kent M., Hamilton C., Braim D., Wooldridge H., Abrahams R., Paton A., Lancaster N., Gibbins A., Hogben K., Desousa P., Muscariu F., Musselwhite J., McKay A., Tan L., Foale C., Brighton J., Flahive K., Nambela E., Townshend P., Ford C., Holder S., Palmer C., Featherstone J., Nasseri M., Sadeghian J., Williams B., Rolls S.-A., Hynes A., Duggan C., Crossey M., Stansfield G., MacNicol C., Wilkins J., Wilhelmsen E., Raymode P., Lee H.-J., Durant E., Bishop R., Ncube N., Tripoli S., Casey R., Cowley C., Miller R., Houghton K., Ducker S., Wright F., Bird B., Baxter G., Keggans J., Hughes M., Grieve E., Young K., Williams D., Ocker K., Hines F., Martin K., Innes C., Valliani T., Fairlamb H., Thornthwaite S., Eastick A., Tanqueray E., Morrison J., Holbrook B., Browning J., Walker K., Congreave S., Verheyden J., Slininger S., Stafford L., O'Donnell D., Ainsworth M., Lord S., Kent L., March L., Dickson C., Simpson D., Longhurst B., Hayes M., Shpuza E., White N., Besley S., Pearson S., Wright A., Jones L., Gunter E., Dewhurst H., Fouracres A., Farrington L., Graves L., Marriott S., Leoni M., Tyrer D., Dali-kemmery L., Lambourne V., Green M., Sirdefield D., Amor K., Colley J., Shinder B., Jones J., Mills M., Carnahan M., Taylor N., Boulton K., Tregonning J., Brown C., Clifford G., Archer E., Hamilton M., Curtis J., Shewan T., Walsh S., Warner K., Netherton K., Mupudzi M., Gunson B., Gitahi J., Gocher D., Batham S., Pateman H., Desmennu S., Conder J., Clement D., Gallagher S., Orpe J., Chan P., Currie L., O'Donohoe L., Oblak M., Morgan L., Quinn M., Amey I., Baird Y., Cotterill D., Cumlat L., Winter L., Greer S., Spurdle K., Allison J., Dyer S., Sweeting H., Kordula J., Aiba Y., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Kawai Y., Kohn S.-S., Gervais O., Migita K., 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., Higuchi 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., Takikawa H., Ohira 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., 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., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Carbone M., Cardamone G., Duga S., Gershwin M.E., Seldin M.F., Invernizzi P., Asselta, R, Paraboschi, E, Gerussi, A, Cordell, H, Mells, G, Sandford, R, Jones, D, Nakamura, M, Ueno, K, Hitomi, Y, Kawashima, M, Nishida, N, Tokunaga, K, Nagasaki, M, Tanaka, A, Tang, R, Li, Z, Shi, Y, Liu, X, Xiong, M, Hirschfield, G, Siminovitch, K, Walker, E, Xie, G, Mason, A, Myers, R, Peltekian, K, Ghent, C, Atkinson, E, Juran, B, Lazaridis, K, Lu, Y, Gu, X, Jing, K, Amos, C, Affronti, A, Brunetto, M, Coco, B, Spinzi, G, Elia, G, Ferrari, C, Lleo, A, Muratori, L, Muratori, P, Portincasa, P, Colli, A, Bruno, S, Colloredo, G, Azzaroli, F, Andreone, P, Bragazzi, M, Alvaro, D, Cardinale, V, Cazzagon, N, Rigamonti, C, Floreani, A, Rosina, F, Ciaccio, A, Cristoferi, L, D'Amato, D, Malinverno, F, Mancuso, C, Massironi, S, Milani, C, O'Donnell, S, Ronca, V, Barisani, D, Lampertico, P, Donato, F, Fagiuoli, S, Almasio, P, Giannini, E, Cursaro, C, Colombo, M, Valenti, L, Miele, L, Andriulli, A, Niro, G, Grattagliano, I, Morini, L, Casella, G, Vinci, M, Battezzati, P, Crosignani, A, Zuin, M, Mattalia, A, Calvaruso, V, Colombo, S, Benedetti, A, Marzioni, M, Galli, A, Marra, F, Tarocchi, M, Picciotto, A, Morisco, F, Fabris, L, Croce, L, Tiribelli, C, Toniutto, P, Strazzabosco, M, Ch'Ng, C, Rahman, M, Yapp, T, Sturgess, R, Healey, C, Czajkowski, M, Gunasekera, A, Gyawali, P, Premchand, P, Kapur, K, Marley, R, Foster, G, Watson, A, Dias, A, Subhani, J, Harvey, R, Mccorry, R, Ramanaden, D, Gasem, J, Evans, R, Mathialahan, T, Shorrock, C, Lipscomb, G, Southern, P, Tibble, J, Gorard, D, Palegwala, A, Jones, S, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, I, Narain, M, Brown, A, Taylor-Robinson, S, Williams, S, Grellier, L, Banim, P, Das, D, Chilton, A, Heneghan, M, Curtis, H, Gess, M, Drake, I, Aldersley, M, Davies, M, Jones, R, Mcnair, A, Srirajaskanthan, R, Pitcher, M, Sen, S, Bird, G, Barnardo, A, Kitchen, P, Yoong, K, Chirag, O, Sivaramakrishnan, N, Macfaul, G, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Fraser, A, Mills, P, Shallcross, C, Campbell, S, Bathgate, A, Shepherd, A, Dillon, J, Rushbrook, S, Przemioslo, R, Macdonald, C, Metcalf, J, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Ninkovic, M, Cramp, M, Sharer, N, Aspinall, R, Goggin, P, Ghosh, D, Douds, A, Hoeroldt, B, Booth, J, Williams, E, Hussaini, H, Stableforth, W, Ayres, R, Thorburn, D, Marshall, E, Burroughs, A, Mann, S, Lombard, M, Richardson, P, Patanwala, I, Maltby, J, Brookes, M, Mathew, R, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Panter, S, Shearman, J, Bray, G, Butcher, G, Forton, D, Mclindon, J, Cowan, M, Whatley, G, Mandal, A, Gupta, H, Sanghi, P, Jain, S, Pereira, S, Prasad, G, Watts, G, Wright, M, Neuberger, J, Gordon, F, Unitt, E, Grant, A, Delahooke, T, Higham, A, Brind, A, Cox, M, Ramakrishnan, S, King, A, Collins, C, Whalley, S, Li, A, Fraser, J, Bell, A, Wong, V, Singhal, A, Gee, I, Ang, Y, Ransford, R, Gotto, J, Millson, C, Bowles, J, Thomas, C, Harrison, M, Galaska, R, Kendall, J, Whiteman, J, Lawlor, C, Gray, C, Elliott, K, Mulvaney-Jones, C, Hobson, L, Van Duyvenvoorde, G, Loftus, A, Seward, K, Penn, R, Maiden, J, Damant, R, Hails, J, Cloudsdale, R, Silvestre, V, Glenn, S, Dungca, E, Wheatley, N, Doyle, H, Kent, M, Hamilton, C, Braim, D, Wooldridge, H, Abrahams, R, Paton, A, Lancaster, N, Gibbins, A, Hogben, K, Desousa, P, Muscariu, F, Musselwhite, J, Mckay, A, Tan, L, Foale, C, Brighton, J, Flahive, K, Nambela, E, Townshend, P, Ford, C, Holder, S, Palmer, C, Featherstone, J, Nasseri, M, Sadeghian, J, Williams, B, Rolls, S, Hynes, A, Duggan, C, Crossey, M, Stansfield, G, Macnicol, C, Wilkins, J, Wilhelmsen, E, Raymode, P, Lee, H, Durant, E, Bishop, R, Ncube, N, Tripoli, S, Casey, R, Cowley, C, Miller, R, Houghton