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

Real-world effects of once-daily inhaled steroid (fluticasone furoate) combined with long-acting beta-2 agonist (vilanterol) and long-acting muscarinic antagonist (umeclidinium) on lung function tests of asthma patients in Japan

Background: The Japanese drug use system allowed the once-daily use of inhaled corticosteroid fluticasone furoate (FF) combined with a long-acting beta-2 agonist vilanterol (VI) and a long-acting muscarinic antagonist umeclidinium (UMEC) against asthma on 18 February 2021. We investigated the real-world effects of these drugs (FF/UMEC/VI) mainly on lung function tests.Methods: This was an open-label, uncontrolled, within-group time-series (before-after) study. Prior asthma treatment (inhaled corticosteroid with/without a long-acting beta-2 agonist with/without a long-acting muscarinic antagonist) was switched to FF/UMEC/VI 200/62.5/25 μg. Subjects were evaluated by lung function tests prior to, and 1–2 months after, initiation of FF/UMEC/VI 200/62.5/25 μg. Patients were asked questions regarding the asthma control test and preference for drugs.Results: Overall, 114 asthma outpatients (97% Japanese) were enrolled from February 2021 to April 2022: 104 subjects completed the study. Forced expiratory volume in 1 s, peak flow, and asthma control test score of FF/UMEC/VI 200/62.5/25 μg-treated subjects were significantly increased (p < 0.001, p < 0.001, and p < 0.01, respectively). In contrast with FF/VI 200/25 μg, instantaneous flow at 25% of the forced vital capacity and expiratory reserve volume were significantly increased by FF/UMEC/VI 200/62.5/25 μg (p < 0.01, p < 0.05, respectively). Sixty-six percent of subjects declared they wanted to continue FF/UMEC/VI 200/62.5/25 μg in the future. Adverse effects, mainly local, were seen in 30% of patients, but no serious adverse effects were seen.Conclusion: Once-daily FF/UMEC/VI 200/62.5/25 μg was effective against asthma without serious adverse events. This is the first report that demonstrated FF/UMEC/VI dilated peripheral airways using lung function tests. This evidence on drug effects may improve our understanding of pulmonary physiology and the pathophysiology of asthma

Upper Respiratory Symptoms as Long COVID: Insight from a Multicenter Cohort Study

Abstract Objective This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated. Study Design Prospective cohort study. Setting A multicenter study involving 26 medical facilities in Japan. Methods Inclusion criteria were patients aged ≥18 years old with a confirmed COVID‐19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient‐reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID. Results Patients with high albumin, low C‐reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282‐6.526) for taste disorders and 3.534 (95% CI, 1.382‐9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores. Conclusion The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID‐19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID