Details of the Researcher

PHOTO

Kazuki Kumada
Section
Tohoku Medical Megabank Organization
Job title
Professor
Degree

  • 博士（理学）（京都大学）

  • 修士（理学）（京都大学）

Research Interests 6

  • バイオバンク

  • 遺伝疾患

  • がんゲノム

  • 染色体構造

  • 染色体分配

  • 細胞周期

Research Areas 2

  • Life sciences / Genomics /

  • Life sciences / Cell biology /

Papers 56

  1. Autoantibodies against endothelial protein C receptor and integrin αvβ6 predict the development of ulcerative colitis.

    Motoi Sawahashi, Yoichi Kakuta, Takeo Naito, Soshi Okazaki, Kinuko Ohneda, Masatsugu Orui, Taku Obara, Soichi Ogishima, Kazuki Kumada, Hisaaki Kudo, Fuji Nagami, Atsushi Hozawa, Hideya Iwaki, Hiroshi Nagai, Yusuke Shimoyama, Rintaro Moroi, Hisashi Shiga, Yoshitaka Kinouchi, Tsuyoshi Shirai, Hiroshi Fujii, Atsushi Masamune

    Journal of gastroenterology　60　(9)　1108-1117　2025/09

    DOI： 10.1007/s00535-025-02263-7 　

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    BACKGROUND: A method for predicting ulcerative colitis (UC) onset has not been established. Serum autoantibodies have been suggested as potential predictive biomarkers for UC onset. We aimed to validate the risks associated with serological and environmental factors and construct a model for predicting UC development. METHODS: Using the population-based cohort studies (n > 83,000), we identified 42 individuals who were diagnosed with UC later in life and compared them with matched healthy controls. We analyzed serum anti-integrin αvβ6 antibody (anti-αvβ6) and anti-endothelial protein C receptor antibody (anti-EPCR) titers, and lifestyle and dietary habits to explore UC onset predictors. The predictive performance of the models was evaluated based on these predictors. RESULTS: The sensitivity and specificity of anti-EPCR for predicting UC onset were 51.4% and 97.8%, respectively, comparable to those of anti-αvβ6 (52.5% and 97.6%, respectively). The proportion of individuals with insomnia was significantly higher in the preclinical UC group (adjusted odds ratio = 2.14, 95% confidence interval [CI] 1.11-4.04, p = 0.019). The predictive performance of anti-EPCR alone was high with an area under the curve (AUC) of 0.89 (95%CI 0.83-0.96), and that of anti-EPCR combined with anti-αvβ6 was even better with an AUC of 0.92 (95%CI 0.87-0.97); the lifestyle model had lower predictive accuracy (AUC = 0.65, 95%CI 0.55-0.74). CONCLUSIONS: Anti-EPCR and anti-αvβ6 each strongly predict UC onset. The combined anti-EPCR and anti-αvβ6 model had stronger predictive performance than the single models.

  2. Systemic activation of NRF2 contributes to the therapeutic efficacy of clinically-approved KRAS-G12C anti-cancer drugs. International-journal

    Liam Baird, Lin Zhang, Takanori Hidaka, Lyu Xi, Ke Wang, Keiko Tateno, Tatsuro Iso, Takafumi Suzuki, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    British journal of cancer　2025/09/01

    DOI： 10.1038/s41416-025-03162-7 　

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    BACKGROUND: The development and clinical success of KRASG12C inhibitors was a landmark achievement in anti-cancer drug development, as oncogenic KRAS had long been considered an intractable therapeutic target. Patients with KRAS mutant lung cancers frequently present with co-mutations in the KEAP1-NRF2 pathway, and because genetic activation of NRF2 results in resistance to all current anti-cancer therapies, we were motivated to explore how aberrant activation of NRF2 impacts the clinical response to KRASG12C inhibitors. METHODS: A broad range of techniques, including genetic knockouts, scRNA-seq and surface plasmon resonance, were used to determine the effect of KRASG12C drugs on NRF2. RESULTS: At physiologically-relevant concentrations, both of the clinically-approved KRASG12C inhibitors Sotorasib and Adagrasib also function as inducers of NRF2. Mechanistically, the same cysteine-targeting functionality which allows these electrophilic drugs to inhibit the mutant KRASG12C protein also facilitates their binding to cysteine-based sensors in KEAP1, resulting in the upregulation of the NRF2-dependent gene expression program. CONCLUSIONS: The activation of NRF2 by KRAS-G12C inhibitors represents a unique example of anti-cancer drugs which positively regulate the activity of a protein which is normally considered to be an oncogene. In both the malignant cells of the tumour and immune cells within the microenvironment, activation of NRF2 by electrophilic KRAS inhibitors positively contributes to the clinical efficacy of these drugs by promoting anti-cancer immunity. This unprecedented situation, in which the NRF2-dependent oxidative stress response is induced globally within cancer patients, has a number of important clinical implications, particularly in relation to ongoing combination chemotherapy clinical trials, as well as for selecting patient populations which may derive the most benefit from G12Ci anti-cancer drugs.

  3. Association of circulating metabolites and polygenic risk score with incident type 2 diabetes: a prospective community-based cohort study. International-journal

    Masato Takase, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Sayuri Tokioka, Kotaro Nochioka, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Seizo Koshiba, Kazuki Kumada, Ikuko Motoike, Eiji Hishinuma, Akira Narita, Taku Obara, Mami Ishikuro, Hisashi Ohseto, Ippei Takahashi, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Koichi Matsuda, Yoko Izumi, Kinuko Ohneda, Kengo Kinoshita, Atsushi Hozawa, Masayuki Yamamoto

    Cardiovascular diabetology　24　(1)　335-335　2025/08/14

    DOI： 10.1186/s12933-025-02849-8 　

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    BACKGROUND: No previous studies have explored metabolites associated with both genetic predispositions to type 2 diabetes (T2DM) and T2DM onset. Therefore, we aimed to explore metabolic profiles using genetic risk to identify pathways for tailored T2DM prevention strategies. METHODS: This prospective community-based cohort study in Japan included a total of 12,461 participants aged ≥ 20 years. Genetic predictors were genome-wide and pathway-based polygenic risk scores (PRSs). We quantified 43 metabolites using nuclear magnetic resonance spectroscopy. T2DM was defined as a non-fasting glucose level of ≥ 200 mg/dL, glycated hemoglobin level ≥ 6.5%, or self-reported T2DM treatment. A modified Poisson regression model was used to examine the associations of PRSs and metabolites with T2DM incidence. Linear associations were tested using the restricted cubic spline, and mediation analysis was conducted to assess the mediating effect of metabolites on the association between PRSs and T2DM incidence. RESULTS: During the 4.3-year median follow-up period, 354 T2DM cases were identified. A higher PRS was associated with incident T2DM (relative risk [RR] 2.09, 95% confidence interval [CI], 1.68-2.60, P < 0.001, 1-standard deviation [SD] increment). The nitrogen compound transport pathway PRS was associated with incident T2DM (RR 1.32, 95% CI 1.03-1.70, P < 0.001, 1-SD increment). Fourteen metabolites like glucose, 2-ketoisocaproic acid, glutamic acid, leucine, 2-aminobutyric acid, 2-hydroxybutyric acid, valine, 3-methyl-2-oxobutyric acid, alanine, 3-hydroxybutyric acid, 3-methyl-2-oxiovaleric acid, formic acid, arginine, and tyrosine were positively associated with the risk of T2DM. Only glycine was inversely associated with the risk of T2DM. Among 43 metabolites, 14 metabolites were positively associated with PRS (P for linear trend < 0.05). 3-hydroxyisobutyric-acid, 2-Aminobutyric acid, 2-ketoisocaproic acid, 2-hydroxybutyric acid, leucine, glycine, and glucose mediated the association between PRS and incident T2DM. CONCLUSIONS: Several metabolites were found to mediate the association between PRS and incident T2DM. These findings may contribute to a better understanding of the metabolic pathways involved in genetic susceptibility to T2DM.

  4. Comparison of genotypes and phenotypes for von Willebrand factor gene variants using Japanese genome database. International-journal

    Takafumi Akimoto, Hiroshi Inaba, Soichi Ogishima, Kazuki Kumada, Ayano Mitsuhashi, Ryui Miyashita, Tomoko Yamaguchi, Masato Bingo, Yushi Chikasawa, Keiko Shinozawa, Takeshi Hagiwara, Kagehiro Amano, Eiichi N Kodama, Ei Kinai

    Blood vessels, thrombosis & hemostasis　2　(3)　100070-100070　2025/08

    DOI： 10.1016/j.bvth.2025.100070 　

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    von Willebrand disease (VWD) is a common inherited bleeding disorder. The aim of this study was to determine the predicted disease states associated with various pathogenic von Willebrand factor (VWF) variants and their phenotypes using the largest Japanese whole-genome database. Of the 5857 VWF gene variants registered in the Japanese Multi-Omics Reference Panel (jMorp), variants with the following criteria were extracted: (1) caused protein abnormalities due to genetic alterations; (2) have already been detected and included in a database, including known association with VWD; and (3) highly likely pathogenic by in silico analysis. We measured VWF activity, antigen, propeptide, and collagen binding activity in stored plasma samples obtained from heterozygous carriers of the selected variants. A total of 29 VWF variants (26 single nucleotide and 3 small insertions/deletions) were detected, and 6 of these were found in Leiden Open Mutation Database. We obtained 43 plasma samples from individuals carrying these 29 variants as heterozygous. For the 43 variant carriers, their mean age was 43.0 years, and blood group was type O in 17 (39.5%). Analysis of these plasma samples showed low VWF levels (<50%) in 6 (14.0%). Low VWF levels were found in 2 of 8 of the nonsense (25%) and 4 of 31 of the missense variants (12.9%). Taking into consideration the limitation of using stored plasma samples, analysis of the jMorp indicated that most VWF gene variants with predicted pathogenic potential did not correlate with phenotypic expression. Our results supported incomplete penetrance and variable expressivity of the VWF gene variants.

  5. Exploring the association between human breast milk lipids and early adiposity rebound in children: A case-control study. International-journal

    Kento Sawane, Ippei Takahashi, Mami Ishikuro, Hiroko Takumi, Masatsugu Orui, Aoi Noda, Genki Shinoda, Hisashi Ohseto, Tomomi Onuma, Fumihiko Ueno, Keiko Murakami, Naoko Higuchi, Takashi Furuyashiki, Tomohiro Nakamura, Seizo Koshiba, Kinuko Ohneda, Kazuki Kumada, Soichi Ogishima, Atsushi Hozawa, Junichi Sugawara, Shinichi Kuriyama, Taku Obara

    Nutrition (Burbank, Los Angeles County, Calif.)　135　112739-112739　2025/07

    DOI： 10.1016/j.nut.2025.112739 　

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    OBJECTIVES: Adiposity rebound (AR) corresponds to the start of the second rise in the body mass index curve during infant growth. Early AR (before age 5) confers increased risk of adiposity and metabolic disorders but is less likely to occur in breastfed infants. Although lipids in breast milk are important in child growth, information is limited regarding which lipids are involved in AR. The object of this study was to explore the association between breast milk lipids and AR status in children. METHODS: We designed a case-control study of 184 mother-child pairs (AR cases: n = 93; controls: n = 91) included from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Breast milk was collected 1 month postpartum and comprehensive lipid analysis was performed. Partial least square-discriminant analysis was used to explore candidate lipids, and multivariable logistic regression analysis was used to evaluate associations with the AR status of children. RESULTS: We detected 667 lipid molecules in 12 lipid classes in breast milk. Partial least square-discriminant analysis revealed the association of fatty acid-hydroxy fatty acid (FAHFA) and cholesterol ester (ChE) with AR status. Multivariable logistic regression analysis showed that in pairs with exclusive breastfeeding at 1 month postpartum, FAHFA (odds ratio 1.57 [95% confidence interval, 1.06-2.32]) was positively associated with early AR, and ChE (odds ratio 0.55 [95% confidence interval, 0.36-0.86]) was negatively associated. CONCLUSIONS: Breast milk lipids (FAHFA, ChE) associated with the AR status of children, indicating the potential to regulate a child's adiposity and possible metabolic disorders in adulthood.

  6. Association Between Human Milk Oligosaccharides and Early Adiposity Rebound in Children: A Case-Control Study of the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. International-journal

    Kento Sawane, Ippei Takahashi, Mami Ishikuro, Hiroko Takumi, Masatsugu Orui, Aoi Noda, Genki Shinoda, Hisashi Ohseto, Tomomi Onuma, Fumihiko Ueno, Keiko Murakami, Naoko Higuchi, Tomoko Tanaka, Takashi Furuyashiki, Tomohiro Nakamura, Seizo Koshiba, Kinuko Ohneda, Kazuki Kumada, Soichi Ogishima, Atsushi Hozawa, Junichi Sugawara, Shinichi Kuriyama, Taku Obara

    The Journal of nutrition　155　(5)　1498-1507　2025/03/07

    DOI： 10.1016/j.tjnut.2025.02.024 　

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    BACKGROUND: Adiposity rebound (AR) is the point when the body mass index (BMI) begins to rise again during early childhood. Early AR (before age 5) is associated with a higher risk of lifelong obesity and metabolic disorders and may be influenced by breastfeeding. Although human milk oligosaccharides (HMOs) in breast milk are crucial for child growth, their association with AR status has not been studied. OBJECTIVE: To explore breast milk HMO compositions and molecules associated with AR status in children. METHODS: In this case-control study, we included 184 mother-child pairs from the Tohoku Medical Megabank Project Birth and Three-Generation (TMM BirThree) Cohort Study (93 AR cases, 91 controls). Breast milk was collected 1 month postpartum, and the concentration of 15 HMO molecules and alpha-diversity index (Inverse Simpson index) were quantified. Wilcoxon's rank-sum test and partial least squares-discriminant analysis (PLS-DA) identified candidate HMOs, and multivariable logistic regression analysis evaluated associations between candidate HMOs and AR status. Analyses were stratified by maternal secretor status (secretor or non-secretor). RESULTS: In secretor mothers, multivariable logistic regression showed that the Inverse Simpson index (OR, 0.54 [95% CI, 0.36-0.82]), sum of sialic acid-bound HMOs (0.61 [0.41-0.91]), and 3'-sialyllactose (0.67 [0.46-0.98]) were inversely associated with early AR in a fully adjusted model. A trend of interaction between sialyl-lacto-N-tetraose a (LSTa) and maternal secretor status on AR was observed in a fully adjusted model (P-value for interaction = 0.051). CONCLUSIONS: Alpha diversity, sialic acid-bound HMOs, and 3'SL may be involved in inhibiting AR in children of secretor mothers, and a trend of interactive effect of LSTa among maternal secretor status on AR was indicated. These findings offer novel perspectives on the associations between breastfeeding and a child's adiposity as well as potential metabolic disorders later in life. REGISTRY NUMBER/WEBSITE: https://www.umin.ac.jp/ (trial registration number: UMIN000047160).

  7. Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan. International-journal

    Kinuko Ohneda, Yoichi Suzuki, Yohei Hamanaka, Shu Tadaka, Muneaki Shimada, Junko Hasegawa-Minato, Masanobu Takahashi, Nobuo Fuse, Fuji Nagami, Hiroshi Kawame, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Tomohiro Nakamura, Soichi Ogishima, Kazuki Kumada, Hisaaki Kudo, Shin-Ichi Kuriyama, Yoko Izumi, Ritsuko Shimizu, Mikako Tochigi, Tokiwa Motonari, Hideki Tokunaga, Atsuo Kikuchi, Atsushi Masamune, Yoko Aoki, Chikashi Ishioka, Takanori Ishida, Masayuki Yamamoto

    Journal of human genetics　70　(3)　147-157　2025/03

    DOI： 10.1038/s10038-024-01314-w 　

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    Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants' understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.

  8. Genome-Wide Association Study of Intraocular Pressure in Population-Based Cohorts in Japan: The Tohoku Medical Megabank Organization Eye Study. International-journal

    Nobuo Fuse, Hayato Anzawa, Miyuki Sakurai, Ikuko N Motoike, Satoshi Nagaie, Tomohiro Nakamura, Akiko Miyazawa, Eiichi N Kodama, Masatsugu Orui, Yohei Hamanaka, Tomoko Kobayashi, Akira Uruno, Makiko Taira, Ritsuko Shimizu, Naoki Nakaya, Mami Ishikuro, Taku Obara, Fuji Nagami, Soichi Ogishima, Fumiki Katsuoka, Kazuki Kumada, Shinichi Kuriyama, Atsushi Hozawa, Yoko Izumi, Kengo Kinoshita, Masayuki Yamamoto

    Ophthalmology science　5　(5)　100821-100821　2025

    DOI： 10.1016/j.xops.2025.100821 　

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    PURPOSE: This study was conducted to elucidate the distribution and determinants of ocular biometric parameters and to assess the association between intraocular pressure (IOP) and single nucleotide polymorphisms (SNPs) in the Japanese population-based genome cohort studies. DESIGN: Cross-sectional analysis involving genome-wide association studies (GWASs). PARTICIPANTS: In total, 22 150 participants aged >18 years from the population cohort (Community-Based Cohort [CommCohort]) and 11 302 participants from the Birth and Three-Generation (BirThree) Cohort of the Tohoku Medical Megabank Organization Eye Study were examined. METHODS: Participant underwent interviews, ophthalmic and physiological examinations, laboratory tests, and microarray analyses. Genome-wide association studies were conducted in the CommCohort (discovery stage) and the BirThree Cohort (replication stage), followed by a meta-analysis. Associations of SNPs and IOP were evaluated using a genome-wide significance threshold (5 × 10- 8). MAIN OUTCOME MEASURES: Association of SNPs with IOP and distributions of IOP by sex and age. RESULTS: In the discovery stage, the mean IOP of the right and left eye was 13.95 and 14.02 mmHg, respectively. In the replication stage, the corresponding values were 14.32 and 14.27 mmHg, respectively. A significant age-related reduction in IOP was observed in both stages (P < 0.001). Genome-wide association studies identified 573 and 2 genome-wide significant SNPs in the discovery and replication stages, respectively. Meta-analysis revealed 1601 significant SNPs across 21 loci on 11 chromosomes (Chrs). Of these loci, 17 were previously known to be associated with IOP or glaucoma, while four-septin-8 (SEPT8; Chr5), aldehyde dehydrogenase 2 (ALDH2; Chr12), collagen type VI alpha 2 chain (COL6A2; Chr21), and Wnt family member 7B (WNT7B; Chr22)-were newly identified. CONCLUSIONS: This large-scale GWAS in a Japanese population identified 21 loci associated with IOP, including 4 novel loci. The findings highlight both genetic similarities and population-specific variations in SNPs influencing IOP and provide valuable insights to enhance eye health care, including glaucoma management. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

  9. Progress Report of the Tohoku Medical Megabank Community-based Cohort Study: Study Profile of the Repeated Center-based Survey During Second Period in Miyagi Prefecture.

