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

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

PRELIMINARY ANALYSIS OF TEMPERATURE CHANGES DUE TO SYNOPTIC SCALE DISTURBANCES AT SYOWA STATION, ANTARCTICA IN WINTER

The Antarctic surface air temperature often increases severely in winter when a synoptic scale disturbance comes close and then decreases after it goes away. The mechanism of these temperature changes in analyzed from the data observed at Syowa Station, Antarctica in 1993 by the 34th Japanese Antarctic Research Expedition (JARE-34). For this purpose, fifteen cases each are selected for both the prominent warming and the succeeding cooling events in winter. The magnitude of changes in temperature due to destruction or reformation of the surface temperature inversion during the events is estimated from comparison of the vertical temperature profiles above Syowa Station before and after each events. Its contribution amounts to about half of the observed change in the surface temperature.The horizontal advection of sensible heat is calculated from the thermal wind shear relation. It is shown that the horizontal advection of warm and cold air are observed in the warming and the cooling events, respectively. It is estimated from the average heat budget that there should be an upward current of 0.2 to 0.8 (cms)^ during the warming events and a downward current of less than 0.4 (cms)^ during the cooling events in the 850 to 300 hPa layer

Thermal structure of proglacial lakes in Patagonia

Calving glaciers are rapidly retreating in many regions under the influence of ice-water interactions at the glacier front. In contrast to the numerous researches conducted on fjords in front of tidewater glaciers, very few studies have been reported on lakes in which freshwater calving glaciers terminate. To better understand ice-water interactions at the front of freshwater calving glaciers, we measured lakewater temperature, turbidity, and bathymetry near Glaciar Perito Moreno, Upsala, and Viedma, large calving glaciers of the Southern Patagonia Icefield. The thermal structures of these lakes were significantly different from those reported in glacial fjords. There was no indication of upwelling subglacial meltwater; instead, turbid and cold glacial water discharge filled the region near the lake bottom. This was because water density was controlled by suspended sediment concentrations rather than by water temperature. Near-surface wind-driven circulation reaches a depth of similar to 180 m, forming a relatively warm isothermal layer (mean temperature of similar to 5-6 degrees C at Perito Moreno, similar to 3-4 degrees C at Upsala, and similar to 6-7 degrees C at Viedma), which should convey heat energy to the ice-water interface. However, the deeper part of the glacier front is in contact with stratified cold water, implying a limited amount of melting there. In the lake in front of Glaciar Viedma, the region deeper than 120 m was filled entirely with turbid and very cold water at pressure melting temperature. Our results revealed a previously unexplored thermal structure of proglacial lakes in Patagonia, suggesting its importance in the subaqueous melting of freshwater calving glaciers