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

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.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

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Mechanisms of Airway Remodeling in Asthma

Asthma is a chronic inflammatory disease characterized by reversible airflow limitation and airway hyperresponsiveness. Persistent inflammation in airway tissues may lead to structural changes known as airway remodeling and consequently airway obstruction that is not fully reversible and progressive loss of lung function over time. It is generally accepted that airway remodeling is closely related to progression of airway hyperresponsiveness, and the severity of asthma. The structural changes observed in chronic persistent asthma, which includes airway smooth muscle hypertrophy and hyperplasia, collagen deposition to sub-epithelial basement membrane, hyperplasia of goblet cells, thickening of airway mucosa and an increase in vascularity, are derived from airway inflammation. For instance, the thickened airway mucosa might be produced by cytokines and growth factors released from inflammatory cells and airway epithelial cells, and associated with bronchial hyperreactivity and asthma severity. To date, many studies have identified candidate mechanisms and mediators for these observed structural changes, which are thus potential targets in the treatment of asthma. In this review, we describe the recent knowledge of the mechanisms and clinical implications of airway remodeling in asthma

The Role of a Self-management Program in the Control of Mild to Moderate Asthma: a Randomized Controlled Study

Background: Asthma patient education has been recognized as an important component of asthma control. The aim of the present study was to carry out a cost-effectiveness analysis of patient education in patients with mild to moderate asthma during 6 months of follow up. Methods: We randomly allocated asthma patients who were covered by health insurance to a control group (group C) or a self-management group (group S). Self-management consisted of measurement of peak expiratory flow (PEF) and monthly individual education and advice by a specialist. Effectiveness was evaluated on the basis of PEF, quality of life, and mean total cost of medical expenses. Furthermore, we asked the patients about symptom improvement and their level of satisfaction with this program. Results: PEF values in group S gradually increased at 3 months after the self-management program and remained at high levels. The total costs decreased by 30% from baseline in group S, whereas they increased by 15% in group C. The cost of one-day visits showed no difference between the two groups, but the frequency of visits to general practitioners decreased in group S as compared with group C. Furthermore, the number of episodes of asthma attacks decreased in group S but not in group C, and 94% of the group S patients replied that they considered the self-management program to have been useful. Conclusions: We conclude that an individual self-management program is not only a safe and effective aid in the treatment of mild to moderate asthma but can also reduce medical expenses

A Case of Severe Asthma with Eosinophilic Otitis Media Successfully Treated with Anti-IgE Monoclonal Antibody Omalizumab

A 51-year-old woman had been receiving medical treatment for asthma since she was 21 years old. However, her asthma was poorly controlled despite treatment involving combination inhalation of high-dose corticosteroid and long-acting β2-aderenergic agonist (LABA) and regularly taking oral steroids. Hearing loss and otorrhea appeared at the age of 44, and she was given a diagnosis of eosinophilic otitis media (EOM) and received medical treatment. In 2007, symptoms of asthma and otitis media deteriorated. In December 2009, omalizumab therapy was started for refractory asthma. After 2 months of omalizumab treatment, not only asthma, but also hearing loss improved. It is suggested that early initiation of omalizumab therapy may inhibit the progression of progressive EOM

Coexistence of diffuse panbronchiolitis and sarcoidosis revealed during splenectomy: a case report

BACKGROUND: Sarcoidosis is a systemic granulomatous disease caused by CD4+ cell-dominant inflammation. Meanwhile, diffuse panbronchiolitis is a chronic inflammatory respiratory disease predominantly caused by CD8+ lymphocytes and neutrophils. Herein, we report a rare case of sarcoidosis in which the clinical presentation had become evident as diffuse panbronchiolitis after splenectomy for sarcoidosis. CASE PRESENTATION: A 23-year-old Japanese woman was referred to our hospital due to splenomegaly of unknown etiology. Upon admission, chest computed tomography scan revealed centrilobular and randomly distributed small nodules in both lungs. Bronchoalveolar lavage revealed a high proportion of lymphocytes and a decreased CD4/CD8 ratio. However, the biopsy specimens obtained from both the liver and lungs revealed noncaseating epithelioid granulomas, which confirmed the diagnosis of sarcoidosis. The patient underwent splenectomy due to progressive cytopenia and high risk of splenic rupture. After the surgery, the condition of the patient was consistently good for 3 months. Then, she gradually developed productive cough and dyspnea. Both sinus and chest computed tomography scan revealed chronic paranasal sinusitis and deterioration of centrilobular nodules in both lung fields, respectively. The second bronchoalveolar lavage revealed a high proportion of neutrophils, and the bronchoalveolar lavage fluid tested positive for Hemophilus influenzae. The titer of cold agglutinin was elevated, thereby confirming the diagnosis of diffuse panbronchiolitis. On the basis of the clinical and radiological findings, the condition of the patient improved with low-dose macrolide therapy for 3 months. CONCLUSIONS: The coexistence of sarcoidosis and diffuse panbronchiolitis has not been previously reported, and the hidden profiles of diffuse panbronchiolitis may have been revealed by splenectomy