    Atsushi Hozawa, Kumi Nakaya, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Junichi Sugawara, Eiichi Kodama, Yohei Hamanaka, Tomoko Kobayashi, Akira Uruno, Naho Tsuchiya, Takumi Hirata, Akira Narita, Akito Tsuboi, Toru Tamahara, Akihito Otsuki, Maki Goto, Makiko Taira, Ritsuko Shimizu, Kichiya Suzuki, Taku Obara, Masahiro Kikuya, Hirohito Metoki, Mami Ishikuro, Inaho Danjoh, Soichi Ogishima, Satoshi Nagaie, Naoko Minegishi, Masahiro Hiratsuka, Kazuki Kumada, Ichiko Nishijima, Takahiro Nobukuni, Yumi Yamaguchi-Kabata, Fuji Nagami, Shigeo Kure, Nobuo Fuse, Kengo Kinoshita, Yoko Izumi, Shinichi Kuriyama, Masayuki Yamamoto

    Journal of epidemiology　34　(9)　434-443　2024/09/05

    DOI： 10.2188/jea.JE20230241 　

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    BACKGROUND: The purpose of this study was to report the basic profile of the Miyagi Prefecture part of a repeated center-based survey during the second period of the Tohoku Medical Megabank Community-Based Cohort Study (TMM CommCohort Study), as well as the participants' characteristics based on their participation type in the baseline survey. METHODS: The second period survey, conducted from June 2017 to March 2021, included participants of the TMM CommCohort Study (May 2013 to March 2016). In addition to the questionnaire, blood, urine, and physiological function tests were performed during the second period survey. There were three main ways of participation in the baseline survey: Type 1, Type 1 additional, or Type 2 survey. The second period survey was conducted in the same manner as the Type 2 survey, which was based on the community support center (CSC). RESULTS: In Miyagi Prefecture, 29,383 (57.7%) of 50,967 participants participated in the second period survey. The participation rate among individuals who had visited the CSC was approximately 80%. Although some factors differed depending on the participation type in the baseline survey, the second period survey respondents in the Type 1 and Type 2 survey groups at baseline had similar traits. CONCLUSION: The second period survey of the TMM CommCohort Study provided detailed follow-up information. Following up on the health conditions of the participants will clarify the long-term effects of disasters and contribute to personalized prevention.

  10. Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

    Sei Harada, Miho Iida, Naoko Miyagawa, Aya Hirata, Kazuyo Kuwabara, Minako Matsumoto, Tomonori Okamura, Shun Edagawa, Yoko Kawada, Atsuko Miyake, Ryota Toki, Miki Akiyama, Atsuki Kawai, Daisuke Sugiyama, Yasunori Sato, Ryo Takemura, Kota Fukai, Yoshiki Ishibashi, Suzuka Kato, Ayako Kurihara, Mizuki Sata, Takuma Shibuki, Ayano Takeuchi, Shun Kohsaka, Mitsuaki Sawano, Satoshi Shoji, Yoshikane Izawa, Masahiro Katsumata, Koichi Oki, Shinichi Takahashi, Tsubasa Takizawa, Hiroshi Maruya, Yuji Nishiwaki, Ryo Kawasaki, Akiyoshi Hirayama, Takamasa Ishikawa, Rintaro Saito, Asako Sato, Tomoyoshi Soga, Masahiro Sugimoto, Masaru Tomita, Shohei Komaki, Hideki Ohmomo, Kanako Ono, Yayoi Otsuka-Yamasaki, Atsushi Shimizu, Yoichi Sutoh, Atsushi Hozawa, Kengo Kinoshita, Seizo Koshiba, Kazuki Kumada, Soichi Ogishima, Mika Sakurai-Yageta, Gen Tamiya, Toru Takebayashi

    Journal of epidemiology　34　(8)　393-401　2024/08/05

    DOI： 10.2188/jea.JE20230192 　

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    The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study used an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability, functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

  11. Fractional exhaled nitric oxide distribution and its relevant factors in the general adult population and its healthy subpopulation. International-journal

    Mitsuhiro Yamada, Masato Takase, Kumi Nakaya, Tomohiro Nakamura, Mana Kogure, Naoki Nakaya, Naoya Fujino, Tsutomu Tamada, Chikashi Iwasaki, Manami Suzuki, Shuichiro Matsumoto, Nobuo Fuse, Akira Uruno, Kazuki Kumada, Soichi Ogishima, Shinichi Kuriyama, Masakazu Ichinose, Hisatoshi Sugiura, Atsushi Hozawa

    The journal of allergy and clinical immunology. Global　3　(3)　100253-100253　2024/08

    DOI： 10.1016/j.jacig.2024.100253 　

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    BACKGROUND: Measurement of fractional exhaled nitric oxide (Feno) has been used in the diagnosis and management of asthma. Understanding the distribution of Feno in a larger resident population and its "healthy" subpopulation would contribute to the interpretation of Feno in clinical practice. OBJECTIVE: This study aimed to investigate the distribution and its associated factors in the adult population and its healthy subpopulations. METHODS: We conducted a cross-sectional study of 8,638 men and 17,288 women aged 20 years or older living in Miyagi prefecture, Japan. We investigated the distribution of Feno and its associated factors in all subjects, a subpopulation with no history of upper and lower airway diseases (healthy subpopulation 1), and a subpopulation with no history of upper and lower airway diseases, normal lung function, and no positivity for other biomarkers of type 2 inflammation (healthy subpopulation 2). RESULTS: The distribution of Feno in healthy subpopulations, especially in healthy subpopulation 2 (median [interquartile range], 17 [12-23] with 95th percentile of 36 ppb) was lower than in all subjects (19 [13-26] ppb with 95th percentile of 47 ppb). In healthy subpopulation 1, 10.3% had elevated Feno (≥35 ppb), and elevated Feno was positively associated with factors including obstructive ventilatory defect, blood eosinophilia, house dust mite-specific IgE positivity, and history of hypertension. Male sex was associated with elevated Feno in all subjects and healthy subpopulations. CONCLUSION: The distribution of Feno in the healthy subpopulation supports the validity of the criteria (≥35 ppb) currently used in Japan for the diagnosis of asthma.

  12. Detection and Correction of Sample Misidentifications in a Biobank Using the MassARRAY System and Genomic Information. International-journal

    Hisaaki Kudo, Noriko Ishida, Takahiro Nobukuni, Yuichi Aoki, Sakae Saito, Ichiko Nishijima, Takahiro Terakawa, Masayuki Yamamoto, Naoko Minegishi, Riu Yamashita, Kazuki Kumada

    Biopreservation and biobanking　22　(4)　373-382　2024/08

    DOI： 10.1089/bio.2022.0211 　

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    With the number of samples increasing in many biobanks, one of the most pressing tasks is recording the correct relationships between information and the specimens. Genomic information is useful in determining the identity of these specimens. The Tohoku Medical Megabank Organization is running one of the largest biobanks in Japan. Here, we introduce a management system, which includes the development of a new probe set for the MassARRAY system for use during the production of proliferating T cells (T cells) and lymphoblastoid cell lines (LCLs). We selected single nucleotide variants that could be detected by next-generation sequencing and showed high resolution with ∼0.5 minor allele frequencies. After checking the set of probes against 96 samples from 48 people, we obtained no contradictory results in comparison with our genome sequence information. When we applied the set to our 3035 LCLs and 2256 T cells, the result showed 98.93% consistency with the corresponding genomic information. We surveyed the handling records of the 1.07% of samples that showed inconsistencies, and found that most had resulted from human errors (ID swapping between samples) during manual operations. After improving a few error-prone protocols, the error rate dropped to 0.47% for LCLs and 0% for T cells. Overall, the system that we developed shows high accuracy with easy and fast operability, and provides a good opportunity to improve the validation procedure to facilitate high-quality banking, especially in cases involving genomic information.

  13. Identifying critical age and gender-based metabolomic shifts in a Japanese population of the Tohoku Medical Megabank cohort. International-journal

    Miyuki Sakurai, Ikuko N Motoike, Eiji Hishinuma, Yuichi Aoki, Shu Tadaka, Mana Kogure, Masatsugu Orui, Mami Ishikuro, Taku Obara, Naoki Nakaya, Kazuki Kumada, Atsushi Hozawa, Shinichi Kuriyama, Masayuki Yamamoto, Seizo Koshiba, Kengo Kinoshita

    Scientific reports　14　(1)　15681-15681　2024/07/08

    DOI： 10.1038/s41598-024-66180-0 　

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    Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases.

  14. Sequential Sampling of the Gastrointestinal Tract to Characterize the Entire Digestive Microbiome in Japanese Subjects. International-journal

    Kota Ishizawa, Toru Tamahara, Suguo Suzuki, Yutaka Hatayama, Bin Li, Michiaki Abe, Yuichi Aoki, Ryutaro Arita, Natsumi Saito, Minoru Ohsawa, Soichiro Kaneko, Rie Ono, Shin Takayama, Muneaki Shimada, Kazuki Kumada, Tomoyuki Koike, Atsushi Masamune, Ko Onodera, Tadashi Ishii, Ritsuko Shimizu, Takeshi Kanno

    Microorganisms　12　(7)　2024/06/28

    DOI： 10.3390/microorganisms12071324 　

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    The gastrointestinal (GI) tract harbors trillions of microorganisms known to influence human health and disease, and next-generation sequencing (NGS) now enables the in-depth analysis of their diversity and functions. Although a significant amount of research has been conducted on the GI microbiome, comprehensive metagenomic datasets covering the entire tract are scarce due to cost and technical challenges. Despite the widespread use of fecal samples, integrated datasets encompassing the entire digestive process, beginning at the mouth and ending with feces, are lacking. With this study, we aimed to fill this gap by analyzing the complete metagenome of the GI tract, providing insights into the dynamics of the microbiota and potential therapeutic avenues. In this study, we delved into the complex world of the GI microbiota, which we examined in five healthy Japanese subjects. While samples from the whole GI flora and fecal samples provided sufficient bacteria, samples obtained from the stomach and duodenum posed a challenge. Using a principal coordinate analysis (PCoA), clear clustering patterns were identified; these revealed significant diversity in the duodenum. Although this study was limited by its small sample size, the flora in the overall GI tract showed unwavering consistency, while the duodenum exhibited unprecedented phylogenetic diversity. A visual heat map illustrates the discrepancy in abundance, with Fusobacteria and Bacilli dominating the upper GI tract and Clostridia and Bacteroidia dominating the fecal samples. Negativicutes and Actinobacteria were found throughout the digestive tract. This study demonstrates that it is possible to continuously collect microbiome samples throughout the human digestive tract. These findings not only shed light on the complexity of GI microbiota but also provide a basis for future research.

