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

Possible Clinical Significance of Serum Soluble Interleukin-2 Receptor Level in Primary Bone Lymphoma: Two Case Reports

In two patients with primary bone lymphoma (PBL) treated in our clinic, serum levels of soluble interleukin-2 receptor (sIL-2R) reflected the clinical course. In both cases, sIL-2R levels were high before treatment and normalized with the therapeutic effects of chemotherapy, coinciding with the changes in lactate dehydrogenase levels and radiographic findings. Adding to the recently reported results of the diagnostic ability of sIL-2R in PBL, our case study highlights the clinical significance of serum sIL-2R levels as a tumor marker in PBL cases

Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still’s Disease: A Case-Based Review

We report the case of a 71-year-old Japanese woman with adult-onset Still’s disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS

Scleroderma renal crisis with coexisting segmental arterial mediolysis presenting as intraperitoneal bleeding: a case report

Abstract Background Segmental arterial mediolysis is a rare nonarteriosclerotic and noninflammatory vascular disease that may cause intraperitoneal bleeding. Scleroderma renal crisis is a rare complication of systemic sclerosis, leading to severe hypertension and renal dysfunction. To the best of our knowledge, this is the first reported case of a patient with concurrent systemic sclerosis with scleroderma renal crisis and pathologically confirmed segmental arterial mediolysis. Case presentation We report a case of a 68-year-old Chinese woman diagnosed with systemic sclerosis who was found to have coexisting segmental arterial mediolysis. She presented with back pain, and massive intraperitoneal bleeding was detected by computed tomography. She underwent laparotomy, and the bleeding was found to originate from the gastroepiploic artery. The pathological examination demonstrated gastroepiploic arterial dissection caused by segmental arterial mediolysis. After surgery, she developed severe hypertension with hyperreninemia and progressive renal dysfunction. Given the risk factors of corticosteroid administration and the presence of anti-ribonucleic acid polymerase III antibody, she was diagnosed with scleroderma renal crisis. The patient was proved to have a very rare case of coexisting scleroderma renal crisis and segmental arterial mediolysis. Conclusions There is no known etiological connection between segmental arterial mediolysis and systemic sclerosis or scleroderma renal crisis, but it is possible that coexisting segmental arterial mediolysis and scleroderma renal crisis may have interacted to trigger the development of the other in our patient