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

Abstract

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.

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

“…This finding was repeated in other studies based on European populations (Ellinghaus et al 2020; Pairo-Castineira et al 2021; Shelton et al 2021), verifying its effects on Covid-19 disease. In Chinese population, common variant studies at this locus did not replicate significance (P. Wu, Chen, et al 2021; H. Zhu et al 2021; Wang et al 2020), and no rare variant studies had been conducted. Our work filled this gap and revealed 3p21.31 as the Covid-19 risk locus.…”

“…Until now, literatures based on Chinese population have replicated and discovered some Covid-19-associated common variants (Wang et al 2020; H. Zhu et al 2021; P. Wu, Chen, et al 2021; P.…”

“…To explore the genetic contributions of rare variants in Covid-19 patients with inborn errors of immunity, we recruited and investigated nearly 500 hospitalized patients from Union hospital of Tongji Medical College of Huazhong University of Science and Technology ( abbr . Union hospital) (H. Zhu et al 2021). Based on patients’ genomic data and clinical information, we carried out three major analyses to investigate the effects of host rare variants: (a) gene- and pathway-level tests of these rare variants between severe and non-severe patients; (b) examination of the significance of previously reported rare variants and genes in our dataset; and c) rare mutation accumulation analysis and protein-protein interaction (PPI) network analysis in only severe patients.…”