, K, Ducker, S, Wright, F, Bird, B, Baxter, G, Keggans, J, Hughes, M, Grieve, E, Young, K, Williams, D, Ocker, K, Hines, F, Martin, K, Innes, C, Valliani, T, Fairlamb, H, Thornthwaite, S, Eastick, A, Tanqueray, E, Morrison, J, Holbrook, B, Browning, J, Walker, K, Congreave, S, Verheyden, J, Slininger, S, Stafford, L, O'Donnell, D, Ainsworth, M, Lord, S, Kent, L, March, L, Dickson, C, Simpson, D, Longhurst, B, Hayes, M, Shpuza, E, White, N, Besley, S, Pearson, S, Wright, A, Jones, L, Gunter, E, Dewhurst, H, Fouracres, A, Farrington, L, Graves, L, Marriott, S, Leoni, M, Tyrer, D, Dali-kemmery, L, Lambourne, V, Green, M, Sirdefield, D, Amor, K, Colley, J, Shinder, B, Jones, J, Mills, M, Carnahan, M, Taylor, N, Boulton, K, Tregonning, J, Brown, C, Clifford, G, Archer, E, Hamilton, M, Curtis, J, Shewan, T, Walsh, S, Warner, K, Netherton, K, Mupudzi, M, Gunson, B, Gitahi, J, Gocher, D, Batham, S, Pateman, H, Desmennu, S, Conder, J, Clement, D, Gallagher, S, Orpe, J, Chan, P, Currie, L, O'Donohoe, L, Oblak, M, Morgan, L, Quinn, M, Amey, I, Baird, Y, Cotterill, D, Cumlat, L, Winter, L, Greer, S, Spurdle, K, Allison, J, Dyer, S, Sweeting, H, Kordula, J, Aiba, Y, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Kawai, Y, Kohn, S, Gervais, O, Migita, K, 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, Higuchi, 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, Takikawa, H, Ohira, 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, 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, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Carbone, M, Cardamone, G, Duga, S, Gershwin, M, Seldin, M, Invernizzi, P, Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P, and LiveR North
Subjects: Canadian-US PBC Consortium, 0301 basic medicine, Male, Linkage disequilibrium, Genome-wide association study, Disease, PBC, Settore MED/03 - GENETICA MEDICA, Linkage Disequilibrium, 0302 clinical medicine, UK-PBC Consortium, Genotype, Mitochondrial Precursor Protein Import Complex Proteins, Italian PBC Genetics Study Group, Odds Ratio, X-Wide Association Study, Japan PBC-GWAS Consortium, X chromosome, Genetics, Liver Cirrhosis, Biliary, Gastroenterology, Forkhead Transcription Factors, DNA-Binding Proteins, Shal Potassium Channels, 030211 gastroenterology & hepatology, Female, Adult, Monosaccharide Transport Proteins, Superenhancer, Locus (genetics), Single-nucleotide polymorphism, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Proto-Oncogene Proteins, Endopeptidases, Humans, Cell Lineage, Genetic Predisposition to Disease, Meta-analysi, Genetic association, Chromosomes, Human, X, Gastroenterology & Hepatology, Hepatology, 1103 Clinical Sciences, Meta-analysis, 030104 developmental biology, Genetic Loci, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, Carrier Proteins, Genome-Wide Association Study
Abstract: Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
Published: 2021

