Rare Variants in Inborn Errors of Immunity Genes Associated with Covid-19 Severity (preprint)

Covid-19 is a contagious disease caused by SARS-CoV-2, a novel severe acute respiratory syndrome coronavirus. Common variants and networks underlying host genetic mechanisms have been extensively studied to identify disease-associated genetic factors. However, there are few studies about the rare variants, typically inborn errors of immunity, in understanding the host genetics behind Covid-19 infection, especially in the Chinese population. To fill this gap, we investigate likely-deleterious missense and high-confidence predicted loss-of-function variants by (a) performing gene- and pathway-level association analyses, (b) examining known genes involved in type I interferon signaling and others previously reported in Covid-19 disease, and (c) identifying candidate genes with accumulating mutations and their potential protein-protein interactions with known genes. Based on our analyses, several putative genes and pathways are uncovered and worth further investigation, for example, genes IL12RB1, TBK1, and TLR3, and pathways Tuberculosis (hsa:05152), Primary Immunodeficiency (hsa:05340), and Influenza A (hsa:05164). These regions generally play an essential role in regulating antiviral innate immunity responses to foreign pathogens and in responding to many inflammatory diseases. We believe that to some extent, as an acute inflammatory disease, Covid-19 is also affected by these inborn errors of immunity. We hope that the identification of these rare genetic factors will provide new insights into the genetic architecture of Covid-19.

A Chinese host genetic study discovered type I interferons and causality of cholesterol levels and WBC counts on COVID-19 severity (preprint)

As of early May 2021, the ongoing pandemic COVID-19 has caused over 160 million of infections and over 3 million deaths worldwide. Many risk factors, such as age, gender, and comorbidities, have been studied to explain the variable symptoms of infected patients. However, these effects may not fully account for the diversity in disease severity. Here, we present a comprehensive analysis of a broad range of patients laboratory and clinical assessments to investigate the genetic contributions to COVID-19 severity. By performing GWAS analysis, we discovered several concrete associations for laboratory features. Based on these findings, we performed Mendelian randomization (MR) analysis to investigate the causality of laboratory traits on disease severity. From the MR study, we identified two causal traits, cholesterol levels and WBC counts. The functional gene related to cholesterol levels is ApoE and people with particular ApoE genotype are more likely to have higher cholesterol levels, facilitating the process that SARS-CoV-2 binds on its receptor ACE2 and aggravating COVID-19 disease. The functional gene related to WBC counts is MHC system that plays a central role in the immune system. The host immune response to the SARS-CoV-2 infection greatly affects the patients severity status and clinical outcome. Additionally, our gene-based and GSEA analysis revealed interferon pathways, including type I interferon receptor binding, regulation of IFNA signaling, and SARS coronavirus and innate immunity. We hope that our work will make a contribution in studying the genetic mechanisms of disease illness and serve as useful reference for the clinical diagnosis and treatment of COVID-19.

Facts and Reflections on Initial Public Health Emergency Response to SARS and COVID-19 Pandemics in Mainland China: A Retrospective Comparative Study (preprint)

Background: Since December 2019, 2019-nCoV has emerged in Wuhan, China, the fast pace of transmission is wreaking global public health crisis. Country’s reaction speed is critical for the control of public health emergency (PHE), especially in the early stage of an outbreak. Compared with SARS pandemic, whether has the efficiency of initial public health emergency response to COVID-19 in mainland China been improved? And whether is there still existing vulnerabilities in current PHE system? Studies on this topic are relatively few. We tried to find the answers, evidences and alternatives. Methods: We conducted a retrospective comparative study. The speed of hospital reporting, pathogen identification and government decision-making between SARS and COVID-19 were compared by selecting 5 critical events from initial public health emergency response timeline. Besides, combining with the two pandemics' progress curves, we discussed the characteristics of their peak time.Results:(1) SARS completed the entire initial public health emergency response in 127 days, and COVID-19 completed in 44 days. Response speed has been shorted nearly by 3 times. (2) Both the first SARS and COVID-19 cases were reported in 19 days. It doesn't appear that hospital reporting speed becomes faster. (3) The accumulated time completing pathogen identification were 118 days for SARS and 31 days for COVID-19. The speed has been improved by more than 3 times. (4) 9 days after the completion of pathogen identification, national government made emergency policies for SARS while the interval between pathogen identification and national government's decision-making for COVID-19 was 13 days. (5) The peak time of SARS came about 80 days later than that of COVID-19. But both the two pandemics' peak occurred about 20 days after the national government's decision-making, and then the curves went down dramatically.Conclusions: The speed of initial public health emergency response to pandemic has been improved due to faster identification. However, some deficiencies and challenges in early alert and authorities' decision-making still remain. Therefore, Chinese government should put more stress on improving hospital's sensitivity to new emerging infectious diseases and timeliness of government's decision-making.