Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

BACKGROUNDEpidemiological studies indicate that as many as 20% of individuals who test positive for COVID-19 develop severe symptoms that can require hospitalization. These symptoms include low platelet count, severe hypoxia, increased inflammatory cytokines and reduced glomerular filtration rate. Additionally, severe COVID-19 is associated with several chronic co-morbidities, including cardiovascular disease, hypertension and type 2 diabetes mellitus. The identification of genetic risk factors that impact differential host responses to SARS-CoV-2, resulting in the development of severe COVID-19, is important in gaining greater understanding into the biological mechanisms underpinning life-threatening responses to the virus. These insights could be used in the identification of high-risk individuals and for the development of treatment strategies for these patients. METHODSAs of June 6, 2020, there were 976 patients who tested positive for COVID-19 and were hospitalized, indicating they had a severe response to SARS-CoV-2. To overcome the limited number of patients with a mild form of COVID-19, we used similar control criteria to our previous study looking at shared genetic risk factors between severe COVID-19 and sepsis, selecting controls who had not developed sepsis despite having maximum co-morbidity risk and exposure to sepsis-causing pathogens. RESULTSUsing a combinatorial (high-order epistasis) analysis approach, we identified 68 protein-coding genes that were highly associated with severe COVID-19. At the time of analysis, nine of these genes have been linked to differential response to viral pathogens including SARS-CoV-2. We also found many novel targets that are involved in key biological pathways associated with the development of severe COVID-19, including production of pro-inflammatory cytokines, endothelial cell dysfunction, lipid droplets, neurodegeneration and viral susceptibility factors. CONCLUSIONThe variants we found in genes relating to immune response pathways and cytokine production cascades, were in equal proportions across all severe COVID-19 patients, regardless of their co-morbidities. This suggests that such variants are not associated with any specific co-morbidity, but are common amongst patients who develop severe COVID-19. This is consistent with being able to find and validate severe disease biomarker signatures when larger patient datasets become available. Several of the genes identified relate to lipid programming, beta-catenin and protein kinase C signalling. These processes converge in a central pathway involved in plasma membrane repair, clotting and wound healing. This pathway is largely driven by Ca2+ activation, which is a known serum biomarker associated with severe COVID-19 and ARDS. This suggests that aberrant calcium ion signalling may be responsible for driving severe COVID-19 responses in patients with variants in genes that regulate the expression and activity of this ion. We intend to perform further analyses to confirm this hypothesis. Among the 68 severe COVID-19 risk-associated genes, we found several druggable protein targets and pathways. Nine are targeted by drugs that have reached at least Phase I clinical trials, and a further eight have active chemical starting points for novel drug development. Several of these targets were particularly enriched in specific co-morbidities, providing insights into shared pathological mechanisms underlying both the development of severe COVID-19, ARDS and these predisposing co-morbidities. We can use these insights to identify patients who are at greatest risk of contracting severe COVID-19 and develop targeted therapeutic strategies for them, with the aim of improving disease burden and survival rates.