36. 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. 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, Charles Millson, Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., 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. S., 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. A., 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. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., 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. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., 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. 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., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byan J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., 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.S., 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.A., 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.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V., 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.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., 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.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

37. 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

38. A Guillain-Barré syndrome-associated SIGLEC10 rare variant impairs its recognition of gangliosides

Author: Matthew Routledge, Nobutoshi Ito, Nobutaka Numoto, Susumu Kusunoki, Amin Alborzian Deh Sheikh, Kazumasa Saigoh, Yuki Hitomi, Takeshi Tsubata, Soha Gomaa, Makoto Tsuiji, Xuexin Li, Hiromu Takematsu, and Takashi Angata
Subjects: 0301 basic medicine, Male, Linkage disequilibrium, Genotype, Immunology, Mutation, Missense, Genome-wide association study, Receptors, Cell Surface, Major histocompatibility complex, Guillain-Barre Syndrome, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Antigen, Gene Frequency, Gangliosides, Lectins, medicine, Immunology and Allergy, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Receptor, Gene, Alleles, Autoantibodies, 030203 arthritis & rheumatology, Binding Sites, Miller Fisher Syndrome, Guillain-Barre syndrome, biology, Sequence Homology, Amino Acid, Autoantibody, Middle Aged, medicine.disease, 030104 developmental biology, biology.protein, Female
Abstract: Guillain-Barre syndrome (GBS), including its variant Miller Fisher syndrome (MFS), is an acute peripheral neuropathy that involves autoimmune mechanisms leading to the production of autoantibodies to gangliosides; sialic acid-containing glycosphingolipids. Although association with various genetic polymorphisms in the major histocompatibility complex (MHC) is shown in other autoimmune diseases, GBS is an exception, showing no such link. No significant association was found by genome wide association studies, suggesting that GBS is not associated with common variants. To address the involvement of rare variants in GBS, we analyzed Siglec-10, a sialic acid-recognizing inhibitory receptor expressed on B cells. Here we demonstrate that two rare variants encoding R47Q and A108V substitutions in the ligand-binding domain are significantly accumulated in patients with GBS. Because of strong linkage disequilibrium, there was no patient carrying only one of them. Recombinant Siglec-10 protein containing R47Q but not A108V shows impaired binding to gangliosides. Homology modeling revealed that the R47Q substitution causes marked alteration in the ligand-binding site. Thus, GBS is associated with a rare variant of the SIGLEC10 gene that impairs ligand binding of Siglec-10. Because Siglec-10 regulates antibody production to sialylated antigens, our finding suggests that Siglec-10 regulates development of GBS by suppressing antibody production to gangliosides, with defects in its function predisposing to disease.
Published: 2020

39. Mapping of susceptible variants for cold medicine-related Stevens-Johnson syndrome by whole-genome resequencing

Author: Ken Nakatani, Yosuke Kawai, Seik-Soon Khor, Shigeru Kinoshita, Chie Sotozono, Yuki Hitomi, Mayumi Ueta, Katsushi Tokunaga, and Masao Nagasaki
Subjects: 0301 basic medicine, In silico, Single-nucleotide polymorphism, Locus (genetics), Biology, QH426-470, Genome-wide association studies, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Genetics, SNP, Acute inflammation, Molecular Biology, Gene, Genetics (clinical), Disease genetics, Chromosome, medicine.disease, Toxic epidermal necrolysis, stomatognathic diseases, 030104 developmental biology, Medicine, 030217 neurology & neurosurgery
Abstract: Stevens–Johnson syndrome (SJS) and its severe condition with extensive skin detachment and a poor prognosis, toxic epidermal necrolysis (TEN), are immunologically mediated severe cutaneous reactions of the skin and mucous membranes such as the ocular surface. Genetic variations on the HLA-A and other autosomal genes have been identified as risk factors for cold medicine-related SJS/TEN with severe ocular complications (CM-SJS/TEN with SOC). Using a whole-genome sequencing (WGS) approach, we explored other susceptible variants of CM-SJS/TEN with SOC, especially among rare variants and structural variants (SVs). WGS was performed on samples from 133 patients with CM-SJS/TEN with SOC and 418 healthy controls to obtain single nucleotide polymorphisms (SNPs) and SVs. Genome-wide association tests were performed with these variants. Our genome-wide association test reproduced the associations of the common variants of HLA-A and loci on chromosome 16q12.1. We also identified novel associations of SVs on these loci and an aggregation of rare coding variants on the TPRM8 gene. In silico gene expression analysis on the HLA-A locus revealed that the SNP (rs12202296), which was significantly associated with susceptibility to CM-SJS/TEN with SOC, was correlated to an increase in HLA-A expression levels in the whole blood (P = 2.9 × 10−17), from the GTEx database. The majority of variants that were significantly associated with CM-SJS/TEN with SOC were found in non-coding regions, indicating the regulatory role of genetic variations in the pathogenesis of CM-SJS/TEN with SOC.
Published: 2020

40. Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome

Author: Xiaoyuan Jia, Tomohiko Yamamura, Rasheed Gbadegesin, Michelle T. McNulty, Kyuyong Song, China Nagano, Yuki Hitomi, Dongwon Lee, Yoshihiro Aiba, Seik-Soon Khor, Kazuko Ueno, Yosuke Kawai, Masao Nagasaki, Eisei Noiri, Tomoko Horinouchi, Hiroshi Kaito, Riku Hamada, Takayuki Okamoto, Koichi Kamei, Yoshitsugu Kaku, Rika Fujimaru, Ryojiro Tanaka, Yuko Shima, Jiwon Baek, Hee Gyung Kang, Il-Soo Ha, Kyoung Hee Han, Eun Mi Yang, Asiri Abeyagunawardena, Brandon Lane, Megan Chryst-Stangl, Christopher Esezobor, Adaobi Solarin, Claire Dossier, Georges Deschênes, Marina Vivarelli, Hanna Debiec, Kenji Ishikura, Masafumi Matsuo, Kandai Nozu, Pierre Ronco, Hae Il Cheong, Matthew G. Sampson, Katsushi Tokunaga, Kazumoto Iijima, Yoshinori Araki, Yoshinobu Nagaoka, Yasuyuki Sato, Asako Hayashi, Toshiyuki Takahashi, Hayato Aoyagi, Michihiko Ueno, Masanori Nakanishi, Nariaki Toita, Kimiaki Uetake, Norio Kobayashi, Shoji Fujita, Kazushi Tsuruga, Naonori Kumagai, Hiroki Kudo, Eriko Tanaka, Tae Omori, Mari Okada, Yoshiho Hatai, Tomohiro Udagawa, Yaeko Motoyoshi, Masao Ogura, Mai Sato, Yuji Kano, Motoshi Hattori, Kenichiro Miura, Yutaka Harita, Shoichiro Kanda, Emi Sawanobori, Anna Kobayashi, Manabu Kojika, Yoko Ohwada, Kunimasa Yan, Hiroshi Hataya, Chikako Terano, Ryoko Harada, Yuko Hamasaki, Junya Hashimoto, Shuichi Ito, Hiroyuki Machida, Aya Inaba, Takeshi Matsuyama, Miwa Goto, Masaki Shimizu, Kazuhide Ohta, Yohei Ikezumi, Takeshi Yamada, Toshiaki Suzuki, Soichi Tamamura, Yukiko Mori, Yoshihiko Hidaka, Daisuke Matsuoka, Tatsuya Kinoshita, Shunsuke Noda, Masashi Kitahara, Naoya Fujita, Satoshi Hibino, Shogo Minamikawa, Keita Nakanishi, Junya Fujimura, Nana Sakakibara, Yuya Aoto, Shinya Ishiko, Kyoko Kanda, Yosuke Inaguma, Yuya Hashimura, Shingo Ishimori, Naohiro Kamiyoshi, Takayuki Shibano, Yasuhiro Takeshima, Hiroaki Ueda, Akira Ashida, Hideki Matsumura, Takuo Kubota, Taichi Kitaoka, Yusuke Okuda, Toshihiro Sawai, Tomoyuki Sakai, Taketsugu Hama, Mikiya Fujieda, Masayuki Ishihara, Shigeru Itoh, Takuma Iwaki, Maki Shimizu, Koji Nagatani, Shoji Kagami, Maki Urushihara, Manao Nishimura, Miwa Yoshino, Ken Hatae, Maiko Hinokiyama, Rie Kuroki, Yasufumi Ohtsuka, Masafumi Oka, Shinji Nishimura, Tadashi