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

Serum 25-Hydroxyvitamin D Concentrations Are Inversely Correlated with Hepatic Lipid Content in Male Collegiate Football Athletes

Lower serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with more weight and fat mass gain in adults in the general population, but it is unknown whether this is the case in collegiate football athletes with greater body weight. This study aimed to investigate associations of serum 25(OH)D concentrations with body fat and ectopic fat accumulation, and to determine which fat indicators are closely related to serum 25(OH)D in male collegiate football athletes. Thirty-four collegiate athletes aged 21 years were recruited. Serum 25(OH)D concentrations and the levels of visceral fat area (VFA), vastus lateralis intramyocellular lipid (IMCL), extramyocellular lipid (EMCL), and intrahepatic lipid (IHCL) were measured. Serum 25(OH)D concentrations were negatively associated with the IHCL values (r = −0.372, p = 0.030), and the relationship remained after adjustment for several factors (r = −0.378, p = 0.047). Additionally, multiple stepwise regression analysis of IHCL content as the dependent variable indicated that 25(OH)D concentrations were a stronger predictor of IHCL content (β = −0.363, p = 0.030) than % body fat and VO2peakFFM. Higher serum 25(OH)D concentrations are more closely related to lower IHCL content rather than any other fat indicators, suggesting that increasing serum 25(OH)D concentrations may have some effect that inhibits lipid accumulation in hepatic tissue, especially in heavy athletes

Changes in Stress and Appetite Responses in Male Power-Trained Athletes during Intensive Training Camp

An intensive consecutive high-volume training camp may induce appetite loss in athletes. Therefore, this study aimed to investigate the changes in stress and appetite responses in male power-trained athletes during an intensive training camp. The measurements at Day 2 and at the end of a 9-day intensive training camp (Camp1 and Camp2, respectively) were compared with those of the resting period (Rest) and the regular training period (Regular; n = 13). The stress state was assessed based on plasma cortisol level, salivary immunoglobulin A level, and a profile of mood states score. The sensation of appetite was assessed using visual analog scale scores, and fasting plasma acylated ghrelin, insulin, and glucose were measured. The cortisol concentrations were significantly higher at Camp2 (466.7 ± 60.7 nmol∙L−1) than at Rest (356.3 ± 100.9 nmol∙L−1; p = 0.002) or Regular (361.7 ± 111.4 nmol∙L−1; p = 0.003). Both prospective and actual food consumption significantly decreased at Camp2, and acylated ghrelin concentration was significantly lower at Camp1 (34.2 ± 8.0 pg∙mL−1) and Camp2 (32.0 ± 8.7 pg∙mL−1) than at Rest (47.2 ± 11.2 pg∙mL−1) or Regular (53.4 ± 12.6 pg∙mL−1). Furthermore, the change in acylated ghrelin level was negatively correlated with the change in cortisol concentration. This study’s findings suggest that an early-phase physiological stress response may decrease the acylated ghrelin level in male power-trained athletes during an intensive training camp