  15. Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals. International-journal

    Yu-Ichi Aoki, Keiko Taguchi, Hayato Anzawa, Junko Kawashima, Noriko Ishida, Akihito Otsuki, Atsushi Hasegawa, Liam Baird, Takafumi Suzuki, Ikuko N Motoike, Kinuko Ohneda, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    Journal of biochemistry　175　(6)　611-627　2024/05/31

    DOI： 10.1093/jb/mvae008 　

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    Whole blood transcriptome analysis is a valuable approach in medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a dataset that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.

  16. Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses. International-journal

    Kouya Shiraishi, Atsushi Takahashi, Yukihide Momozawa, Yataro Daigo, Syuzo Kaneko, Takahisa Kawaguchi, Hideo Kunitoh, Shingo Matsumoto, Hidehito Horinouchi, Akiteru Goto, Takayuki Honda, Kimihiro Shimizu, Masahiro Torasawa, Daisuke Takayanagi, Motonobu Saito, Akira Saito, Yuichiro Ohe, Shun-Ichi Watanabe, Koichi Goto, Masahiro Tsuboi, Katsuya Tsuchihara, Sadaaki Takata, Tomomi Aoi, Atsushi Takano, Masashi Kobayashi, Yohei Miyagi, Kazumi Tanaka, Hiroyuki Suzuki, Daichi Maeda, Takumi Yamaura, Maiko Matsuda, Yoko Shimada, Takaaki Mizuno, Hiromi Sakamoto, Teruhiko Yoshida, Yasushi Goto, Tatsuya Yoshida, Taiki Yamaji, Makoto Sonobe, Shinichi Toyooka, Kazue Yoneda, Katsuhiro Masago, Fumihiro Tanaka, Megumi Hara, Nobuo Fuse, Satoshi S Nishizuka, Noriko Motoi, Norie Sawada, Yuichiro Nishida, Kazuki Kumada, Kenji Takeuchi, Kozo Tanno, Yasushi Yatabe, Kuniko Sunami, Tomoyuki Hishida, Yasunari Miyazaki, Hidemi Ito, Mitsuhiro Amemiya, Hirohiko Totsuka, Haruhiko Nakayama, Tomoyuki Yokose, Kazuyoshi Ishigaki, Toshiteru Nagashima, Yoichi Ohtaki, Kazuhiro Imai, Ken Takasawa, Yoshihiro Minamiya, Kazuma Kobayashi, Kenichi Okubo, Kenji Wakai, Atsushi Shimizu, Masayuki Yamamoto, Motoki Iwasaki, Koichi Matsuda, Johji Inazawa, Yuichi Shiraishi, Hiroyoshi Nishikawa, Yoshinori Murakami, Michiaki Kubo, Fumihiko Matsuda, Yoichiro Kamatani, Ryuji Hamamoto, Keitaro Matsuo, Takashi Kohno

    Cancer communications (London, England)　44　(2)　287-293　2024/02

    DOI： 10.1002/cac2.12498 　

  17. 新生児臍帯血の網羅的エピゲノム解析による妊娠初期までの喫煙経験が次世代に及ぼす影響

    美辺 詩織, 小巻 翔平, 大桃 秀樹, 高嶋 聰, 小野 加奈子, 山崎 弥生, 須藤 洋一, 田高 周, 水野 聖士, 石黒 真美, 工藤 久智, 小原 拓, 熊田 和貴, 勝岡 史城, 荻島 創一, 木下 賢吾, 菅原 準一, 栗山 進一, 清水 厚志

    DOHaD研究　11　(3)　37-37　2023/08

    Publisher: (一社)日本DOHaD学会

    ISSN： 2187-2562

    eISSN： 2187-2597

  18. Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study: Rationale, Design, and Background.

    Makiko Taira, Shunji Mugikura, Naoko Mori, Atsushi Hozawa, Tomo Saito, Tomohiro Nakamura, Hideyasu Kiyomoto, Tadao Kobayashi, Soichi Ogishima, Fuji Nagami, Akira Uruno, Ritsuko Shimizu, Tomoko Kobayashi, Jun Yasuda, Shigeo Kure, Miyuki Sakurai, Ikuko N Motoike, Kazuki Kumada, Naoki Nakaya, Taku Obara, Kentaro Oba, Atsushi Sekiguchi, Benjamin Thyreau, Tatsushi Mutoh, Yuji Takano, Mitsunari Abe, Norihide Maikusa, Yasuko Tatewaki, Yasuyuki Taki, Nobuo Yaegashi, Hiroaki Tomita, Kengo Kinoshita, Shinichi Kuriyama, Nobuo Fuse, Masayuki Yamamoto

    JMA journal　6　(3)　246-264　2023/07/14

    DOI： 10.31662/jmaj.2022-0220 　

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    The Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study (TMM Brain MRI Study) was established to collect multimodal information through neuroimaging and neuropsychological assessments to evaluate the cognitive function and mental health of residents who experienced the Great East Japan Earthquake (GEJE) and associated tsunami. The study also aimed to promote advances in personalized healthcare and medicine related to mental health and cognitive function among the general population. We recruited participants for the first (baseline) survey starting in July 2014, enrolling individuals who were participating in either the TMM Community-Based Cohort Study (TMM CommCohort Study) or the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). We collected multiple magnetic resonance imaging (MRI) sequences, including 3D T1-weighted sequences, magnetic resonance angiography (MRA), diffusion tensor imaging (DTI), pseudo-continuous arterial spin labeling (pCASL), and three-dimensional fluid-attenuated inversion recovery (FLAIR) sequences. To assess neuropsychological status, we used both questionnaire- and interview-based rating scales. The former assessments included the Tri-axial Coping Scale, Impact of Event Scale in Japanese, Profile of Mood States, and 15-item Depression, Anxiety, and Stress Scale, whereas the latter assessments included the Mini-Mental State Examination, Japanese version. A total of 12,164 individuals were recruited for the first (baseline) survey, including those unable to complete all assessments. In parallel, we returned the MRI results to the participants and subsequently shared the MRI data through the TMM Biobank. At present, the second (first follow-up) survey of the study started in October 2019 is underway. In this study, we established a large and comprehensive database that included robust neuroimaging data as well as psychological and cognitive assessment data. In combination with genomic and omics data already contained in the TMM Biobank database, these data could provide new insights into the relationships of pathological processes with neuropsychological disorders, including age-related cognitive impairment.

  19. 出生三世代コホートにおける7人家族のエピゲノム研究基盤構築

    美辺 詩織, 小巻 翔平, 大桃 秀樹, 高嶋 聰, 小野 加奈子, 山崎 弥生, 須藤 洋一, 田高 周, 水野 聖士, 石黒 真美, 工藤 久智, 小原 拓, 熊田 和貴, 勝岡 史城, 荻島 創一, 木下 賢吾, 菅原 準一, 栗山 進一, 清水 厚志

    日本抗加齢医学会総会プログラム・抄録集　23回　252-252　2023/06

    Publisher: (一社)日本抗加齢医学会

  20. Reduced antiviral seropositivity among patients with inflammatory bowel disease treated with immunosuppressive agents. International-journal

    Hisashi Shiga, Takahiro Takahashi, Manabu Shiraki, Yasuhiro Kojima, Tsuyotoshi Tsuji, Sho Takagi, Keiichiro Hiramoto, Naonobu Yokoyama, Mikako Sugimura, Masahiro Iwabuchi, Katsuya Endo, Motoyuki Onodera, Yuichirou Sato, Yosuke Shimodaira, Eiki Nomura, Tatsuya Kikuchi, Hirofumi Chiba, Shinya Oomori, Hisaaki Kudo, Kazuki Kumada, Satoshi Nagaie, Soichi Ogishima, Fuji Nagami, Yusuke Shimoyama, Rintaro Moroi, Masatake Kuroha, Yoichi Kakuta, Takashi Ishige, Yoshitaka Kinouchi, Atsushi Masamune

    Scandinavian journal of gastroenterology　58　(4)　360-367　2023/04

    DOI： 10.1080/00365521.2022.2132831 　

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    BACKGROUND: Although live-attenuated vaccines are contraindicated under immunosuppression, the immune status of patients with inflammatory bowel disease (IBD) has not been fully assessed prior to immunosuppressive therapy. AIMS: To investigate antiviral serostatus against viruses requiring live vaccines for prevention in IBD patients undergoing immunosuppressive therapy. METHODS: This multicenter study included IBD patients who were aged <40 years and were treated with thiopurine monotherapy, molecular-targeted monotherapy, or combination therapy. Gender- and age-matched healthy subjects (HS) living in the same areas were included as control group. Antibody titers against measles, rubella, mumps, and varicella were measured by enzyme-linked immunosorbent assays. RESULTS: A total of 437 IBD patients (163 ulcerative colitis [UC] and 274 Crohn's disease [CD]) and 225 HS were included in the final analysis. Compared with HS, IBD patients had lower seropositivity rates for measles (IBD vs. HS = 83.91% vs. 85.33%), rubella (77.55% vs. 84.89%), mumps (37.50% vs. 37.78%), and varicella (91.26% vs. 96.44%). Gender- and age-adjusted seropositivity rates were lower in UC patients than in both CD patients and HS for measles (UC, CD, and HS = 81.60%, 85.29%, and 85.33%), rubella (76.40%, 78.23%, and 84.89%), mumps (27.16%, 43.70%, and 37.78%), and varicella (90.80%, 91.54%, and 96.44%); the difference was significant for all viruses except measles. Divided by the degree of immunosuppression, there were no significant differences in seropositivity rates among IBD patients. CONCLUSIONS: IBD patients, especially those with UC, exhibit reduced seropositivity rates and may benefit from screening prior to the initiation of immunosuppressive therapy.

