Yoshihiko Tomofuji

The University of Tokyo

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シングルセル情報とゲノム情報の統合解析によるCOVID-19重症化メカニズムの解明

Proceedings for Annual Meeting of The Japanese Pharmacological Society (2023)

Edahiro Ryuya Yuya Shirai Yusuke Takeshima Shuhei Sakakibara Yuta Yamaguchi

Mechanisms underpinning the dysfunctional immune response in SARS-CoV-2 infection are not yet fully understood. In addition, the functional roles of the genetic variants identified by COVID-19 genome-wide association study (GWAS) remain elusive, especially in non-European ancestry. We analyzed single-cell transcriptomes and T and B cell receptors of > 895,000 peripheral blood mononuclear cells from 73 COVID-19 patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell-cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19, suggesting that the dysfunction of ncMono might be closely involved in the immunopathology of COVID-19 severity. Clonal expansions of B cell receptors were evident in plasmablasts of patients. Putative disease genes identified by the GWAS of severe phenotypes showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had COVID-19-specific and monocyte-specific expression quantitative trait loci effects, indicating the enrichment of host genetic risk in innate immune cells. Our multimodal and integrative single-cell analyses highlight biological and host genetic involvement of innate immune cells in COVID-19 severity.

Genome-wide Association Study

Cell type

10.1254/jpssuppl.97.0_1-b-s05-2

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Fibroblasts as a source of self-antigens for central immune tolerance

Nature Immunology (2020)

Takeshi Nitta Masanori Tsutsumi Sachiko Nitta Ryunosuke Muro Emma C. Suzuki

Self Tolerance

10.1038/s41590-020-0756-8

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Citations (69)

ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts

Nature Immunology (2022)

Minglu Yan Noriko Komatsu Ryunosuke Muro Nam Cong‐Nhat Huynh Yoshihiko Tomofuji

ETS1

10.1038/s41590-022-01285-0

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Citations (36)

Analysis of gut microbiome, host genetics, and plasma metabolites reveals gut microbiome-host interactions in the Japanese population

Cell Reports (2023)

Yoshihiko Tomofuji Toshihiro Kishikawa Kyuto Sonehara Yuichi Maeda Kotaro Ogawa

Interaction between the gut microbiome and host plays a key role in human health. Here, we perform a metagenome shotgun-sequencing-based analysis of Japanese participants to reveal associations between the gut microbiome, host genetics, and plasma metabolome. A genome-wide association study (GWAS) for microbial species (n = 524) identifies associations between the PDE1C gene locus and Bacteroides intestinalis and between TGIF2 and TGIF2-RAB5IF gene loci and Bacteroides acidifiaciens. In a microbial gene ortholog GWAS, agaE and agaS, which are related to the metabolism of carbohydrates forming the blood group A antigen, are associated with blood group A in a manner depending on the secretor status determined by the East Asian-specific FUT2 variant. A microbiome-metabolome association analysis (n = 261) identifies associations between bile acids and microbial features such as bile acid metabolism gene orthologs including bai and 7β-hydroxysteroid dehydrogenase. Our publicly available data will be a useful resource for understanding gut microbiome-host interactions in an underrepresented population.

Genome-wide Association Study

Metabolome

10.1016/j.celrep.2023.113324

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Citations (4)

A case of complete atrioventricular block in secondary hemophagocytic syndrome/hemophagocytic lymphohistiocytosis recovered by plasma exchange and cytokine absorbing therapy with AN69ST continuous hemodiafiltration

Immunological Medicine (2020)

Yoshihiro Harano Yuichi Ishikawa Koto Hattori Mami Ichinose Yoshihiko Tomofuji

We report a case of incipient systemic lupus erythematosus (SLE) that rapidly progressed to complete atrioventricular block (cAVB). A 20-year-old man was admitted with facial erythema, painless oral aphtha, polyarthritis, and myalgia of each extremity. On admission, he developed first-degree atrioventricular block, pericarditis, pleuritis, renal failure, hemophagocytic lymphohistiocytosis, neurophychiatric SLE (left cerebellar infarction), and Staphylococcus aureus bacteremia. He was subsequently diagnosed with SLE based on several positive findings on immunological tests (including positive for antinuclear antibody). Despite immediate glucocorticoid pulse therapy and plasma exchange (PE) along with antibiotic, he developed cAVB that required temporary pacing on day 2. Because it was thought that hypercytokinemia exacerbated pericarditis, which progressed to myocarditis and cAVB, we decided to PE and cytokine-adsorbing therapy with AN69ST-continuous hemodiafiltration (CHDF). Other than renal failure, his organ dysfunctions improved with the multidisciplinary therapy. CAVB improved and temporary pacing was no longer required on day 11. Even a first-degree atrioventricular block can rapidly progress to cAVB; therefore, strict attention to electrocardiogram is necessary in severe SLE cases. When presenting with organ dysfunctions caused by hypercytokinemia such as severe SLE cases or SLE with severe infection cases, use of the combination of PE and AN69ST-CHDF might be beneficial.