Sato, Seiji Tanaka, Ayuko Zaitsu, Hitoshi Nakazato, Hiroshi Tamura, Koichi Nakanishi, Min Hyun Cho, Tae-Sun Ha, Ji Hyun Kim, Peong Gang Park, Myung Hyun Cho, Alejandro Quiroga, Asha Moudgil, Blanche Chavers, Charles Kwon, Corinna Bowers, Deb Gipson, Deepa Chand, Donald Jack Weaver, Elizabeth Abraham, Halima Janjua, Jen-Jar Lin, Larry Greenbaum, Mahmoud Kallash, Michelle Rheault, Nilka De Jeus Gonzalez, Patrick Brophy, Shashi Nagaraj, Susan Massengill, Tarak Srivastava, Tray Hunley, Yi Cai, Abiodun Omoloja, Cynthia Silva, Adebowale Adeyemo, Shenal Thalgahagoda, Jameela A. Kari, Sherif El Desoky, Mohammed Abdelhadi, Rachida Akil, Sonia Azib, Romain Basmaci, Gregoire Benoist, Philippe Bensaid, Philippe Blanc, Olivia Boyer, Julie Bucher, Anne Chace, Arnaud Chalvon, Marion Cheminee, Sandrine Chendjou, Patrick Daoud, Ossam Elias, Chantal Gagliadone, Vincent Gajdos, Aurélien Galerne, Evelyne Jacqz Aigrain, Lydie Joly Sanchez, Mohamed Khaled, Fatima Khelfaoui, Yacine Laoudi, Anis Larakeb, Tarek Limani, Fouad Mahdi, Alexis Mandelcwaijg, Stephanie Muller, Kacem Nacer, Sylvie Nathanson, Béatrice Pellegrino, Isabelle Pharaon, Véronica Roudault, Sébastien Rouget, Marc Saf, Tabassom Simon, Cedric Tahiri, Tim Ulinski, Férielle Zenkhri, CHU Tenon [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Tumor Necrosis Factor Ligand Superfamily Member 15, 0301 basic medicine, podocyte, Steroid-sensitive nephrotic syndrome, 030232 urology & nephrology, Polygenic disease, glomerulus, Biology, Monogenic disease, Article, 03 medical and health sciences, 0302 clinical medicine, pediatric nephrology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Child, Gene, Allele frequency, Congenital nephrotic syndrome, Alleles, ComputingMilieux_MISCELLANEOUS, Genetics, nephrotic syndrome, Membrane Proteins, Odds ratio, medicine.disease, 3. Good health, 030104 developmental biology, Haplotypes, Nephrology, Mutation, Steroids, Nephrotic syndrome, Genome-Wide Association Study
Abstract: To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (P(meta)=6.71E-28, OR=1.88) and TNFSF15 (P(meta)=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).
Published: 2020
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41. 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

42. Croissamide, a proline-rich cyclic peptide with an N-prenylated tryptophan from a marine cyanobacterium Symploca sp

Author: Osamu Ohno, Yuki Hitomi, Keitaro Iwasaki, Kiyotake Suenaga, Takuya Sano, Shimpei Sumimoto, and Arihiro Iwasaki
Subjects: chemistry.chemical_classification, 010405 organic chemistry, Stereochemistry, Organic Chemistry, Tryptophan, Absolute configuration, 010402 general chemistry, 01 natural sciences, Biochemistry, Cyclic peptide, Hydrolysate, 0104 chemical sciences, Chiral column chromatography, chemistry, Prenylation, Drug Discovery, Proline rich
Abstract: Croissamide, a proline-rich cyclic peptide that contains an N-prenylated tryptophan, was isolated from a marine cyanobacterium Symploca sp. Its gross structure was determined by spectroscopic analyses, and the absolute configuration was established based on chiral HPLC analyses of acid hydrolysates.
Published: 2018
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43. Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Author: Xiaoyuan Jia, Seik-Soon Khor, Emi Sawanobori, Yuko Shima, Yusuke Okuda, Koichi Nakanishi, Tomoko Horinouchi, Kaname Kojima, Kazumoto Iijima, Kandai Nozu, Yuki Hitomi, Naonori Kumagai, Hitoshi Nakazato, Rika Fujimaru, Yosuke Kawai, Takayuki Okamoto, Katsushi Tokunaga, Koichi Kamei, Yoshitsugu Kaku, Kazuhide Ohta, Akemi Shono, Yasufumi Ohtsuka, Ryojiro Tanaka, Akira Ashida, Yoko Ohwada, Kenji Ishikura, Masao Nagasaki, Yosuke Omae, and Ken Hatae
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, Haplotype, 030232 urology & nephrology, Genome-wide association study, General Medicine, Odds ratio, Human leukocyte antigen, Minor allele frequency, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Nephrology, Internal medicine, medicine, Genetic predisposition, Allele, business, Genotyping
Abstract: Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84×10-23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72×10-25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82×10-9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09×10-12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01×10-11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.
Published: 2018
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44. 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
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45. The ubiquinone synthesis pathway is a promising drug target for Chagas disease

Author: Nara, Takeshi, primary, Nakagawa, Yukari, additional, Tsuganezawa, Keiko, additional, Yuki, Hitomi, additional, Sekimata, Katsuhiko, additional, Koyama, Hiroo, additional, Ogawa, Naoko, additional, Honma, Teruki, additional, Shirouzu, Mikako, additional, Fukami, Takehiro, additional, Matsuo, Yuichi, additional, Inaoka, Daniel Ken, additional, Kita, Kiyoshi, additional, and Tanaka, Akiko, additional
Published: 2021
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46. 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
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47. FMODB: The World’s First Database of Quantum Mechanical Calculations for Biomacromolecules Based on the Fragment Molecular Orbital Method

Author: Takaya, Daisuke, primary, Watanabe, Chiduru, additional, Nagase, Shunpei, additional, Kamisaka, Kikuko, additional, Okiyama, Yoshio, additional, Moriwaki, Hirotomo, additional, Yuki, Hitomi, additional, Sato, Tomohiro, additional, Kurita, Noriyuki, additional, Yagi, Yoichiro, additional, Takagi, Tatsuya, additional, Kawashita, Norihito, additional, Takaba, Kenichiro, additional, Ozawa, Tomonaga, additional, Takimoto-Kamimura, Midori, additional, Tanaka, Shigenori, additional, Fukuzawa, Kaori, additional, and Honma, Teruki, additional
Published: 2021
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48. Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer

Author: Shirai, Fumiyuki, primary, Mizutani, Anna, additional, Yashiroda, Yoko, additional, Tsumura, Takeshi, additional, Kano, Yuko, additional, Muramatsu, Yukiko, additional, Chikada, Tsubasa, additional, Yuki, Hitomi, additional, Niwa, Hideaki, additional, Sato, Shin, additional, Washizuka, Kenichi, additional, Koda, Yasuko, additional, Mazaki, Yui, additional, Jang, Myung-Kyu, additional, Yoshida, Haruka, additional, Nagamori, Akiko, additional, Okue, Masayuki, additional, Watanabe, Takashi, additional, Kitamura, Kouichi, additional, Shitara, Eiki, additional, Honma, Teruki, additional, Umehara, Takashi, additional, Shirouzu, Mikako, additional, Fukami, Takehiro, additional, Seimiya, Hiroyuki, additional, Yoshida, Minoru, additional, and Koyama, Hiroo, additional
Published: 2020
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49. Coronin-1 is phosphorylated at Thr-412 by protein kinase Cα in human phagocytic cells