  21. Autocleavage of separase suppresses its premature activation by promoting binding to cyclin B1. International-journal

    Norihisa Shindo, Kazuki Kumada, Kenji Iemura, Jun Yasuda, Haruna Fujimori, Mai Mochizuki, Keiichi Tamai, Kozo Tanaka, Toru Hirota

    Cell reports　41　(9)　111723-111723　2022/11/29

    DOI： 10.1016/j.celrep.2022.111723 　

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    Accurate chromosome segregation requires timely activation of separase, a protease that cleaves cohesin during the metaphase-to-anaphase transition. However, the mechanism that maintains the inactivity of separase prior to this event remains unclear. We provide evidence that separase autocleavage plays an essential role in this process. We show that the inhibition of separase autocleavage results in premature activity before the onset of anaphase, accompanied by the formation of chromosomal bridges and spindle rocking. This deregulation is attributed to the reduced binding of cyclin B1 to separase that occurs during the metaphase-to-anaphase transition. Furthermore, when separase is mutated to render the regulation by cyclin B1 irrelevant, which keeps separase in securin-binding form, the deregulation induced by autocleavage inhibition is rescued. Our results reveal a physiological role of separase autocleavage in regulating separase, which ensures faithful chromosome segregation.

  22. Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology. International-journal

    Akihito Otsuki, Yasunobu Okamura, Noriko Ishida, Shu Tadaka, Jun Takayama, Kazuki Kumada, Junko Kawashima, Keiko Taguchi, Naoko Minegishi, Shinichi Kuriyama, Gen Tamiya, Kengo Kinoshita, Fumiki Katsuoka, Masayuki Yamamoto

    Communications biology　5　(1)　991-991　2022/09/20

    DOI： 10.1038/s42003-022-03953-1 　

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    Long-read sequencing technology enable better characterization of structural variants (SVs). To adapt the technology to population-scale analyses, one critical issue is to obtain sufficient amount of high-molecular-weight genomic DNA. Here, we propose utilizing activated T lymphocytes, which can be established efficiently in a biobank to stably supply high-grade genomic DNA sufficiently. We conducted nanopore sequencing of 333 individuals constituting 111 trios with high-coverage long-read sequencing data (depth 22.2x, N50 of 25.8 kb) and identified 74,201 SVs. Our trio-based analysis revealed that more than 95% of the SVs were concordant with Mendelian inheritance. We also identified SVs associated with clinical phenotypes, all of which appear to be stably transmitted from parents to offspring. Our data provide a catalog of SVs in the general Japanese population, and the applied approach using the activated T-lymphocyte resource will contribute to biobank-based human genetic studies focusing on SVs at the population scale.

  23. dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project. International-journal

    Soichi Ogishima, Satoshi Nagaie, Satoshi Mizuno, Ryosuke Ishiwata, Keita Iida, Kazuro Shimokawa, Takako Takai-Igarashi, Naoki Nakamura, Sachiko Nagase, Tomohiro Nakamura, Naho Tsuchiya, Naoki Nakaya, Keiko Murakami, Fumihiko Ueno, Tomomi Onuma, Mami Ishikuro, Taku Obara, Shunji Mugikura, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Akito Tsuboi, Shu Tadaka, Fumiki Katsuoka, Akira Narita, Mika Sakurai, Satoshi Makino, Gen Tamiya, Yuichi Aoki, Ritsuko Shimizu, Ikuko N Motoike, Seizo Koshiba, Naoko Minegishi, Kazuki Kumada, Takahiro Nobukuni, Kichiya Suzuki, Inaho Danjoh, Fuji Nagami, Kozo Tanno, Hideki Ohmomo, Koichi Asahi, Atsushi Shimizu, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Teiji Tominaga, Shigeo Kure, Nobuo Yaegashi, Kengo Kinoshita, Makoto Sasaki, Hiroshi Tanaka, Masayuki Yamamoto

    Human genome variation　8　(1)　44-44　2021/12/10

    DOI： 10.1038/s41439-021-00175-5 　

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    To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.

  24. Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs. International-journal

    Mika Sakurai-Yageta, Kazuki Kumada, Chinatsu Gocho, Satoshi Makino, Akira Uruno, Shu Tadaka, Ikuko N Motoike, Masae Kimura, Shin Ito, Akihito Otsuki, Akira Narita, Hisaaki Kudo, Yuichi Aoki, Inaho Danjoh, Jun Yasuda, Hiroshi Kawame, Naoko Minegishi, Seizo Koshiba, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    Journal of biochemistry　170　(3)　399-410　2021/10/12

    DOI： 10.1093/jb/mvab060 　

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    Ethnic-specific SNP arrays are becoming more important to increase the power of genome-wide association studies in diverse population. In the Tohoku Medical Megabank Project, we have been developing a series of Japonica Arrays (JPA) for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. Here, we designed a novel version of the SNP array for the Japanese population, called Japonica Array NEO (JPA NEO), comprising a total of 666,883 markers. Among them, 654,246 tag SNPs of autosomes and X chromosome were selected from an expanded reference panel of 3,552 Japanese, 3.5KJPNv2, using pairwise r2 of linkage disequilibrium measures. Additionally, 28,298 markers were included for the evaluation of previously identified disease risk markers from the literature and databases, and those present in the Japanese population were extracted using the reference panel. Through genotyping 286 Japanese samples, we found that the imputation quality r2 and INFO score in the minor allele frequency bin >2.5-5% were >0.9 and >0.8, respectively, and >12 million markers were imputed with an INFO score >0.8. From these results, JPA NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores.

  25. Wide-Targeted Metabolome Analysis Identifies Potential Biomarkers for Prognosis Prediction of Epithelial Ovarian Cancer. International-journal

    Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Daisuke Saigusa, Bin Li, Kei Kudo, Keita Tsuji, Shogo Shigeta, Hideki Tokunaga, Kazuki Kumada, Keigo Komine, Hidekazu Shirota, Yuichi Aoki, Ikuko N Motoike, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto, Seizo Koshiba, Nobuo Yaegashi

    Toxins　13　(7)　2021/06/30

    DOI： 10.3390/toxins13070461 　

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    Epithelial ovarian cancer (EOC) is a fatal gynecologic cancer, and its poor prognosis is mainly due to delayed diagnosis. Therefore, biomarker identification and prognosis prediction are crucial in EOC. Altered cell metabolism is a characteristic feature of cancers, and metabolomics reflects an individual's current phenotype. In particular, plasma metabolome analyses can be useful for biomarker identification. In this study, we analyzed 624 metabolites, including uremic toxins (UTx) in plasma derived from 80 patients with EOC using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Compared with the healthy control, we detected 77 significantly increased metabolites and 114 significantly decreased metabolites in EOC patients. Especially, decreased concentrations of lysophosphatidylcholines and phosphatidylcholines and increased concentrations of triglycerides were observed, indicating a metabolic profile characteristic of EOC patients. After calculating the parameters of each metabolic index, we found that higher ratios of kynurenine to tryptophan correlates with worse prognosis in EOC patients. Kynurenine, one of the UTx, can affect the prognosis of EOC. Our results demonstrated that plasma metabolome analysis is useful not only for the diagnosis of EOC, but also for predicting prognosis with the variation of UTx and evaluating response to chemotherapy.

  26. The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer. International-journal

    Hodaka Tayama, Hideaki Karasawa, Akihiro Yamamura, Yasunobu Okamura, Fumiki Katsuoka, Hideyuki Suzuki, Taiki Kajiwara, Minoru Kobayashi, Yuuri Hatsuzawa, Masahiro Shiihara, Li Bin, Md Yeashin Gazi, Mizuki Sato, Kazuki Kumada, Shigehiro Ito, Muneaki Shimada, Toru Furukawa, Takashi Kamei, Shinobu Ohnuma, Michiaki Unno

    Biochemical and biophysical research communications　560　59-65　2021/06/30

    DOI： 10.1016/j.bbrc.2021.04.130 　

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    The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.

  27. Identification of Dominant Transcripts in Oxidative Stress Response by a Full-Length Transcriptome Analysis. International-journal

    Akihito Otsuki, Yasunobu Okamura, Yuichi Aoki, Noriko Ishida, Kazuki Kumada, Naoko Minegishi, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    Molecular and cellular biology　41　(2)　2021/01/25

    DOI： 10.1128/MCB.00472-20 　

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    Our body responds to environmental stress by changing the expression levels of a series of cytoprotective enzymes/proteins through multilayered regulatory mechanisms, including the KEAP1-NRF2 system. While NRF2 upregulates the expression of many cytoprotective genes, there are fundamental limitations in short-read RNA sequencing (RNA-Seq), resulting in confusion regarding interpreting the effectiveness of cytoprotective gene induction at the transcript level. To precisely delineate isoform usage in the stress response, we conducted independent full-length transcriptome profiling (isoform sequencing; Iso-Seq) analyses of lymphoblastoid cells from three volunteers under normal and electrophilic stress-induced conditions. We first determined the first exon usage in KEAP1 and NFE2L2 (encoding NRF2) and found the presence of transcript diversity. We then examined changes in isoform usage of NRF2 target genes under stress conditions and identified a few isoforms dominantly expressed in the majority of NRF2 target genes. The expression levels of isoforms determined by Iso-Seq analyses showed striking differences from those determined by short-read RNA-Seq; the latter could be misleading concerning the abundance of transcripts. These results support that transcript usage is tightly regulated to produce functional proteins under electrophilic stress. Our present study strongly argues that there are important benefits that can be achieved by long-read transcriptome sequencing.