Atrioventricular block

Anasarca

Myopericarditis

10.1080/25785826.2020.1761145

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OMARU: a robust and multifaceted pipeline for metagenome-wide association study

NAR Genomics and Bioinformatics (2022)

Toshihiro Kishikawa Yoshihiko Tomofuji Hidenori Inohara Yukinori Okada

Microbiome is an essential omics layer to elucidate disease pathophysiology. However, we face a challenge of low reproducibility in microbiome studies, partly due to a lack of standard analytical pipelines. Here, we developed OMARU (Omnibus metagenome-wide association study with robustness), a new end-to-end analysis workflow that covers a wide range of microbiome analysis from phylogenetic and functional profiling to case-control metagenome-wide association studies (MWAS). OMARU rigorously controls the statistical significance of the analysis results, including correction of hidden confounding factors and application of multiple testing comparisons. Furthermore, OMARU can evaluate pathway-level links between the metagenome and the germline genome-wide association study (i.e. MWAS-GWAS pathway interaction), as well as links between taxa and genes in the metagenome. OMARU is publicly available (https://github.com/toshi-kishikawa/OMARU), with a flexible workflow that can be customized by users. We applied OMARU to publicly available type 2 diabetes (T2D) and schizophrenia (SCZ) metagenomic data (n = 171 and 344, respectively), identifying disease biomarkers through comprehensive, multilateral, and unbiased case-control comparisons of metagenome (e.g. increased Streptococcus vestibularis in SCZ and disrupted diversity in T2D). OMARU improves accessibility and reproducibility in the microbiome research community. Robust and multifaceted results of OMARU reflect the dynamics of the microbiome authentically relevant to disease pathophysiology.

Genome-wide Association Study

Genetic Association

10.1093/nargab/lqac019

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Citations (4)

Identification of serum metabolome signatures associated with retinal and renal complications of type 2 diabetes

Communications Medicine (2023)

Yoshihiko Tomofuji Ken Suzuki Toshihiro Kishikawa Nobuhiro Shojima Jun Hosoe

Type 2 diabetes is a common disease around the world and its major complications are diabetic retinopathy (DR) and diabetic kidney disease (DKD). Persons with type 2 diabetes with complications, especially who have both DR and DKD, have poorer prognoses than those without complications. Therefore, prevention and early identification of the complications of type 2 diabetes are necessary to improve the prognosis of persons with type 2 diabetes. The aim of this study is to identify factors associated with the development of multiple complications of type 2 diabetes.We profiled serum metabolites of persons with type 2 diabetes with both DR and DKD (N = 141) and without complications (N = 159) using a comprehensive non-targeted metabolomics approach with mass spectrometry. Based on the serum metabolite profiles, case-control comparisons and metabolite set enrichment analysis (MSEA) were performed.Here we show that five metabolites (cyclohexylamine, P = 4.5 × 10-6; 1,2-distearoyl-glycero-3-phosphocholine, P = 7.3 × 10-6; piperidine, P = 4.8 × 10-4; N-acetylneuraminic acid, P = 5.1 × 10-4; stearoyl ethanolamide, P = 6.8 × 10-4) are significantly increased in those with the complications. MSEA identifies fatty acid biosynthesis as the type 2 diabetes complications-associated biological pathway (P = 0.0020).Our metabolome analysis identifies the serum metabolite features of the persons with type 2 diabetes with multiple complications, which could potentially be used as biomarkers.In the management of type 2 diabetes, prevention and early identification of diabetes complications are important. In particular, people with type 2 diabetes with diabetic retinopathy (DR), affecting the eye, and diabetic kidney disease (DKD), have poorer outcomes than those without complications and need early intervention. Here, we comprehensively profiled blood metabolites, or breakdown products of the biological processes occurring in the body, of people with type 2 diabetes with both DR and DKD and those without complications. We found that five metabolites were significantly increased in those with complications, and we identified a specific metabolic pathway associated with having complications. Our analysis identified the blood metabolite features of people with type 2 diabetes with multiple complications, which could potentially be used as markers in the future.

Metabolome

10.1038/s43856-022-00231-3

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Citations (14)

Incomplete human reference genomes can drive false sex biases and expose patient-identifying information in metagenomic data

Nature Communications (2025)

Caitlin Guccione Lucas Patel Yoshihiko Tomofuji Daniel McDonald Antonio González

Abstract As next-generation sequencing technologies produce deeper genome coverages at lower costs, there is a critical need for reliable computational host DNA removal in metagenomic data. We find that insufficient host filtration using prior human genome references can introduce false sex biases and inadvertently permit flow-through of host-specific DNA during bioinformatic analyses, which could be exploited for individual identification. To address these issues, we introduce and benchmark three host filtration methods of varying throughput, with concomitant applications across low biomass samples such as skin and high microbial biomass datasets including fecal samples. We find that these methods are important for obtaining accurate results in low biomass samples (e.g., tissue, skin). Overall, we demonstrate that rigorous host filtration is a key component of privacy-minded analyses of patient microbiomes and provide computationally efficient pipelines for accomplishing this task on large-scale datasets.

Identification

Benchmark (surveying)

10.1038/s41467-025-56077-5

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Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases

Nature Genetics (2024)

Chi Tian Yuntian Zhang Yihan Tong Kian Hong Kock Donald Yuhui Sim

Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5′ splice site of TCHP exon 4 that putatively modulates the risk of Graves' disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution. This analysis of single-cell RNA sequencing data from peripheral blood mononuclear cells for 474 individuals of diverse Asian ancestries in the Asian Immune Diversity Atlas links cell-type-specific splicing variation with autoimmune and inflammatory disease risk.

Cell type

10.1038/s41588-024-02019-8

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Citations (1)

Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune Tolerance

Cell (2015)

Hiroyuki Takaba Yasuyuki Morishita Yoshihiko Tomofuji Lynett Danks Takeshi Nitta

Self Tolerance

Expression (computer science)

10.1016/j.cell.2015.10.013

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Citations (339)