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

Impact of relative dose intensity in gemcitabine–cisplatin chemotherapy for metastatic urothelial carcinoma

Objectives: To evaluate the impact of relative dose intensity for gemcitabine–cisplatin chemotherapy in patients with metastatic urothelial carcinoma. Methods: We retrospectively reviewed the medical records of 18 patients with metastatic urothelial carcinoma, who received gemcitabine–cisplatin regimen as the first-line chemotherapy between 2009 and 2015. The doses of gemcitabine and cisplatin were reduced or the intervals between treatment cycles were prolonged according to the treatment efficacy and adverse events during the first and second cycles. The individually optimal relative dose intensity was set as the actual dose per the standard dose in the first and second cycles. From the third course onward, patients received the gemcitabine–cisplatin chemotherapy with the same relative dose intensity. Overall survival was compared with the groups according to the value of relative dose intensity. Results: The median age was 72.5 (range, 56–79) years and 15 men and 3 women were enrolled in the study. The median number of cycles of first-line gemcitabine–cisplatin chemotherapy was 8 (range, 2–17), and the median survival time from initiation of first-line chemotherapy was 20.1 (range, 3.5–32.8) months. The total median relative dose intensity of gemcitabine–cisplatin chemotherapy was 56.1%. The median survival time of 10 patients in the group with the relative dose intensity of less than 60% was significantly longer than that of 8 patients in the group with the relative dose intensity of more than 60% (19.2 and 11.0 months, respectively, p = 0.04). Conclusion: Individual low relative dose intensity management in the first-line gemcitabine–cisplatin chemotherapy may be an acceptable option for patients with metastatic urothelial carcinoma

Chronoradiation Therapy for Prostate Cancer:Morning Proton Beam Therapy Ameliorates Worsening Lower Urinary Tract Symptoms

Background and Purpose: Worsening lower urinary tract symptoms (LUTS) are a frequent adverse event following proton beam therapy (PBT) for localized prostate cancer. We investigated the dierences in worsening LUTS among patients who received PBT at dierent times of day. Participants and Methods: Among 173 patients who underwent PBT for prostate cancer, 168 patients (median age 68.5 years) completed international prostate symptom score (IPSS) questionnaires and were included.Changes in the IPSS from baseline to the end of PBT were assessed by multiple linear regression analysis for age, National Comprehensive Cancer Network risk classification, androgen deprivation therapy, fractional PBT dose, clinical target volume, severity of IPSS, diabetes, LUTS medication use before PBT, anti-coagulant therapy and radiation time of day (morning (08:30–10:30), around noon (10:31–14:30), and late afternoon (14:31–16:30)). Results: IPSS total score and IPSS-Quality of Life (QoL) score (12 patients were excluded due to missing IPSS-QoL score) increased from eight to 14.9 (p < 0.0001) and from two to four (p < 0.0001), respectively. Time of day (morning) was the only determinant for worsening LUTS ( = ????0.24, p < 0.01), voiding subscore ( = ????0.22, p < 0.05) and IPSS-QoL ( = ????0.27, p < 0.005), and was a determinant in item four (urgency) ( = ????0.28, p < 0.005) with age ( = 0.19, p < 0.05). Conclusions: Morning PBT for localized prostate cancer significantly ameliorated worsening LUTS and improved QoL compared with treatment around noon or late afternoon. Chronoradiation therapy for localized prostate cancer may be eective and further research to elucidate the underlying mechanism is warranted

Whole-Blood Gene Expression Profiles Correlate with Response to Immune Checkpoint Inhibitors in Patients with Metastatic Renal Cell Carcinoma

In metastatic renal cell carcinoma (mRCC), the clinical response to immune checkpoint inhibitors (ICIs) is limited in a subset of patients and the need exists to identify non-invasive, blood-based, predictive biomarkers for responses. We performed RNA sequencing using whole-blood samples prospectively collected from 49 patients with mRCC prior to the administration of ipilimumab (IPI) and/or nivolumab (NIVO) to determine whether gene expression profiles were associated with responses. An analysis from 33 mRCC patients with complete responses (n = 5), partial responses (n = 14), and progressive disease (n = 14) showed 460 differentially expressed genes (DEGs) related to immune responses between the responder and non-responder groups with significant differences. A set of 14 genes generated from the initial 460 DEGs accurately classified responders (sensitivity 94.7% and specificity 50.0%) while consensus clustering defined clusters with significantly differing response rates (92.3% and 35.0%). These clustering results were replicated in a cohort featuring 16 additional SD patients (49 total patients): response rates were 95.8% and 48.0%. Collectively, whole-blood gene expression profiles derived from mRCC patients treated with ICIs clearly differed by response and hierarchical clustering using immune response DEGs accurately classified responder patients. These results suggest that such screening may serve as a predictor for ICI responses in mRCC patients