  28. Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2). International-journal

    Hideki Tokunaga, Keita Iida, Atsushi Hozawa, Soichi Ogishima, Yoh Watanabe, Shogo Shigeta, Muneaki Shimada, Yumi Yamaguchi-Kabata, Shu Tadaka, Fumiki Katsuoka, Shin Ito, Kazuki Kumada, Yohei Hamanaka, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

    PloS one　16　(1)　e0236907　2021

    DOI： 10.1371/journal.pone.0236907 　

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    Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.

  29. Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines. International-journal

    Noriko Ishida, Yuichi Aoki, Fumiki Katsuoka, Ichiko Nishijima, Takahiro Nobukuni, Hayato Anzawa, Li Bin, Miyuki Tsuda, Kazuki Kumada, Hisaaki Kudo, Takahiro Terakawa, Akihito Otsuki, Kengo Kinoshita, Riu Yamashita, Naoko Minegishi, Masayuki Yamamoto

    Free radical biology & medicine　161　71-83　2020/12

    DOI： 10.1016/j.freeradbiomed.2020.09.023 　

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    Human lymphoblastoid cell lines (LCLs) are valuable for the functional analyses of diseases. We have established more than 4200 LCLs as one of the resources of an integrated biobank. While oxidative and inflammatory stresses play critical roles in the onset and progression of various diseases, the responsiveness of LCLs, especially that of biobank-made LCLs, to these stresses has not been established. To address how LCLs respond to these stresses, in this study, we performed RNA sequencing of eleven human LCLs that were treated with an electrophile, diethyl maleate (DEM) and/or an inflammatory mediator, lipopolysaccharide (LPS). We found that over two thousand genes, including those regulated by a master regulator of the electrophilic/oxidative stress response, NRF2, were upregulated in LCLs treated with DEM, while approximately three hundred genes, including inflammation-related genes, were upregulated in LPS-treated LCLs. Of the LPS-induced genes, a subset of proinflammatory genes was repressed by DEM, supporting the notion that DEM suppresses the expression of proinflammatory genes through NRF2 activation. Conversely, a part of DEM-induced gene was repressed by LPS, suggesting reciprocal interference between electrophilic and inflammatory stress-mediated pathways. These data clearly demonstrate that LCLs maintain, by and large, responsive pathways against oxidative and inflammatory stresses and further endorse the usefulness of the LCL supply from the biobank.

  30. Analysis of HLA-G long-read genomic sequences in mother-offspring pairs with preeclampsia. International-journal

    Ayako Nishizawa, Kazuki Kumada, Keiko Tateno, Maiko Wagata, Sakae Saito, Fumiki Katsuoka, Satoshi Mizuno, Soichi Ogishima, Masayuki Yamamoto, Jun Yasuda, Junichi Sugawara

    Scientific reports　10　(1)　20027-20027　2020/11/18

    DOI： 10.1038/s41598-020-77081-3 　

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    Preeclampsia is a pregnancy-induced disorder that is characterized by hypertension and is a leading cause of perinatal and maternal-fetal morbidity and mortality. HLA-G is thought to play important roles in maternal-fetal immune tolerance, and the associations between HLA-G gene polymorphisms and the onset of pregnancy-related diseases have been explored extensively. Because contiguous genomic sequencing is difficult, the association between the HLA-G genotype and preeclampsia onset is controversial. In this study, genomic sequences of the HLA-G region (5.2 kb) from 31 pairs of mother-offspring genomic DNA samples (18 pairs from normal pregnancies/births and 13 from preeclampsia births) were obtained by single-molecule real-time sequencing using the PacBio RS II platform. The HLA-G alleles identified in our cohort matched seven known HLA-G alleles, but we also identified two new HLA-G alleles at the fourth-field resolution and compared them with nucleotide sequences from a public database that consisted of coding sequences that cover the 3.1-kb HLA-G gene span. Intriguingly, a potential association between preeclampsia onset and the poly T stretch within the downstream region of the HLA-G*01:01:01:01 allele was found. Our study suggests that long-read sequencing of HLA-G will provide clues for characterizing HLA-G variants that are involved in the pathophysiology of preeclampsia.

  31. Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy Peer-reviewed

    Matsuyuki Shirota, Daisuke Saigusa, Riu Yamashita, Yasutake Kato, Mitsuyo Matsumoto, Junya Yamagishi, Noriko Ishida, Kazuki Kumada, Yuji Oe, Hisaaki Kudo, Junji Yokozawa, Yoko Kuroki, Ikuko Motoike, Fumiki Katsuoka, Masao Nagasaki, Seizo Koshiba, Keiko Nakayama, Osamu Tanabe, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara

    Medical Mass Spectrometry　4　(1)　36-49　2020/06/25

    DOI： 10.24508/mms.2020.06.001 　

    ISSN： 2432-7441 2432-745X

  32. Biobank Establishment and Sample Management in the Tohoku Medical Megabank Project. Peer-reviewed

    Naoko Minegishi, Ichiko Nishijima, Takahiro Nobukuni, Hisaaki Kudo, Noriko Ishida, Takahiro Terakawa, Kazuki Kumada, Riu Yamashita, Fumiki Katsuoka, Soichi Ogishima, Kichiya Suzuki, Makoto Sasaki, Mamoru Satoh, Tohoku Medical Megabank Project Study Group, Masayuki Yamamoto

    The Tohoku journal of experimental medicine　248　(1)　45-55　2019/05

    DOI： 10.1620/tjem.248.45 　

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    The Tohoku Medical Megabank biobank (TMM biobank) is the first major population-based biobank established in Japan. The TMM biobank was established based on two population cohorts and is a reconstruction program from the Great East Japan Earthquake and Tsunami of 2011. The biobank stores more than 3.4 million tubes of biospecimens and associated health and analytic data obtained from approximately 150,000 TMM cohort participants between May 2013 and December 2018, and the TMM biobank currently shares high-quality specimens and data. Various biospecimens, including peripheral and cord blood mononuclear cells, buffy coat, plasma, serum, urine, breast milk and saliva have been collected in the TMM biobank. To minimize human error and maintain the quality of data and specimens, we have been utilizing laboratory information management system into various biobank procedures from registration to storage with various automation systems, such as liquid dispensing, DNA extraction and their storage. The biobank procedures for the quality management system (ISO 9001:2015) and information security management system (ISO 27001:2013) are certified by the International Organization for Standardization. The quality of our biobank samples fulfills the pre-analytical requirements for researchers conducting next-generation whole genome sequencing, DNA array analyses, proteomics, metabolomics, etc. We established analytical centers to conduct standard genomic and multiomic analyses in-house and share the generated data. Additionally, we generate thousands of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and proliferating T cells for functional studies. The TMM biobank serves as an indispensable infrastructure for academic, clinical and industrial research to actualize next-generation medicine in Japan.

  33. Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. International-journal Peer-reviewed

    Yumi Yamaguchi-Kabata, Jun Yasuda, Akira Uruno, Kazuro Shimokawa, Seizo Koshiba, Yoichi Suzuki, Nobuo Fuse, Hiroshi Kawame, Shu Tadaka, Masao Nagasaki, Kaname Kojima, Fumiki Katsuoka, Kazuki Kumada, Osamu Tanabe, Gen Tamiya, Nobuo Yaegashi, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure

    Human genetics　138　(4)　389-409　2019/04

    DOI： 10.1007/s00439-019-01998-7 　

    ISSN： 0340-6717

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    Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.

  34. Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare. International-journal Peer-reviewed

    Jun Yasuda, Kengo Kinoshita, Fumiki Katsuoka, Inaho Danjoh, Mika Sakurai-Yageta, Ikuko N Motoike, Yoko Kuroki, Sakae Saito, Kaname Kojima, Matsuyuki Shirota, Daisuke Saigusa, Akihito Otsuki, Junko Kawashima, Yumi Yamaguchi-Kabata, Shu Tadaka, Yuichi Aoki, Takahiro Mimori, Kazuki Kumada, Jin Inoue, Satoshi Makino, Miho Kuriki, Nobuo Fuse, Seizo Koshiba, Osamu Tanabe, Masao Nagasaki, Gen Tamiya, Ritsuko Shimizu, Takako Takai-Igarashi, Soichi Ogishima, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Akito Tsuboi, Hideyasu Kiyomoto, Tadashi Ishii, Hiroaki Tomita, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroshi Kawame, Hiroshi Tanaka, Yasuyuki Taki, Nobuo Yaegashi, Shigeo Kure, Fuji Nagami, Kenjiro Kosaki, Yoichi Sutoh, Tsuyoshi Hachiya, Atsushi Shimizu, Makoto Sasaki, Masayuki Yamamoto

    Journal of biochemistry　165　(2)　139-158　2019/02/01

    DOI： 10.1093/jb/mvy096 　

    ISSN： 0021-924X

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    Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM CommCohort (adult general population) and a TMM BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC.

