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

Safety evaluation of remdesivir administration in patients with severe renal impairment and coronavirus disease: a systematic review and meta-analysis

Abstract Background We conducted a comprehensive systematic review and meta-analysis to evaluate whether remdesivir (RDV) is safe for patients with severe renal impairment (SRI) and COVID-19, compared to non-SRI patients or those not receiving RDV. Methods This study was conducted according to the PRISMA guidelines for reporting systematic reviews and meta-analyses. We searched PubMed, Cohcrane, CINAHL, and Ichushi databases up to October 11, 2024. The outcomes assessed kidney injury, hepatic disorder and mortality. Randomized controlled trials and retrospective and cohort studies reporting kidney injury, hepatotoxicity, and mortality in (i) SRI patients treated with RDV versus without RDV or (ii) SRI patients versus non-SRI patients treated with RDV were included. Targeted patients were defined as adults with COVID-19 based on a positive reverse transcription polymerase chain reaction or rapid antigen test for SARS-CoV-2 from nasopharyngeal or salivary swabs regardless of symptoms. Results One randomized controlled trial and 14 cohort studies met the inclusion criteria and were included in the final meta-analysis. Among SRI patients, RDV significantly reduced the incidence of kidney injury (risk ratio [RR] = 0.51, 95% confidence interval [CI] = 0.27–0.97) but had no significant difference in the development of hepatic disorder (RR = 0.88, 95% CI = 0.39–1.98) and mortality (RR = 0.79, 95% CI = 0.55–1.15). In the comparison between SRI and non-SRI patients treated with RDV, SRI patients demonstrated a significantly higher incidence of kidney injury (odds ratio [OR] = 2.51, 95% CI = 1.49–4.23), with no significant difference in the development of hepatic disorder (OR = 1.04, 95% CI = 0.43–2.53). Meanwhile, SRI patients treated with RDV exhibited significantly higher mortality than non-SRI patients treated with RDV (OR = 2.20, 95% CI = 1.51–3.22). Conclusion Our meta-analysis demonstrated that RDV administration in SRI patients with COVID-19 was safe compared to non-SRI or SRI patient treated without RDV. We suggest that the use of RDV should be actively considered for SRI patients