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

Calcium concentration in leaf litter alters the community composition of soil invertebrates in warm-temperate forests

Many studies have shown the effects of aboveground plant species on soil organisms due to differences in litter quality. However, the calcium concentration in soil has received less attention as a controlling factor of soil invertebrate communities, even though it is an essential element for many animals, especially crustaceans. Litter of Japanese cedar (Cryptomeria japonica) plantations, which account for 19% of the forested area in Japan, has a higher calcium concentration compared to other taxa such as broad-leaved trees. We predicted that C. japonica plantations affect soil invertebrates by altering calcium availability. We compared soil properties including exchangeable calcium concentration and soil invertebrate communities between C. japonica plantations and natural broad-leaved forests. Exchangeable calcium was significantly higher in soil from cedar plantations than in that from broad-leaved forests. The invertebrate community composition differed between the two forest types and was best explained by the exchangeable calcium concentration. In particular, two major taxa of soil crustaceans (Talitridae and Ligidium japonicum) were found only in cedar plantations. Our results suggest that calcium concentrations in soil are altered in C. japonica plantations and that this affects soil invertebrate communities. (C) 2014 Elsevier GmbH. All rights reserved

The cardiac blood supply-workload balance in children

It is well known that the reflected pressure wave in small children returns earlier than that in adolescent. The reason of early return of the reflected pressure wave in infancy is their height. The short distance between heart and reflection point makes the reflected pressure wave returning to the heart earlier. In adult, the early return (during systole) of the reflected pressure wave means disadvantage to cardiac blood supply-workload balance. The purpose of this study was to clarify whether the early return of the reflected pressure wave in small children impairs the cardiac blood supply-workload balance. This study enrolled 37 small left-to-right shunt patients with normal aortic circulation below 15 years of age. The aortic pressure waveform was recorded using a pressure sensor mounted catheter, and augmentation index and subendocardial viability ratio were calculated. The age of patients was 6.1 ± 3.2 years. The augmentation index was 8.7 ± 14.3 % and the index had a negative correlation with patients' age (r = -0.6243, p < 0.0001). The subendocardial viability ratio, which means the cardiac blood supply-workload balance, was 0.92 ± 0.14 and the index had a positive relationship with patients' age (r = 0.6435, p < 0.0001). The cardiac blood supply-workload balance gradually improves from infancy to young adulthood. One of the causes of the unfavorable cardiac blood supply-workload balance in infancy would be the accelerated aortic pressure wave reflection due to their short height