  35. The putative ceramide-conjugation protein Cwh43 regulates G0 quiescence, nutrient metabolism and lipid homeostasis in fission yeast. International-journal Peer-reviewed

    Norihiko Nakazawa, Takayuki Teruya, Kenichi Sajiki, Kazuki Kumada, Alejandro Villar-Briones, Orie Arakawa, Junko Takada, Shigeaki Saitoh, Mitsuhiro Yanagida

    Journal of cell science　131　(16)　2018/08/21

    DOI： 10.1242/jcs.217331 　

    ISSN： 0021-9533

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    Cellular nutrient states control whether cells proliferate, or whether they enter or exit quiescence. Here, we report characterizations of fission yeast temperature-sensitive (ts) mutants of the evolutionarily conserved transmembrane protein Cwh43, and explore its relevance to utilization of glucose, nitrogen source and lipids. GFP-tagged Cwh43 localizes at ER associated with the nuclear envelope and the plasma membrane, as in budding yeast. We found that cwh43 mutants failed to divide in low glucose and lost viability during quiescence under nitrogen starvation. In cwh43 mutants, comprehensive metabolome analysis demonstrated dramatic changes in marker metabolites that altered under low glucose and/or nitrogen starvation, although cwh43 cells apparently consumed glucose in the culture medium. Furthermore, we found that cwh43 mutant cells had elevated levels of triacylglycerols (TGs) and coenzyme A, and that they accumulated lipid droplets. Notably, TG biosynthesis was required to maintain cell division in the cwh43 mutant. Thus, Cwh43 affects utilization of glucose and nitrogen sources, as well as storage lipid metabolism. These results may fit a notion developed in budding yeast stating that Cwh43 conjugates ceramide to glycosylphosphatidylinositol (GPI)-anchored proteins and maintains integrity of membrane organization.

  36. Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project. International-journal Peer-reviewed

    Jun Yasuda, Fumiki Katsuoka, Inaho Danjoh, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Sakae Saito, Yumi Yamaguchi-Kabata, Shu Tadaka, Ikuko N Motoike, Kazuki Kumada, Mika Sakurai-Yageta, Osamu Tanabe, Nobuo Fuse, Gen Tamiya, Koichiro Higasa, Fumihiko Matsuda, Nobufumi Yasuda, Motoki Iwasaki, Makoto Sasaki, Atsushi Shimizu, Kengo Kinoshita, Masayuki Yamamoto

    BMC genomics　19　(1)　551-551　2018/07/24

    DOI： 10.1186/s12864-018-4942-0 　

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    BACKGROUND: Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels. RESULTS: We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%. CONCLUSIONS: 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population's genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago.

  37. Evolutionary acquired robustness and vulnerability in cancer genome: Negligible negative selection in carcinogenesis Peer-reviewed

    Kazuki Kumada, Jun Yasuda

    Translational Cancer Research　7　S445-S448　2018/04/01

    Publisher: AME Publishing Company

    DOI： 10.21037/tcr.2018.02.15 　

    ISSN： 2219-6803 2218-676X

  38. 妊娠高血圧症候群の原因解明を目指した長鎖型シークエンサーによるHLA-G遺伝子解析技術の開発

    西澤 絢子, 熊田 和貴, 舘野 恵子, 和形 麻衣子, 勝岡 史城, 山本 雅之, 菅原 準一, 安田 純

    生命科学系学会合同年次大会　2017年度　[2P-1139]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  39. Separase sensor reveals dual roles for separase coordinating cohesin cleavage and cdk1 inhibition. International-journal Peer-reviewed

    Norihisa Shindo, Kazuki Kumada, Toru Hirota

    Developmental cell　23　(1)　112-23　2012/07/17

    DOI： 10.1016/j.devcel.2012.06.015 　

    ISSN： 1534-5807

  40. M期チェックポイントと染色体分配 動原体ストレッチングは中期後期移行を促進する(Mitotic checkpoint and chromosome segregation Kinetochore stretching promotes the metaphase-to-anaphase transition)

    内田 和彦, 高垣 謙太郎, 熊田 和貴, 広田 亨

    日本細胞生物学会大会講演要旨集　61回　104-104　2009/05

    Publisher: (一社)日本細胞生物学会

  41. Kinetochore stretching inactivates the spindle assembly checkpoint. International-journal Peer-reviewed

    Kazuhiko S K Uchida, Kentaro Takagaki, Kazuki Kumada, Youko Hirayama, Tetsuo Noda, Toru Hirota

    The Journal of cell biology　184　(3)　383-90　2009/02/09

    DOI： 10.1083/jcb.200811028 　

    ISSN： 0021-9525

  42. 染色体を動かすしくみ 染色体腕部コヒーシン解離におけるセパレースの関与について(Molecular mechanisms of chromosome dynamics The complete removal of cohesin from chromosome arms depends on separase)

    中島 真人, 熊田 和貴, 野田 哲生, 広田 亨

    日本細胞生物学会大会講演要旨集　60回　89-89　2008/06

    Publisher: (一社)日本細胞生物学会

  43. The complete removal of cohesin from chromosome arms depends on separase. International-journal Peer-reviewed

    Masato Nakajima, Kazuki Kumada, Katsuyoshi Hatakeyama, Tetsuo Noda, Jan-Michael Peters, Toru Hirota

    Journal of cell science　120　(Pt 23)　4188-96　2007/12/01

    DOI： 10.1242/jcs.011528 　

    ISSN： 0021-9533

  44. 染色体腕からのcohesinの完全除去はseparase依存性である(The complete removal of cohesin from chromosome arms depends on separase)

    中島 真人, 熊田 和貴, 野田 哲生, 広田 亨

    日本癌学会総会記事　66回　454-454　2007/08

    Publisher: 日本癌学会

    ISSN： 0546-0476

  45. The selective continued linkage of centromeres from mitosis to interphase in the absence of mammalian separase. International-journal Peer-reviewed

    Kazuki Kumada, Ryoji Yao, Tokuichi Kawaguchi, Mika Karasawa, Yutaka Hoshikawa, Koji Ichikawa, Yoshinobu Sugitani, Issei Imoto, Johji Inazawa, Minoru Sugawara, Mitsuhiro Yanagida, Tetsuo Noda

    The Journal of cell biology　172　(6)　835-46　2006/03/13

    DOI： 10.1083/jcb.200511126 　

    ISSN： 0021-9525

  46. Ectopic chromosome around centrosome in metaphase cells as a marker of high-risk human papillomavirus-associated cervical intraepithelial neoplasias. International-journal Peer-reviewed

    Reiko Furuta, Yasuo Hirai, Katsuyoshi Katase, Shinichi Tate, Tokuichi Kawaguchi, Futoshi Akiyama, Yo Kato, Kazuki Kumada, Tsuyoshi Iwasaka, Nobuo Yaegashi, Koji Kanazawa, Hiroyuki Yoshikawa, Tomoyuki Kitagawa

    International journal of cancer　106　(2)　167-71　2003/08/20

    DOI： 10.1002/ijc.11216 　

    ISSN： 0020-7136

  47. Control of metaphase-anaphase progression by proteolysis: cyclosome function regulated by the protein kinase A pathway, ubiquitination and localization Peer-reviewed

    M Yanagida, YM Yamashita, H Tatebe, K Ishii, K Kumada, Y Nakaseko

    PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES　354　(1389)　1559-1569　1999/09

    DOI： 10.1098/rstb.1999.0499 　

    ISSN： 0962-8436

  48. Fission yeast APC/cyclosome subunits, Cut20/Apc4 and Cut23/Apc8, in regulating metaphase-anaphase progression and cellular stress responses Peer-reviewed

    YM Yamashita, Y Nakaseko, K Kumada, T Nakagawa, M Yanagida

    GENES TO CELLS　4　(8)　445-463　1999/08

    ISSN： 1356-9597

    eISSN： 1365-2443

  49. Cut1 is loaded onto the spindle by binding to Cut2 and promotes anaphase spindle movement upon Cut2 proteolysis Peer-reviewed

    K Kumada, T Nakamura, K Nagao, H Funabiki, T Nakagawa, M Yanagida

    CURRENT BIOLOGY　8　(11)　633-641　1998/05

    ISSN： 0960-9822

  50. Distinct subunit functions and cell cycle regulated phosphorylation of 20S APC/cyclosome required for anaphase in fission yeast Peer-reviewed

    H Yamada, K Kumada, M Yanagida

    JOURNAL OF CELL SCIENCE　110　1793-1804　1997/08

    ISSN： 0021-9533

    eISSN： 1477-9137

  51. Requirement for PP1 phosphatase and 20S cyclosome/APC for the onset of anaphase is lessened by the dosage increase of a novel gene sds23(+) Peer-reviewed

    K Ishii, K Kumada, T Toda, M Yanagida

    EMBO JOURNAL　15　(23)　6629-6640　1996/12

    ISSN： 0261-4189

  52. Fission yeast cut1 and cut2 are essential for sister chromatid separation, concentrate along the metaphase spindle and form large complexes Peer-reviewed

    H Funabiki, K Kumada, M Yanagida

    EMBO JOURNAL　15　(23)　6617-6628　1996/12

    ISSN： 0261-4189

  53. 20S cyclosome complex formation and proteolytic activity inhibited by the cAMP/PKA pathway Peer-reviewed

    YM Yamashita, Y Nakaseko, Samejima, I, K Kumada, H Yamada, D Michaelson, M Yanagida

    NATURE　384　(6606)　276-279　1996/11

    DOI： 10.1038/384276a0 　

    ISSN： 0028-0836

  54. Cut2 proteolysis required for sister-chromatid separation in fission yeast Peer-reviewed

    H Funabiki, H Yamano, K Kumada, K Nagao, T Hunt, M Yanagida

    NATURE　381　(6581)　438-441　1996/05

    DOI： 10.1038/381438a0 　

    ISSN： 0028-0836

  55. Caffeine resistance in fission yeast is caused by mutations in a single essential gene, crm1(+) Peer-reviewed

    K Kumada, M Yanagida, T Toda

    MOLECULAR AND GENERAL GENETICS　250　(1)　59-68　1996/01

    ISSN： 0026-8925

  56. FISSION YEAST TPR-FAMILY PROTEIN NUC2 IS REQUIRED FOR G(1)-ARREST UPON NITROGEN STARVATION AND IS AN INHIBITOR OF SEPTUM FORMATION Peer-reviewed