Author: Tsutomu Tsuji, Rie Ishii, Yutaka Kaneko, Satoshi Toyoshima, Yuki Hitomi, Teruaki Oku, and Makoto Tsuiji
Subjects: 0301 basic medicine, Small interfering RNA, QH301-705.5, Short Communication, Phagosome-lysosome fusion, Phagocytosis, PBS, phosphate-buffered saline, Biophysics, Coronin, QD415-436, macromolecular substances, Coronin-1, Actin-binding protein, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Protein kinase C, PKC, protein kinase C, OpZ, opsonized zymosan, Biology (General), Protein kinase A, Phagosome, biology, Chemistry, SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, ATP, adenosine 5’-triphosphate, HRP, horseradish peroxidase, PS, phosphatidylserine, Cell biology, 030104 developmental biology, siRNA, small interfering RNA, 030220 oncology & carcinogenesis, biology.protein, Phosphorylation
Abstract: Coronin-1, a hematopoietic cell-specific actin-binding protein, is thought to be involved in the phagocytic process through its interaction with actin filaments. The dissociation of coronin-1 from phagosomes after its transient accumulation on the phagosome surface is associated with lysosomal fusion. We previously reported that 1) coronin-1 is phosphorylated by protein kinase C (PKC), 2) coronin-1 has two phosphorylation sites, Ser-2 and Thr-412, and 3) Thr-412 of coronin-1 is phosphorylated during phagocytosis. In this study, we examined which PKC isoform is responsible for the phosphorylation of coronin-1 at Thr-412 by using isotype-specific PKC inhibitors and small interfering RNAs (siRNAs). Thr-412 phosphorylation of coronin-1 was suppressed by Gö6976, an inhibitor of PKCα and PKCβI. This phosphorylation was attenuated by siRNA for PKCα, but not by siRNA for PKCβ. Furthermore, Thr-412 of coronin-1 was phosphorylated by recombinant PKCα in vitro, but not by recombinant PKCβ. We next examined the effects of Gö6976 on the intracellular distribution of coronin-1 in HL60 cells during phagocytosis. The confocal fluorescence microscopic observation showed that coronin-1 was not dissociated from phagosomes in Gö6976-treated cells. These results indicate that phosphorylation of coronin-1 at Thr-412 by PKCα regulates intracellular distribution during phagocytosis., Highlights • Phosphorylation of coronin-1 at Thr-412 is suppressed by PKCα/β inhibitor. • PKCα not PKCβ phosphorylates coronin-1 at Thr-412 in vitro. • Dissociation of coronin-1 from phagosome is regulated by PKCα. • Phosphorylation of coronin-1 at Thr-412 may trigger phagosome maturation.
Published: 2021
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50. Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice

Author: Junji Hamuro, Yuji Naito, Norihiko Yokoi, Katsuhiko Shinomiya, Naomi Nakamura, Katsura Mizushima, Shigeru Kinoshita, Norito Katoh, Yuki Hitomi, Risa Tamagawa-Mineoka, Mayumi Ueta, Chie Sotozono, Hiromi Nishigaki, and Katsushi Tokunaga
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Conjunctiva, Immunology, Mucocutaneous zone, Mice, Transgenic, Human skin, Inflammation, Biology, Polymerase Chain Reaction, Ikaros Transcription Factor, Mice, 03 medical and health sciences, medicine, Animals, Humans, Immunology and Allergy, Allergic contact dermatitis, Skin, Zinc finger, Mice, Inbred BALB C, Epidermis (botany), medicine.disease, Keratin 5, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Stevens-Johnson Syndrome, Keratin-5, medicine.symptom
Abstract: Background Our genome-wide association study documented an association between cold medicine related Stevens-Johnson syndrome / toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. Methods Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. Results We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was up-regulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly up-regulated in the epidermis of Ikzf1 Tg compared with wild-type. Conclusion Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation. This article is protected by copyright. All rights reserved.
Published: 2017
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