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

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Chimpanzees can visually perceive differences in the freshness of foods

Colour vision in primates is believed to be an adaptation for finding ripe fruit and young leaves. The contribution of the luminance distribution, which influences how humans evaluate the freshness of food, has not been explored with respect to the detection of subtle distinctions in food quality in non-human primates. We examined how chimpanzees, which are closely related to humans, perceive the freshness of foods. The findings suggest that chimpanzees were able to choose fresher cabbage based on both colour and grey-scale images. Additional tests with images of novel cabbage, spinach, and strawberries revealed that one chimpanzee could detect the freshness of other fruits and vegetables. The critical factor in determining the judgements of freshness made by the chimpanzees was the spatial layout of luminance information. These findings provide the first known evidence that chimpanzees discriminate between images representing various degrees of freshness based solely on luminance information

Mechanism Underlying the Onset of Internal Blue Discoloration in Japanese Radish (Raphanus sativus) Roots

The internal blue discoloration observed in Japanese radish (Raphanus sativus L.) roots is a physiological phenomenon caused by storage following harvest at approximately 20 °C and poses a serious problem for farmers. Here, we describe the mechanism underlying the onset of internal blue discoloration of three cultivars: Hukuhomare, SC8-260, and Yuto. Each cultivar was maintained under the same conditions. Additionally, Hukuhomare radish roots were maintained at three different cultivation conditions in a related experiment. The blue discoloration in radish roots was caused by the oxidation of 4-hydroxyglucobrassicin as a result of an increase in oxidative stress involving peroxidase. Thus, the extent of blue discoloration was influenced by the chemical balance involving 4-hydroxyglucobrassicin content, antioxidant capacity, and oxidation activity

Association of alcohol consumption with prevalence of fatty liver after adjustment for dietary patterns: Cross-sectional analysis of Japanese middle-aged adults.

BACKGROUND & AIMS: Moderate alcohol intake is associated with reduced prevalence or incidence of fatty liver. However, whether or not the association is independent of dietary patterns remains unclear. We aimed to evaluate the cross-sectional association of alcohol intake with fatty liver after accounting for dietary patterns and obesity. METHODS: We assessed 4579 adults aged 30-79 years who participated in routine clinical examinations in St. Luke's International Hospital, Japan (January to March, 2015). We assessed their habitual diet using diet-history questionnaire, estimated alcohol intake, and derived dietary pattern variables using factor analysis. Fatty liver was ascertained using ultrasonography. Linear and U-shaped associations of alcohol intake with fatty liver were evaluated using Poisson regression, and a post hoc analysis was conducted after detecting potential outliers for alcohol intake and excluding them using sex-specific statistics (median plus 2 × interquartile range). RESULTS: Fatty liver was ascertained in 1120 participants (24.5%). Whereas no significant association of alcohol intake with fatty liver was observed when potential outliers of alcohol intake were included (p = 0.25), a significant U-shaped association was observed after excluding the outliers with and without adjustment for dietary patterns (p = 0.003 and 0.02, respectively). The lowest prevalence was estimated when alcohol consumption was approximately 7% of energy, with a prevalence ratio of 0.72 (95% confidence interval = 0.59-0.86) compared to non-drinkers. The association became imprecise and attenuated toward the null after further adjustment for body mass index (p = 0.06). CONCLUSIONS: Alcohol intake showed a U-shaped association with fatty liver prevalence. This association was independent of underlying dietary patterns, while it was sensitive to excessive alcohol intake and obesity status, providing clinical implications for the prevention of fatty liver.This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant numbers 14J11939 and 23240104). JSPS had no role in the design, analysis, or writing of this article

Association of alcohol consumption with prevalence of fatty liver after adjustment for dietary patterns: Cross-sectional analysis of Japanese middle-aged adults.

BACKGROUND & AIMS: Moderate alcohol intake is associated with reduced prevalence or incidence of fatty liver. However, whether or not the association is independent of dietary patterns remains unclear. We aimed to evaluate the cross-sectional association of alcohol intake with fatty liver after accounting for dietary patterns and obesity. METHODS: We assessed 4579 adults aged 30-79 years who participated in routine clinical examinations in St. Luke's International Hospital, Japan (January to March, 2015). We assessed their habitual diet using diet-history questionnaire, estimated alcohol intake, and derived dietary pattern variables using factor analysis. Fatty liver was ascertained using ultrasonography. Linear and U-shaped associations of alcohol intake with fatty liver were evaluated using Poisson regression, and a post hoc analysis was conducted after detecting potential outliers for alcohol intake and excluding them using sex-specific statistics (median plus 2 × interquartile range). RESULTS: Fatty liver was ascertained in 1120 participants (24.5%). Whereas no significant association of alcohol intake with fatty liver was observed when potential outliers of alcohol intake were included (p = 0.25), a significant U-shaped association was observed after excluding the outliers with and without adjustment for dietary patterns (p = 0.003 and 0.02, respectively). The lowest prevalence was estimated when alcohol consumption was approximately 7% of energy, with a prevalence ratio of 0.72 (95% confidence interval = 0.59-0.86) compared to non-drinkers. The association became imprecise and attenuated toward the null after further adjustment for body mass index (p = 0.06). CONCLUSIONS: Alcohol intake showed a U-shaped association with fatty liver prevalence. This association was independent of underlying dietary patterns, while it was sensitive to excessive alcohol intake and obesity status, providing clinical implications for the prevention of fatty liver.This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant numbers 14J11939 and 23240104). JSPS had no role in the design, analysis, or writing of this article