    K KUMADA, S SU, M YANAGIDA, T TODA

    JOURNAL OF CELL SCIENCE　108　895-905　1995/03

    ISSN： 0021-9533

    eISSN： 1477-9137

Show all ︎Show first 5

Misc. 2

  1. Variants of uncertain significance of the cancer-predisposing genes in two thousand Japanese whole-genome sequencing data

    Jun Yasuda, Keita Iida, Kazuki Kumada, Soichi Ogishima, Yusuke Shibuya, Hideki Tokunaga, Nobuo Yaegashi

    CANCER RESEARCH　78　(13)　2018/07

    DOI： 10.1158/1538-7445.AM2018-4465 　

    ISSN： 0008-5472

    eISSN： 1538-7445

  2. 染色体分配制御におけるSeparaseの自己切断の役割

    熊田和貴, 進藤軌久, 広田亨

    日本分子生物学会年会プログラム・要旨集(Web)　35th　2012

Research Projects 10

  1. Advocacy for personalized treatment of pancreatic and biliary cancer based on genome evolution and expression type diversity

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2024/04/01 - 2027/03/31

  2. Study regarding metabolomics of participants with higher genetic risk of life-style related diseases

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2024/04/01 - 2027/03/31

  3. 膵癌肺転移及び腹膜播種の免疫微小環境をターゲットとした新規治療開発

    青木 修一, 熊田 和貴, 井上 亨悦, 松居 彩, 村上 圭吾

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2023/04/01 - 2026/03/31

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    切除可能膵癌に対する術前化学療法（neoadjuvant therapy:NAT）の有用性が多施設共同前向き試験（PREP02/JSAP05試験）で証明され、NAT後の外科的切除が標準治療となった。しかし、NAT後の手術を行なっても約60%の症例で術後再発を認め、予後不良の原因となる。膵癌術後の再発部位として、肝臓、リンパ節、肺が主であり、転移部位によって治療反応の違いが報告されている。 大腸癌細胞株を用いたマウスモデルによる最近の報告では、大腸癌肝転移に対する免疫チェックポイント阻害薬（ICB）の有用性は示されなかったが、大腸癌皮下腫瘍ではICBが腫瘍増殖を有意に抑制することが報告された。2つの腫瘍では、腫瘍内免疫細胞の構成が全く異なり、ICBの効果の違いに起因している。ヒト膵癌切除サンプルにおいて、肺、腹膜および肝転移の免疫染色解析を行った他の報告では、腹膜や肝転移に比べ、肺転移ではCD8-infilitrated T細胞が増加し、PD-L1の発現が亢進している。さらに、術後肺転移の患者は、腹膜転移や肝転移の患者よりも予後が良好である。 一般に、膵癌腫瘍内は不均一な細胞成分の集合体であり、多クローン性を有する。その中で、転移部位の微小環境に適応した特異的なクローンだけが、遠隔臓器の転移巣を形成することができる。つまり、臓器特異的な微小環境が転移クローンの増殖に重要な役割を果たしており、それら再発部位の微小環境の違いを明らかにすることで、再発部位に即した治療戦略開発が行える。本研究の目的は、膵癌肺転移と肝転移、腹膜播種における腫瘍微小環境の違いを明らかにし、それぞれの転移増殖の分子メカニズムを探り、最終的に膵癌術後再発に対する分子標的治療やICBとの併用療法などの新しい治療戦略を開発することである。

  4. セパラーゼの自己切断による染色体分離の一斉性制御 Competitive

    熊田 和貴

    Offer Organization: 日本学術振興会

    System: 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 沖縄科学技術大学院大学

    2013/04 - 2015/09

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    細胞がゲノムを安定に維持するには、分裂期において姉妹染色分体間の対合を切断し、染色体分離を引き起こすプロテアーゼ、セパラーゼの適切な活性制御が重要である。申請者はほ乳類のセパラーゼが分裂期の異なる時期に様式の異なる複数の自己切断を行うことを見出しており、本研究は、こうしたそれぞれの自己切断の性質や制御の解析を行うことで、その生理学的な意義を解明し、分裂期におけるセパラーゼの急激な活性化機構について明らかにすることを目的としていた。 これまでに、BAC mutagenesisの系を用いて、マウスのセパラーゼを変異させ、特定の自己切断が起きないように細工した変異セパラーゼを作製し、これをヒト子宮がん由来のHeLa細胞に導入して、変異セパラーゼの安定発現細胞株を取得した。さらに、なるべく生理的な条件下でのこれらの特定の自己切断が起きない変異タンパク質の機能を調べるため、作製したマウス由来の変異セパラーゼ安定発現株において、内在性の野生型ヒトセパラーゼのみをRNAiによって除去することにより、外来性の変異セパラーゼと内在性の野生型セパラーゼを完全に置き換えることができる系も確立した。また、これらの細胞と系を用いて、特定の自己切断が起きない条件下での細胞や染色体の挙動を調べ、それによって、それぞれの自己切断が持つ性質や制御についての解析を行い、いくつか興味深い知見を得ることもできた。 しかしながら本年度は、現職場である沖縄科学技術大学院大学との契約切れのため、これ以上の解析の続行が困難となり、本研究をここで廃止することとなった。このため本年度はこれまでに得られたデータの整理に終始し、新たな解析を行うことはできなかった。 これまでの本研究で得られた結果は姉妹染色体分離機構の理解を大きく助けるものと考えており、いずれ機会があれば、さらなる解析を加えたうえで発表できればと思っている。

  5. The regulation of separase-securin in the maintenance of chromosomal stability, and its abnormality in cancer development Competitive

    KUMADA Kazuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Japanese Foundation For Cancer Research

    2010/04 - 2012/03

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    I found that auto-cleavage of separase, a protease that is inhibited by securin, is crucial for the proper regulation of separase activity, and the timely chromosome segregation. I also showed that a disturbance of the chromosome stability plays a role in the cell transformation induced by over-expression of securin. These data demonstrate the relationship between the function of separase-securin for the stable chromosome segregation and the tumor development.

  6. A new method to evaluate the function of mitotic kinases by monitoring chromosome dynamics

    HIROTA Toru, ABE Yusuke, UCHIDA Kazuhiko, SHINDO Norihisa, KUMADA Kazuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Japanese Foundation For Cancer Research

    2011 - 2012

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    Mitotic kinases play crucial roles in separating chromosomes correctly and safely as cells divide. Dysfunction of mitotic kinases therefore causes defective chromosome movements and segregation. In this study, we aimed to develop an assay to indicate cryptic dysfunction of mitotic kinases by monitoring chromosome behavior during mitosis, which is otherwise difficult to detect in conventional means. We found that increasing dose of specific inhibitors of mitotic kinases, caused abnormal chromosomal movements progressively. This what we called the stepwise-challenging assay was then used to address the function of mitotic kinases in several cancer cells that are known to have chromosomal instability

  7. Role of kinetochore stretching in controlling the spindle-assembly checkpoint

    HIROTA Toru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Japanese Foundation For Cancer Research

    2009 - 2011

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    Faithful segregation of chromosomes relies on the spindle-assembly checkpoint(SAC), which delays anaphase onset until all kinetochores are attached to microtubules(MT). The SAC monitors MT attachment at kinetochores, but whether it also senses the presence of 'tension' has long been a matter of debate. We found that 'tension' applied across sister kinetochores, which stretches centromeres, is dispensable, but stretching of kinetochores is required for silencing the SAC(Uchida et al., 2009). It is therefore crucial to investigate if 'tension' underlies kinetochore stretching. We addressed this question experimentally by engineering the conditions that microtubules are attached to kinetochors but free from the pulling force. Under these conditions, we found that kinetochores underwent stretching upon MT attachment. These results suggest that intact kinetochore-pulling force is not required for kinetochore stretching, thus challenging the notion that SAC directly monitors the presence of tension.

  8. Control of mitotic apparatus by mitotic kinases

    HIROTA Toru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: Japanese Foundation For Cancer Research

    2007 - 2011

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    Cell division is a basis of cell proliferation, and thus must be under rigorous control. The research aimed to elucidate how mitotic apparatus are regulated by mitotic kinases including Cdk1, Aurora and Polo kinases. To study this, we first established a series of cell lines that stably express fluorescence labeled proteins in chromosomes, kinetochores and microtubules. We then set up a condition to study protein dynamics using the fluorescence recovery after photobleaching assay. Using these cell lines and technique, we obtained the following results: 1) Aurora B promotes the release of HP1α from chromosome arms in mitosis, but a small subset of HP1α become a part of the chromosomal passenger-complex (CPC) in a phosphorylation-dependent manner. HP1α was found out to be an essential component of the CPC to prevent mis-segregation of chromosomes. 2) Cdk1 targets a subunit of condensin II complex, CAP-D3 to initiate chromosome condensation as cells enter mitosis. A Cdk1-mediated phosphorylation of CAP-D3 induces recruitment of Plk1 and further propagation of phosphorylation widely on the complex, which promotes condensin II to assemble chromosomes. These findings highlight the distinct properties of Aurora and Polo kinases in regulating mitotic apparatus.

  9. Analysis of securin and separase functions in mammalian cell cycle regulation. Competitive

    KUMADA Kazuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Japanese Foundation For Cancer Research

    2008/04 - 2010/03

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    I analyzed the detailed functions of separase and securin proteins in mammalian cell regulation, and found that both proteins cooperatively played another unknown role in DNA damage response, besides the previously well-known one in chromosome separation. I also found that the oncogenic activity of securin protein mainly resulted from the disturbance of its function in chromosome separation.

  10. 染色体分配に必須なCu+1/Cu+2複合体機能のタンパク質レベルでの解析

    熊田 和貴

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特別研究員奨励費

    Institution: 京都大学

    1999 - 2001

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