Keisuke Onoi

Suita Tokushukai Hospital

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Yusuke Chihara

Suita Tokushukai Hospital

Yukinori Okada

Osaka University

Keigo Kobayashi

Sapporo Kosei General Hospital

Ken Arimura

Tokyo Women's Medical University

Yuichiro Kitagawa

Gifu University

Morio Nakamura

Saiseikai Central Hospital

Noboru Takayanagi

Saitama Prefecture

Tomouki Ogata

JA Toride Medical Center

Taka‐aki Nakada

Chiba University

Takanori Hasegawa

Tokyo Medical and Dental University

Cooperative Institutions

University of Edinburgh

386

University of Siena

354

International Severe Acute Respiratory and Emerging Infection Consortium

287

University of Oxford

266

Roslin Institute

244

University of Liverpool

232

St Mary's Hospital

231

National Institute for Health Research

219

University College London

215

Keio University

200

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Blood DNA virome associates with autoimmune diseases and COVID-19

Nature Genetics (2025)

Noah Sasa Shohei Kojima Rie Koide Takanori Hasegawa Ho Namkoong

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases. Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

Human virome

10.1038/s41588-024-02022-z

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AXL-SHC1 Signaling Axis Mediates Intrinsic Resistance to HER2-Targeted Tyrosine Kinase Inhibitors in HER2-Aberrant Lung and Gastric Cancers

Masaki Ishida Tadaaki Yamada Yuki Katayama Hayato Kawachi Ryo Sawada

10.2139/ssrn.5126664

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Impact of maintenance therapy following induction immunochemotherapy for untreated advanced non-small cell lung cancer patients

Journal of Cancer Research and Clinical Oncology (2021)

Ryota Nakamura Tadaaki Yamada Kenji Morimoto Akira Nakao Yasuhiro Gotô

Maintenance therapy

Hematology

10.1007/s00432-021-03866-2

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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

Nature Communications (2022)

Qingbo Wang Ryuya Edahiro Ho Namkoong Takanori Hasegawa Yuya Shirai

Abstract Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1 ), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1 ), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2 ). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

10.1038/s41467-022-32276-2

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Citations (19)

Impact of Maintenance Therapy Following Induction Immunochemotherapy for Untreated Advanced Non-Small Cell Lung Cancer Patients

Research Square (Research Square) (2021)

Ryota Nakamura Tadaaki Yamada Kenji Morimoto Akira Nakao Yasuhiro Gotô

Abstract Purpose The primary objective of this study was to identify the potential predictors to assess impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). Methods We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at eight hospitals in Japan between January 2019 to December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune-checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. Results Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). Conclusions This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy.

Maintenance therapy

Augment

Combination therapy

10.21203/rs.3.rs-866475/v1

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Osimertinib in first line setting: for Asian patients

Translational Lung Cancer Research (2019)

Keisuke Onoi Yoshiko Kaneko Junji Uchino

The discovery of the epidermal growth factor receptor ( EGFR ) gene as the first driver gene in lung cancer has led to a major paradigm shift in lung cancer treatment. Gefitinib and other EGFR-tyrosine kinase inhibitors (TKIs) have demonstrated excellent antitumor activity against EGFR mutation-positive non-small cell lung cancer (NSCLC). However, resistance to TKI emerged over the course of treatment, and resistance due to T790M mutations was noted in approximately half of the cases (1,2).

Osimertinib

10.21037/tlcr.2019.03.06

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Gastrointestinal symptoms in COVID-19 and disease severity: a Japanese registry-based retrospective cohort study

Journal of Gastroenterology (2024)

Yuta Matsubara Hiroki Kiyohara Yohei Mikami Kosaku Nanki Ho Namkoong

10.1007/s00535-023-02071-x

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Immune Checkpoint Inhibitors for Lung Cancer Treatment: A Review

Journal of Clinical Medicine (2020)

Keisuke Onoi Yusuke Chihara Junji Uchino Takayuki Shimamoto Yoshie Morimoto

The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer.

Atezolizumab

Durvalumab

Avelumab

10.3390/jcm9051362

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Citations (141)

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

medRxiv (Cold Spring Harbor Laboratory) (2021)

Ho Namkoong Ryuya Edahiro Koichi Fukunaga Yuya Shirai Kyuto Sonehara

Abstract To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO , and IFNAR2 ), but also found a variant on 5q35 (rs60200309-A at DOCK2 ) that was associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 × 10 -8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Genome-wide Association Study

Pandemic

Mendelian Randomization

10.1101/2021.05.17.21256513

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Quantification of escape from X chromosome inactivation with single-cell omics data reveals heterogeneity across cell types and tissues

Cell Genomics (2024)

Yoshihiko Tomofuji Ryuya Edahiro Kyuto Sonehara Yuya Shirai Kian Hong Kock

Several X-linked genes escape from X chromosome inactivation (XCI), while differences in escape across cell types and tissues are still poorly characterized. Here, we developed scLinaX for directly quantifying relative gene expression from the inactivated X chromosome with droplet-based single-cell RNA sequencing (scRNA-seq) data. The scLinaX and differentially expressed gene analyses with large-scale blood scRNA-seq datasets consistently identified the stronger escape in lymphocytes than in myeloid cells. An extension of scLinaX to a 10x multiome dataset (scLinaX-multi) suggested a stronger escape in lymphocytes than in myeloid cells at the chromatin-accessibility level. The scLinaX analysis of human multiple-organ scRNA-seq datasets also identified the relatively strong degree of escape from XCI in lymphoid tissues and lymphocytes. Finally, effect size comparisons of genome-wide association studies between sexes suggested the underlying impact of escape on the genotype-phenotype association. Overall, scLinaX and the quantified escape catalog identified the heterogeneity of escape across cell types and tissues.

Cell type

Single-Cell Analysis

10.1016/j.xgen.2024.100625

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Citations (1)